Archive for the ‘Gene Therapy Research’ Category

Scientists have explored the effectiveness of replacing mutated genes in mice with congenital blindness.

Describing their findings in Nature Communications, researchers highlighted that replacing a mutated sequence in blind mice resulted in approximately 10% of photoreceptors being rescued.

Following the procedure, the light sensitivity and visual acuity of the mice improved.

The new approach is an alternative strategy to gene supplementation, which has limitations when treating patients with defects in larger genes.

Koji Nishiguchi, from Tohoku Universitys department of advanced ophthalmic medicine, explained that the new technique enables the replacement of a mutated sequence with its healthy counterpart.

The platform paves the way for treating patients with mutations in larger genes, which comprise the vast majority of those with inherited retinal degeneration. Furthermore, a similar approach can be applied to treat almost any ocular and non-ocular inherited conditions, he shared.

The research team are developing the genome editing platform for application in patients with retinitis pigmentosa. A clinical trial could be undertaken by 2025.

Image credit: Pixabay/Arek Socha

See the article here:
Mice display improvements in vision following gene therapy - AOP

Abstract

Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) LmnaG609G mutation, called progerin. The Lmnaf/f;TC mice with progerin expression induced by Tie2-Cre exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of Sirt7 alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endotheliumtargeted Sirt7 gene therapy, driven by an ICAM2 promoter, improves neovascularization, ameliorates aging features, and extends life span in Lmnaf/f;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.

Aging represents the largest risk factor for many age-related diseases, as exemplified by cardiovascular diseases (CVDs) (1). The blood vessel consists of the tunica intima [composed of endothelial cells (ECs)], the tunica media [composed of vascular smooth muscle cells (VSMCs)], and the tunica adventitia (consisting of connective tissue) (2). The endothelium separates the vessel wall from blood flow and has an irreplaceable role in regulating vascular tone and homeostasis. Age-related functional decline in ECs and VSMCs is a main cause of CVDs (3). ECs secrete various vasodilators and vasoconstrictors that act on VSMCs and induce blood vessel contraction and relaxation (4). For instance, nitric oxide (NO) is synthesized from l-arginine by endothelial NO synthase (eNOS) and then released on VSMCs to induce blood vessel relaxation (5). When ECs become senescent or dysfunctional, vasoconstrictive, procoagulative, and proinflammatory cytokines are released; this effect reduces NO bioavailability and, in turn, increases vascular intimal permeability and EC migration (6). Despite advances in the understanding of mechanisms of endothelial dysfunction, it is unclear whether it directly triggers organismal aging.

Accumulating evidences suggest that the mechanisms underlying physiological aging are similar to those governing Hutchinson-Gilford progeria syndrome (HGPS)a premature aging syndrome in which affected patients typically succumb to CVDs (7). HGPS is predominantly caused by an a.c. 1824 C>T, p. G608G mutation in LMNA gene, which activates an alternate splicing event and generates a 50amino acid truncated form of Lamin A, referred to as progerin (8). The murine LmnaG609G, which is equivalent to LMNAG608G in humans, causes aging phenotypes resembling HGPS (9). It has been shown that progerin targets SMCs and causes blood vessel calcification and atherosclerosis (10, 11). Recent work by two groups showed that SMC-specific progerin knock-in (KI) mice are healthy and have a normal life span but suffer from blood vessel calcification, atherosclerosis, and shortened life span when crossed to Apoe/ mice (12, 13). In contrast to SMCs, the contributing roles of the vascular endothelium (VE) to systemic/organismal aging are still elusive. To address these issues, we generated a conditional progerin (LmnaG609G) KI model, i.e., Lmnaf/f mice. In combination with E2A-Cre and Tie2-Cre mice, in which the expression of Cre is ubiquitous including germ cells (14) or driven by the endothelial-specific Tie2 promoter (15), we aimed to investigate the roles of VE dysfunction to systemic aging and the targeting potential for the clinical treatment of HGPS.

To study the mechanism of VE aging, we generated a mouse model of conditional progerin KI, in which the LmnaG609G mutation, equivalent to HGPS LMNAG608G, was flanked with loxP sites, i.e., Lmnaf/f mice (fig. S1A). The Lmnaf/f mice were crossed to E2A-Cre mice, in which the Cre recombinase is ubiquitously expressed including germ cells, to generate LmnaG609G/G609G and LmnaG609G/+ mice. Progerin was ubiquitously expressed in LmnaG609G/G609G and LmnaG609G/+ mice, which recapitulated many progeroid features found in HGPS, including growth retardation and shortened life span (fig. S1, B to D).

To understand primary alterations in the VE, we isolated CD31+ murine lung ECs (MLECs) (16) from three pairs of LmnaG609G/G609G (G609G) and Lmnaf/f (Flox) mice by fluorescence-activated cell sorting (FACS) (Fig. 1A) and performed 10 Genomics single-cell RNA sequencing. We recovered 6004 cells (4137 from G609G and 1867 from Flox mice) and used the k-means clustering algorithm to cluster the cells into four groups (Fig. 1B). As expected, one group exhibited high Cd31, Cd34, and Cdh5 expression and thus largely represented MLECs. The other three groups, copurified with CD31+ MLECs by FACS, showed relatively lower Cd31 expression at the mRNA level (>10-fold lower than MLECs) but high Cd45 expression (fig. S2). Further analysis revealed that these clusters most likely contained B lymphocytes (B-like) with high Cd22, Cd81, and Ly6d expression; T lymphocytes (T-like) with high Cd3d, Cd3e, and Cd28 expression; and macrophages (M-like) with high Cd14, Cd68, and Cd282 expression (Fig. 1C). Most of the marker gene expression levels were comparable between G609G and Flox mice, except for Cd34 and Icam1, which were significantly elevated in G609G ECs, and Cd14 and Vcam1, which were increased in G609G M-like cells (Fig. 1D). Of note, Icam1 and Vcam1 are among the most conserved markers of endothelial senescence and atherosclerosis (17). Thus, we established an Lmnaf/f conditional progerin KI mouse model and revealed a unique EC population for mechanistic study.

(A) Purity analysis of sorted CD31+ MLECs by FACS. SSC, side scatter; FSC, forward scatter; PE, phycoerythrin. (B) t-Distributed stochastic neighbor embedding (t-SNE) projection of CD31+ cells revealed four clusters: ECs (green), B lymphocytes (B-like; orange), T lymphocytes (T-like; blue), and macrophages (M-like; red). (C) Marker gene expression in the four clusters: ECs (Cd31, Cd34, and Cdh5), B-like (Ly6d, Cd22, and Cd81), T-like (Cd3d, Cd3e, and Cd28), and M-like (Cd14, Cd68, and Cd282). (D) Heatmap showing marker gene expression levels in LmnaG609G/G609G (G609G) and Lmnaf/f (Flox) mice.

Of the four clusters of CD31+ MLECs, ECs and M-like cells showed high levels of p21Cip1/Waf1 (fig. S2A), a typical senescence marker (18). This finding suggests that these cells are the main target of progerin in the context of aging. A previous study reported that M-specific progerin, achieved by crossing Lmnaf/+ to Lyz-Cre mice, caused minimal aging phenotypes (12), implicating that M might have only a minor role in organismal aging. We thus focused on ECs for further analysis. We recovered 899 and 445 ECs from E2A and Flox mice, respectively (Fig. 2A). Genes with >1.5-fold change in expression between these mice were chosen for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. We observed a significant enrichment in the pathways that regulate chemotaxis, immune responses in malaria and Chagas diseases, inflammatory bowel disease, and rheumatoid arthritis and pathways essential for cardiac function (Fig. 2, B to D). To confirm this observation and to exclude paracrine effects from other cell types, we overexpressed progerin in human umbilical vein ECs (HUVECs) and analyzed representative genes by quantitative polymerase chain reaction (PCR). Most of the examined genes, e.g., IL6, IL8, IL15, CXCL1, IL1, etc., were significantly up-regulated upon ectopic progerin overexpression (Fig. 2E). Together, these data suggest that progerin causes an inflammatory response in VE, which might lead to systemic aging.

(A) t-SNE projection of LmnaG609G/G609G (G609G; green) and Lmnaf/f (Flox; orange) CD31+ MLECs according to transcriptomic data. (B to D) GO and KEGG pathway enrichment of differentially expressed genes between G609G and Flox cells. LmnaG609G/G609G MLECs show enrichment in genes that regulate the inflammatory response (C) and genes related to heart dysfunction (D). FC, fold change; FDR, false discovery rate. (E) Quantitative PCR analysis of altered genes observed in (C) and (D) in HUVECs with ectopic expression of progerin or wild-type LMNA. Data represent means SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 (Students t test).

To test whether the VE dysfunction has essential roles in systemic aging, we crossed Lmnaf/f mice to a Tie2-Cre line to generate Lmnaf/f;TC mice, in which the expression of Cre recombinase is driven by the promoter/enhancer of endothelial-specific Tie2 gene (15). Single-cell transcriptome analysis confirmed that Tie2 was mainly detected in ECs (fig. S2B). Consistently, progerin was observed in the VE of Lmnaf/f;TC, but not in that of Lmnaf/f control mice or other tissues (fig. S3). VE-specific progerin induced intima-media thickening in Lmnaf/f;TC mice, in a similar manner to total KI mice, i.e., LmnaG609G/G609G mice (Fig. 3, A and B). We performed functional analysis of the VE based on acetylcholine (ACh)regulated vasodilation. ACh-induced thoracic aorta relaxation was significantly compromised in Lmnaf/f;TC mice (Fig. 3C). Similar defects were observed in LmnaG609G/G609G and LmnaG609G/+ mice (Fig. 3D and fig. S4), where progerin was expressed in both ECs and SMCs (12). To gain more evidence supporting VE-specific dysfunction, we examined thoracic aorta relaxation induced by sodium nitroprusside (SNP), which is an SMC-dependent vasodilator. Little difference was observed in thoracic aorta vasodilation in LmnaG609G/G609G and LmnaG609G/+ compared to Lmnaf/f control mice (Fig. 3E and fig. S4), supporting the notion that the VE dysfunction is a key contributor of vasodilation defects in progeria mice. As NO is the most potent vasodilator (19), we examined eNOS levels in the thoracic aorta of Lmnaf/f;TC and Lmnaf/f control mice. As expected, the level of eNOS was significantly reduced in Lmnaf/f;TC mice compared to Lmnaf/f control mice (Fig. 3F). Thus, the data confer a VE-specific dysfunction in progeria mice.

(A and B) Hematoxylin and eosin staining of thoracic aorta sections from (A) Lmnaf/f;TC and (B) LmnaG609G/G609G and Lmnaf/f control mice showing intima-media thickening. Scale bar, 20 m. (C) ACh-induced thoracic aorta vasodilation in Lmnaf/f;TC and Lmnaf/f control mice. **P < 0.01. 5-HT, 5-hydroxytryptamine. (D) ACh-induced thoracic aorta vasodilation in LmnaG609G/G609G and control mice. **P < 0.01. (E) SNP-induced thoracic aorta vasodilation in LmnaG609G/G609G and control mice. (F) eNOS level in thoracic aorta sections from Lmnaf/f;TC and control mice. Scale bar, 20 m. (G) Immunofluorescence staining (left) and quantification (right) of CD31+ gastrocnemius muscle in Lmnaf/f;TC and Lmnaf/f mice. Scale bar, 50 m. DAPI, 4,6-diamidino-2-phenylindole. (H) CD31 immunofluorescence staining in Lmnaf/f;TC and Lmnaf/f liver. Scale bar, 50 m. (I) Representative microcirculation images (left) and quantification of blood flow recovery (right) following hindlimb ischemia in Lmnaf/f;TC and Lmnaf/f mice. (J) Representative transverse sections and quantification of CD31+ gastrocnemius muscle 14 days after femoral artery ligation. Scale bar, 50 m. All data represent means SEM. P values were calculated by Students t test. Photo credits: Shimin Sun, School of Life Sciences, Shandong University of Technology; Medical Research Center, Shenzhen University (A, B, F, H, and J); Weifeng Qin, Medical Research Center, Shenzhen University (G and I).

The reduced capillary density and neovascularization capacity are both characteristics of endothelial dysfunction (1). We examined the microvasculature in various tissues of Lmnaf/f;TC mice by immunofluorescence staining. We observed a significant loss in CD31+ ECs in Lmnaf/f;TC mice compared to controls (Fig. 3, G and H). We further examined ischemia-induced neovascularization ability in Lmnaf/f;TC mice following femoral artery ligation. Limb perfusion after ischemia was significantly blunted in Lmnaf/f;TC mice compared to controls (Fig. 3I). Histological analysis confirmed that the defect in blood flow recovery in Lmnaf/f;TC mice was a reflection of an impaired ability to form new blood vessels in the ischemic region (Fig. 3J). Together, Lmnaf/f;TC mice are characterized by a loss of ECs, a reduced capillary density, and defective neovascularization capacity.

The single-cell transcriptome implicates heart dysfunction in LmnaG609G/G609G mice (Fig. 2). A correlation with gene alterations associated with atherosclerosis and osteoporosis was obvious in LmnaG609G/G609G ECs (the Online Mendelian Inheritance in Man; https://omim.org) (fig. S5). We thus reasoned that endothelial-specific dysfunction might be enough to trigger systemic aging. Notably, atherosclerosis was prominent in Lmnaf/f;TC mice (aorta atheromatous plaque observed in all nine examined mice; Fig. 4A), as well as severe fibrosis in the arteries and hearts (Fig. 4, B and C); both are typical features of aging. Moreover, the heart/body weight ratio was significantly increased in Lmnaf/f;TC compared to Lmnaf/f control mice (Fig. 4D), indicating dilated cardiomyopathy (20). Echocardiography confirmed that heart rate, cardiac output, left ventricular ejection fraction, and fractional shortening were significantly reduced in 7- to 8-month-old Lmnaf/f;TC compared to Lmnaf/f control mice. The running endurance was largely compromised in Lmnaf/f;TC mice (Fig. 4E), which is likely a reflection of amyotrophy. Moreover, the microcomputed tomography (CT) identified a decrease in trabecular bone volume/tissue volume, trabecular thickness, and trabecular number but an increase in trabecular separation in Lmnaf/f;TC mice (Fig. 4F), indicative of osteoporosis, which is an important hallmark of systemic aging (21). The VE-specific dysfunction not only accelerated aging in various tissues/organs but also shortened the median life span of Lmnaf/f;TC mice (24 weeks) to a similar extent to LmnaG609G/G609G mice (21 weeks) (Fig. 4G). LmnaG609G/G609G mice suffered from body weight loss roughly from 8 weeks of age, while Lmnaf/f;TC mice only showed a slight drop in body weight (Fig. 4H), suggesting that body weight loss itself is a less likely primary causal factor to progeria compared to endothelial dysfunction. Together, these results implicate that endothelial dysfunction, at least in progeria, acts as a causal factor of systemic aging.

(A to C) Masson trichrome staining showing an atheromatous plaque in the aorta (A), SMC loss (B), and cardiac fibrosis (C) in Lmnaf/f;TC mice. Scale bar, 20 m. (D) Heart weight and echocardiographic parameters, including heart rate, cardiac output, left ventricular (LV) ejection fraction (LVEF), and left ventricular ejection shortening (LVFS). *P < 0.05, Lmnaf/f;TC versus Lmnaf/f mice. (E) Decreased running endurance in Lmnaf/f;TC mice. ***P < 0.001. (F) Micro-CT analysis showing a decrease in trabecular bone volume/tissue volume (BV/TV), trabecular number, and trabecular thickness and an increase in trabecular separation in Lmnaf/f;TC mice. *P < 0.05, Lmnaf/f;TC versus Lmnaf/f mice. (G) Life span of LmnaG609G/G609G, LmnaG609G/+, Lmnaf/f;TC, and Lmnaf/f mice. (H) Body weight of male LmnaG609G/G609G, LmnaG609G/+, Lmnaf/f;TC, and Lmnaf/f mice. *P < 0.05, Lmnaf/f;TC versus Lmnaf/f mice; ***P < 0.001, LmnaG609G/G609G versus Lmnaf/f mice. All data represent means SEM. P values were calculated by Students t test, except that statistical comparison of the survival data was performed by log-rank test. Photo credits: Weifeng Qin, Medical Research Center, Shenzhen University (A and B); Shimin Sun, School of Life Sciences, Shandong University of Technology; Medical Research Center, Shenzhen University (C).

Loss of Sirt7, an NAD+ (nicotinamide adenine dinucleotide)dependent deacylase, causes heart dysfunction with systemic inflammation and accelerates aging (22, 23). We noticed defective neovascularization in Sirt7 knockout mice (Fig. 5A). Knockdown of Sirt7 up-regulated the levels of interleukin-1 (IL-1) and IL6 in HUVECs, as determined by Western blotting and real-time PCR (Fig. 5, B and C). Significantly, the protein level of Sirt7 was reduced almost 50% in Lmnaf/f;TC MLECs (Fig. 5D). By contrast, the levels of Sirt6 and Sirt1 were hardly decreased in Lmnaf/f;TC MLECs. Furthermore, co-immunoprecipitation revealed that Lamin A interacted with Sirt7, which was significantly enhanced in the case of progerin (Fig. 5E). FLAG-SIRT7 was polyubiquitinated, which was enhanced in the presence of progerin compared with Lamin A (Fig. 5F). Ectopic expression of progerin in human embryonic kidney (HEK) 293 accelerated SIRT7 protein degradation, which was inhibited by MG132 (a proteasome inhibitor) (Fig. 5G). These data suggest that accumulation of progerin destabilizes Sirt7 by proteasomal pathway in progeria cells.

(A) Quantification of blood flow recovery following hindlimb ischemia in Sirt7/ and Sirt7+/+ mice. (B) Left: Representative immunoblots showing indicated protein levels in HUVECs treated with si-SIRT7 or scramble (Scram). Right: Quantification of relative protein levels. *P < 0.05 and **P < 0.01, small interfering RNA (siRNA) versus Scram. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (C) Real-time PCR analysis of the indicated gene expression in HUVECs treated with si-SIRT7 or Scram. *P < 0.05, siRNA versus Scram. (D) Left: Representative immunoblots showing indicated sirtuin protein levels in FACS-sorted MLECs. Right: Quantification of relative protein levels. *P < 0.05. Note that down-regulated Sirt7 but rather up-regulated Sirt6 and hardly changed SIRT1 in Lmnaf/f;TC MLECs. (E) Left: Co-immunoprecipitation (IP) experiments showing hemagglutinin (HA)SIRT7 in antiFLAGLamin A and antiFLAG-progerin immunoprecipitates. Right: Quantification of relative protein levels. *P < 0.05. (F) Left: Representative immunoblots showing polyubiquitinated SIRT7, which was up-regulated in the presence of progerin but rather down-regulated in the presence of Lamin A. Right: Quantification of relative protein levels. *P < 0.05. (G) Representative immunoblots showing SIRT7 protein levels in the presence of Lamin A or progerin in HEK293 cells treated with cycloheximide (CHX) and/or MG132 (M). Quantification of relative SIRT7 protein levels was shown. *P < 0.05, progerin versus Lamin A. All data represent means SEM. P values were calculated by Students t test. Photo credit: Xiaolong Tang, Medical Research Center, Shenzhen University (B, D, E, F, and G).

We reasoned that Sirt7 might underlie the VE dysfunction in progeria mice. To test this hypothesis, we first examined whether ectopic Sirt7 could rescue the exacerbated inflammatory response in HUVECs. As shown, overexpression of SIRT7 significantly down-regulated the expression of multiple inflammatory genes such as IL1 (Fig. 6A). To test the in vivo function of Sirt7 in defective neovascularization, we generated a recombinant AAV serotype 1 (rAAV1) cassette with Sirt7 gene expression driven by a synthetic ICAM2 promoter (IS7O), which ensures VE-specific expression (24, 25). As shown, on-site injection of IS7O at a dose of 1.25 1010 viral genome-containing particles (vg)/50 l significantly improved blood vessel formation in Lmnaf/f;TC mice (Fig. 6B). The ectopic expression of Sirt7 and the increase in CD31-labeled ECs were evidenced by fluorescence confocal microscopy in ECs of regenerated blood vessels (Fig. 6, C and D).

(A) Real-time PCR analysis of genes that are aberrantly up-regulated in progerin-overexpressing HUVECs upon overexpression of SIRT7. *P < 0.05, **P < 0.01, and ***P < 0.001. (B) Neovascularization assay in Lmnaf/f;TC mice with hindlimb ischemia, treated with or without IS7O particles. **P < 0.01. (C) Immunofluorescence microscopy analysis of FLAG-SIRT7 and CD31 expression in gastrocnemius muscle 14 days after femoral artery ligation. Scale bar, 25 m. (D) Percent CD31+ ECs in Lmnaf/f;TC mice treated with or without IS7O particles. ***P < 0.001. (E) Representative immunofluorescence images of the liver, aorta, and muscle of Lmnaf/f;TC mice after IS7O therapy, showing CD31+ ECs with FLAG-SIRT7 expression. Scale bar, 50 m. (F) Representative immunoblots showing expression of FLAG-SIRT7 in aorta and WBMCs. Note that FLAG-SIRT7 was merely detected in WBMCs. (G) Life span of IS7O-treated and untreated Lmnaf/f;TC and LmnaG609G/+ mice. (H) Body weight of IS7O-treated and untreated Lmnaf/f;TC and Lmnaf/f mice. All data represent means SEM. P values were calculated by Students t test, except that the statistical comparison of survival data was performed by log-rank test. Photo credits: Shimin Sun, School of Life Sciences, Shandong University of Technology; Medical Research Center, Shenzhen University (C and E); Xiaolong Tang, Medical Research Center, Shenzhen University (F).

We next asked whether IS7O could ameliorate premature aging and extend life span. To this end, the IS7O particles were injected via tail vein from 21 weeks of age, when progeria mice start to die. The injection was repeated every other week at a concentration of 5 1010 vg/200 l per mouse. While all untreated mice died before 34 weeks of age, most IS7O-treated mice were still alive at the age of 44 weeks, when they were euthanized for histological analysis. The ectopic expression of FLAG-SIRT7 was observed in the ECs of liver, muscle, and aorta, but not in whole bone marrow cells (WBMCs), determined by fluorescence microscopy and/or Western blotting (Fig. 6, E and F). The median life span was extended by 76%from 25 to >44 weeks (Fig. 6G). The age-related body weight loss was slightly rescued upon IS7O therapy in Lmnaf/f;TC mice (Fig. 6H). These data suggest that progerin-caused VE dysfunction and systemic aging are partially, if not entirely, attributable to Sirt7 decline.

Mounting evidence supports the idea that endothelial dysfunction is a conspicuous marker for vascular aging and CVDs (2628). However, the fundamental question whether VE dysfunction causally triggers systemic aging remains. The heterogeneity of vascular cells and their close communication with the bloodstream render it difficult to understand the primary function of the VE. The murine LmnaG609G mutation, equivalent to the LMNAG608G found in humans with HGPS, causes premature aging phenotypes in various tissues and organs, thus providing an ideal model for studying aging mechanisms at both tissue and organismal levels. Data from the LmnaG609G model suggest that SMCs are the primary cause of vascular diseases, such as atherosclerosis (10, 11). A recent study showed that specific expression of LmnaG609G in SMCs causes atherosclerosis and shortens life span in atherosclerosis-prone Apoe/ mice (12). We used Tie2-Cre line to generate the VE-specific LmnaG609G mouse model. Lmnaf/f;TC mice exhibited vascular dysfunction, accelerated aging, and a shortened life span to a similar extent to the whole-body LmnaG609G model. Tie2 expression was reported not only in ECs but also in hematopoietic lineages (29). Our single-cell transcriptomic data identified Tie2 transcripts mainly in MLECs instead of B-, T-, or M-like cells. When a synthetic ICAM2 promoter was used to drive ectopic expression of FLAG-SIRT7 in the rescue experiments, ectopic FLAG-SIRT7 was successfully detected in ECs of the aorta, muscle, and liver but hardly detected in WBMCs. Therefore, Tie2-driven progerin expression combined with synthetic ICAM2-drivern SIRT7 rescue largely ensures the EC-specific contribution in systemic aging. Of note, although the number and function of hematopoietic stem cells decline in another progeria model, Zmpste24/ mice (30), little effect was observed when healthy hematopoietic progenitor cells were transplanted to Zmpste24/ mice in the context of systemic aging. Recently, Hamczyk et al. (12) found that knocking in the LmnaG609G allele in macrophages mediated by LysM-Cre merely affects aging and life span. Therefore, our data strongly suggest that, as the largest secretory organ (3), VE is pivotal in regulating systemic aging and longevity. In support of our findings, Foisner et al. (31) reported that VE-cadherin promoter-driven expression of progerin in a transgenic line causes cardiovascular abnormalities and shortens life span.

One limitation in the understanding of mechanisms of VE dysfunction is the vascular cell heterogeneity and the lack of appropriate in vitro system for ECs. Here, we took advantage of single-cell RNA sequencing technique to analyze the transcriptomes of MLECs. Unexpectedly, although >95% purity was achieved by FACS, MLECs isolated by CD31 immunofluorescence labeling turned out to be a mixture of cells, including ECs and T-, B-, and M-like cells. Although enriched by FACS, these non-ECs expressed low level of CD31 mRNA, raising the possibility that cell surface proteins such as CD31 T-, B-, and M-like cells might be obtained from neighbor ECs via intercellular protein transfer (32). Nevertheless, these findings suggest that one cannot just purify CD31+ cells and pool them together for mechanistic study, because one might arrive at a misleading conclusion. We compared the expression of genes that are associated with atherosclerosis, arthritis, heart failure, osteoporosis, or amyotrophy (the Online Mendelian Inheritance in Man; https://omim.org) between progeroid and control in all four clusters. An obvious alteration of these genes/pathways was observed mainly in ECs and M-like cells (fig. S2). At the current stage, it is hard to separate cell-autonomous and paracrine effects among different cell populations. In the future, it would be worthwhile to do an analysis in Lmnaf/f;TC MLECs. The data will be useful to study the paracrine effect of ECs on other cell populations.

Since the identification of the causal link between LMNA G608G mutation and HGPS, numerous efforts have been put on the development of treatment for HGPS. Farnesyltransferase inhibitors (33), resveratrol, and N-acetyl cysteine (30) treatment alleviate premature aging features and extend life span in progeria murine models. Rapamycin (34) and metformin (35) incubation rescue senescence in HGPS cells. On the basis of these notions, patients with HGPS taking a farnesyltransferase inhibitor, lonafarnib, in a clinical trial showed significant improvement of health status, reduction of mortality rate, and a potential extension of life span (about 1 to 2 years) (36). Taking advantage of gene therapy and the dispensable role of Lamin A, morpholino oligos (9), and CRISPR-Cas9 designs (37, 38), which prevent Lamin A/progerin generation, can alleviate aging features and extend life span from 25 to 40% in progeria mice. However, considering the indispensable function of Lamin A in humans, these genome-modifying strategies need further experimentation before potential clinical application. Here, applying a different strategy, we showed that rAAV1-SIRT7 (IS7O), targeting dysfunctional VE, largely ameliorates progeroid features and almost doubles the median life span (from 25 to >44 weeks). To our best knowledge, this is the most marked rescue of progeria in a mouse model via gene therapy. Given that SIRT7 elicits deacylase activity to modulate cellular functions (22, 23), it is worthwhile to identify small molecules that specifically target SIRT7 activity for therapeutics in the future. Resveratrol is a potential activator of SIRT1, as well as SIRT7 (39), and has protective effects on vascular function and blood pressure (40). Further depicting the relationship of SIRT7 and resveratrol in the regulation of vascular function would help in seeking leading compounds of SIRT7 specific activators.

Collectively, we reveal VE dysfunction as a primary trigger of systemic aging and as a risk factor for age-related diseases such as atherosclerosis, heart failure, and osteoporosis. Drugs and molecules that target VE might serve as good candidates in the treatment of age-related diseases other than CVDs. The findings in SIRT7-based gene therapy implicate great clinical potentials for progeria as well as in antiaging applications.

Lmnaf/+ allele (LmnaG609G mutation flanked by two loxP sites) was generated by Cyagen Biosciences Inc., China. Briefly, the 5 and 3 homology arms were amplified from bacterial artificial chromosome clones RP23-21K15 and RP23-174J9, respectively. The G609G (GGC to GGT) mutation was introduced into exon 11 in the 3 homology arm. C57BL/6 embryonic stem cells were used for gene targeting. To obtain ubiquitous expression of progerin (LmnaG609G/G609G), Lmnaf/f mice were bred with E2A-Cre mice. To obtain VE-specific expression of progerin, Lmnaf/f mice were bred with Tie2-cre mice. Mice were housed and handled in accordance with protocols approved by the Committee on the Use of Live Animals in Teaching and Research of Shenzhen University, China.

Four-month-old male mice were anesthetized with 4% chloral hydrate (0.20 ml/20 g) by intraperitoneal injection. Hindlimb ischemia was performed by unilateral femoral artery ligation and excision, as previously described (41). In brief, the neurovascular pedicle was visualized under a light microscope following a 1-cm incision in the skin of the left hindlimb. Ligations were made in the left femoral artery proximal to the superficial epigastric artery branch and anterior to the saphenous artery. Then, the femoral artery and the attached branches between ligations were excised. The skin was closed using a 4-0 suture line, and erythromycin ointment was applied to prevent wound infection after surgery. Recovery of the blood flow was evaluated before and after surgery using a dynamic microcirculation imaging system (Teksqray, Shenzhen, China). Relative blood flow recovery is expressed as the ischemia-to-nonischemia ratio. At least three mice were included in each experimental group.

HEK293 cells and HUVECs were purchased from the American Type Culture Collection. HEK293 cells were cultured in Gibco Dulbeccos modified Eagles medium (Life Technologies, USA) supplemented with 10% fetal bovine serum at 37C, 5% CO2. HUVECs were cultured in Gibco M199 (Life Technologies, USA) supplemented with 15% fetal bovine serum, EC growth supplement (50 g/ml), and heparin (100 g/ml) at 37C, 5% CO2. All cell lines used were authenticated by short tandem repeat profile analysis and were mycoplasma free.

Total RNA was extracted from cells or mouse tissues using TRIzol reagent RNAiso Plus (Takara, Japan) and transcribed into complementary DNA (cDNA) using 5 PrimeScript RT Master Mix (Takara, Japan), following the manufacturers instructions. The mRNA levels were determined by quantitative PCR with SYBR Premix Ex Taq II (Takara, Japan) detected on a CFX Connect Real-Time PCR Detection System (Bio-Rad). All primer sequences are listed in table S1.

For protein extraction, cells were suspended in SDS lysis buffer and boiled. Then, the lysate was centrifuged at 12,000g for 2 min, and the supernatant was collected. For Western blotting, protein samples were separated on SDS-polyacrylamide gels, transferred to polyvinylidene difluoride membranes (Millipore, USA), blocked with 5% nonfat milk, and incubated with the relevant antibodies. Images were acquired on a Bio-Rad system. All antibodies are listed in table S2.

Frozen sections of aorta, skeletal muscle, and liver tissues were fixed in 4% paraformaldehyde (PFA), permeabilized with 0.3% Triton X-100, blocked with 5% bovine serum albumin and 1% goat serum, and then incubated with primary antibodies at room temperature for 2 hours or at 4C overnight. After three washes with phosphate-buffered saline with Tween 20, the sections were incubated with secondary antibodies for 1 hour at room temperature and then stained with 4,6-diamidino-2-phenylindole antifade mounting medium. Images were captured under a Zeiss LSM 880 confocal microscope. All antibodies are listed in table S2.

Paraffin-embedded sections of PFA-fixed tissues were dewaxed and hydrated. Staining was then performed using a Masson trichrome staining kit (Beyotime, China). In brief, the sections were dipped in Bouin buffer for 2 hours at 37C and then successively stained with Celestine blue staining solution, hematoxylin staining solution, Ponceau S staining solution, and aniline blue solution for 3 min. After dehydrating with ethyl alcohol three times, the sections were mounted with Neutral Balsam Mounting Medium (BBI Life Science, China). Images were captured under a Zeiss LSM 880 confocal microscope.

Mice were euthanized by decapitation. The lungs were then collected, cut into small pieces, and then digested with collagenase I (200 U/ml) and neutral protease (0.565 mg/ml) for 1 hour at 37C. The isolated cells were incubated with phycoerythrin-conjugated anti-CD31 antibody for 1 hour at 4C and then 7-aminoactinomycin D (7-AAD) (1:100) for 5 min. CD31-positive and 7-AADnegative cells were sorted on a flow cytometer (BD Biosciences, USA).

Four-month-old male mice were anesthetized with 4% chloral hydrate by intraperitoneal injection. Thoracic aortas were collected, rinsed in ice-cold Krebs solution, and cut into 2-mm-length rings. Each aorta ring was bathed in 5-ml oxygenated (95% O2 and 5% CO2) Krebs solution at 37C for 30 min in a myograph chamber (620M, Danish Myo Technology). Each ring was stretched in a stepwise fashion to the optimal resting tension (thoracic aortas to ~9 mN) and equilibrated for 30 min. Then, 100 mM K+ Krebs solution was added to the chambers to elicit a reference contraction and then washed out with Krebs solution at 37C until a baseline was achieved. Vasodilation induced by Ach or SNP (1 nM to 100 M) was recorded in 5-hydroxytryptamine (2 M) contracted rings. Data are represented as a percentage of force reduction and the peak of K+-induced contraction. At least three mice were included in each experimental group.

Seven- to 8-month-old male mice were anesthetized by isoflurane gas inhalation and then subjected to transthoracic echocardiography (iU22, Philips). Parameters, including heart rate, cardiac output, left ventricular posterior wall dimension, left ventricular end-diastolic dimension, left ventricular end-systolic diameter, LV ejection fraction, and LV fractional shortening, were acquired. At least three mice were included in each experimental group.

Seven- to 8-month-old male mice were euthanized by decapitation. The thigh bone was fixed in 4% PFA at 4C overnight. The relevant data were collected by micro-CT (Scanco Medical, CT100). At least three mice were included in each experimental group.

A Rota-Rod Treadmill (YLS-4C, Jinan Yiyan Scientific Research Company, China) was used to monitor fatigue resistance. Briefly, mice were placed on the rotating lane, and the speed of the rotations gradually increased to 40 rpm. When the mice were exhausted, they were safely dropped from the rotating lane, and the latency to fall was recorded. At least three mice were included in each experimental group.

CD31+ cells isolated from murine lung by FACS (>90% viability) were used for single-cell RNA sequencing. A sequence library was built according to the Chromium Single-Cell Instrument library protocol (42). Briefly, single-cell RNAs were barcoded and reverse-transcribed using the Chromium Single-Cell 3 Reagent Kits v2 (10 Genomics) and then fragmented and amplified to generate cDNAs. The cDNAs were quantified using an Agilent Bioanalyzer 2100 DNA Chip, and the library was sequenced using an Illumina Hiseq PE150 with ~10 to 30M raw data assigned for each cell. The reads were mapped to the mouse mm9 genome and analyzed using STAR: >90% reads mapped confidently to genomic regions and >50% mapped to exonic regions. Cell Ranger 2.1.0 was used to align reads, generate feature-barcode matrices, and perform clustering and gene expression analysis. Mean reads (>80,000) and 900 median genes per cell were obtained. The unique molecular identifier counts were used to quantify the gene expression levels, and the t-distributed stochastic neighbor embedding (t-SNE) algorithm was used for dimensionality reduction. The cell population was then clustered by k-means clustering (k = 4). The Log2FoldChange was the ratio of gene expression of one cluster to that of all other cells. The P value was calculated using the negative binomial test, and the false discovery rate was determined by the Benjamini-Hochberg procedure. GO and KEGG enrichment analyses were performed in DAVID version 6.8 (43).

A two-tailed Students t test was used to determine statistical significance, except that the statistical comparison of survival data was performed by log-rank test. All data are presented as the means SD or means SEM, as indicated, and a P value <0.05 was considered statistically significant.

Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/6/8/eaay5556/DC1

Fig. S1. Generation of Lmnaf/f mice and phenotypic analysis of LmnaG609G/G609G mice.

Fig. S2. Single-cell transcriptomic analysis of CD31+ MLECs.

Fig. S3. VE-specific progerin expression.

Fig. S4. Vasodilation analysis of LmnaG609G/+ mice.

Fig. S5. Expression of atherosclerosis- and osteoporosis-associated genes in MLEC transcriptomes.

Table S1. List of primer sequences.

Table S2. List of antibodies.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: We thank J. Tamanini (Shenzhen University and ETediting) for editing the manuscript before submission. Funding: This study was supported by grants from the National Natural Science Foundation of China (91849208, 81571374, 91439133, 81871114, 81601215, 81972602, and 81702909), the National Key R&D Program of China (2017YFA0503900), the Science and Technology Program of Guangdong Province (2014A030308011, 2017B030301016, and 2019B030301009), and the Shenzhen Municipal Commission of Science and Technology Innovation (JCYJ20160226191451487, KQJSCX20180328093403969, JCYJ20180507182044945, ZDSYS20190902093401689, and Discipline Construction Funding of Shenzhen 2016-1452). Author contributions: B.L. designed and supervised the project. S.S., W.Q., and X.T. conducted experiments with help from W.H., S.Z., M.Q., Z.L., X.C., Q.P., and B.Z. Y.M. performed bioinformatic analysis. Z.W. and Z.Z. provided resources. S.S., X.T., and B.L. wrote the manuscript. All authors discussed the experimental results and reviewed the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The data of single-cell transcriptomics are available in the GEO database (GSE138975). Additional data related to this paper may be requested from the authors.

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Vascular endotheliumtargeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model - Science...

Its point-of-care platform advances the development of gene-based medicine through collaborations and in-licensing

Inc () announced a collaboration with Johns Hopkins University to utilize its point-of-care platform to develop and supply gene therapies and technologies.

The companys POCare cell therapy platform is designed to advance the development of Advanced Therapy Medicinal Products medicines based on genes, tissues or cells through collaborations and in-licensing with other companies.

CEO Vered Caplan is confident in the pedigree and resources of the Baltimore research university.

JHU has unparalleled capabilities in the cell and gene therapy sector, Caplan said in a statement. Our POCare platform is designed to provide unique cell and gene therapy solutions in a cost effective, high quality and scalable manner, using closed systems and other advanced cell processing technologies at the point of care.

We look forward to utilizing our POCare platform to support JHUs growing development and processing needs in order to advance and accelerate cell and gene based clinical therapeutic research. We believe this collaboration with JHU, a clear leader in the field of cell and gene therapy, further validates the significant value proposition of our POCare platform.

Johns Hopkins is the third major institution to sign an agreement with , Caplan said. Last month, the company reached a deal with the University of California, Davis.

With its introduction of Orgenesiss POCare platform, hospitals are able to implement the company's proprietary automated, closed systems and know-how to collect, process and supply cells for various treatments such as the manufacturing of CAR-T cell therapies.

The Germantown, Maryland-based company provides centralized contract development and manufacturing organization (CDMO) services, as well as localized point-of-care development and processing centers through its subsidiary Orgenesis Maryland Inc.

Contact Andrew Kessel at [emailprotected]

Follow him on Twitter @andrew_kessel

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Orgenesis teams up with Johns Hopkins University to develop gene therapies with its POCare platform - Proactive Investors USA & Canada

Audentes Therapeutics, an Astellas company based in San Francisco, California, will open a new facility in Lee County, Governor Roy Cooper announced Tuesday.

The life-sciences company has purchased a recently-completed shell building located in Central Carolina Enterprise Park and will create 209 jobs at an average salary of $83,900. The company will be investing $109.4M in Sanford over a five year period.

With our powerhouse research centers and highly-skilled workforce, biotech pioneers recognize North Carolinas role as a leader in the life sciences, said Governor Cooper. Lee County is a perfect fit for Audentes as they seek to become a global leader in genetic medicines.

Audentes Therapeutics, Inc., an Astellas company, is an AAV-based genetic medicines company focused on developing and commercializing innovative therapies that can offer transformative benefits to patients.

In addition to its gene therapy portfolio targeting serious rare neuromuscular diseases, the company states, Audentes is leveraging Astellas global resources, industry leadership in immune biology, and deep scientific expertise to expand its reach and deliver valuable new genetic medicines to patients around the world.

Lee County Board of Commissioners Chair Amy Dalrymple gave remarks during the announcement, saying, Thank you to Audentes for recognizing the strengths of the Lee County community and for investing in us to create over 200 jobs for Central North Carolina. Lee County looks forward to working together and building a long-term partnership where Audentes and the Lee County community flourishes.

Sanford Mayor Chet Mann stated, We are overjoyed at having Audentes Therapeutics in our community. Their decision to locate here is proof that our Public / Private Partnership and the efforts toward making Sanford a desirable place to live and work have been a success. A company of this quality and the important work they do will have tremendous impact; creating a new Life Sciences cluster that will pay future dividends. We truly look forward to a great partnership with Audentes and we enthusiastically welcome them here.

Sanford Area Growth Alliance Board of Directors Chair Kirk Bradley commented, Its been a little less than 5 years since Mark Sweeney, of the site selection firm, McCallum Sweeney, addressed a group of community and Civic leaders on July 30, 2015 about how Prepared Communities Win.

This message resonated and the announcement of Audentes Therapeutics is the culmination of what can happen to a community that listens to experts and harnesses private and public capital for a common objective of economic growth.

Today Sanford, Broadway and Lee County has one of the most, if not THE most, thriving economic development eco-system in the State of North Carolina. We are honored that Governor Cooper would make this historic announcement. We welcome Audentes Therapeutics to our community as a new corporate citizen with open arms for a successful future!

Contributed

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Leading gene therapy company to invest $109M in Sanford - Sandhill Sentinel

Dive Brief:

Bluebird's commercial operations are just getting off the ground. In its latest earnings report, the Cambridge, Massachusetts-based biotech detailed how it has inked agreements with health insurers in Germany that should provide coverage for LentiGlobin, which is sold under the brand name Zyntegloin Europe, for up to 50% of eligible beta-thalassemia patients. Bluebird expects the first commercial patient to be treated before July.

Across the Atlantic, U.S. patients are looking at a longer timeline before LentiGlobin becomes available. Stifel analysts wrote in a note to clients that they don't foresee any stateside patients receiving the therapy commercially in 2020 "given what we anticipate will be a complicated negotiation process with payors."

Analysts at Raymond James, meanwhile, downgraded Bluebird to a "Market Perform" rating, writing that "execution issues on the regulatory, clinical and manufacturing side outweigh our support for the innovative drug products."

As Bluebird works through the latest delay in beta-thalassemia,it will also be preparing for an expanded research program in sickle cell. The company already intended to kick off a late-stage study in sickle cell patients with a history of vaso-occlusive crises in the first half of 2020. With Tuesday's earnings presentation, though, came plans to initiate a second late-stage study sometime this year, which will evaluate LentiGlobin's effects in about 18 children with sickle cell and elevated stroke risk.

A sickle cell approval, though a ways off, could boost Bluebird's bottom line. Beta-thalassemiais rarer in U.S. than other parts of the world, and certainly less common than sickle cell. According to estimates cited by the National Organization of Rare Disorders, roughly 3,300 U.S. patients have beta-thalassemiaversus the 100,000 who have sickle cell.

An expanded program could provide more evidence of LentiGlobin's benefit in this larger patient pool.Yet the updates don't seem to have alleviated investor concerns. Bluebird shares were down nearly 10% in late Wednesday morning, trading around $80 apiece.

"LentiGlobin in Sickle Cell Disease remains a bright spot, in our view, but with [late-stage studies] expected to get underway this year, we don't expect investor sentiment to change anytime soon," Stifel analysts wrote.

The investment bank models Zyntelgo bringing in $12 million worth of revenue in 2020 from the beta-thalassemia indication, increasing to $53 million in 2021 and $390 million by 2030. Conversely, it models $48 million in 2022 from the sickle cell indication, increasing to almost $2 billion by 2030.

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Bluebird's gene therapy hits another delay, this time in the US - BioPharma Dive

The vaccine and cell and gene therapy biomanufacturing sectors are growing at an accelerated rate with the US and Europe driving a significant segment of this growth. European biopharma and CDMO scientists often ask if we have representation in the region as they search for innovative tools to alleviate their production and QC bottlenecks; we can now finally say yes to this important question," says Dr. Sean Hart, LumaCytes Chief Executive Officer. In support of these efforts, LumaCyte has hired analytical instrumentation veteran, Christof Hasse, PhD to manage sales and service as part of its European expansion. At LumaCyte, were obsessed with delivering exceptional customer service, so having Laser Force Cytology (LFC) experts who understand our customers unique needs, and are located in the same region, is critical to delivering the highest level of service, says Rene Hart, LumaCyte President and Chief Business Officer. We are excited to have Christof on board as he brings LumaCytes transformative Laser Force Cytology to the hands of European researchers and production scientists.

About LumaCyte

LumaCyte is an advanced research and bioanalytics instrumentation company headquartered in Charlottesville, VA. LumaCyte produces label-free, single cell analysis and sorting instrumentation where the use of antibody or genetic labeling is not required for cellular analysis. This revolutionary technology utilizes Laser Force Cytology (LFC) to measure optical and fluidic forces within a microfluidic channel to identify and measure the intrinsic cellular properties of each cell. The multivariate nature of the data has enabled a host of Big Data strategies and cloud computing capabilities that drive advanced analytics, allowing a deeper understanding of cell based biological systems. Applications of LumaCyte's label-free platform technology include viral infectivity for vaccine development and manufacturing, cell and gene therapy, cancer biology R&D, CAR T cell immunotherapy, adventitious agent testing (AAT), iPSCs, infectious disease, and pre-clinical drug discovery, in addition to multiple applications across the biomanufacturing sector for quality control and process optimization.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200220005263/en/

Excerpt from:
LumaCyte Expands into Europe Tackling Expansive Vaccine and Cell and Gene Therapy Markets - BioSpace

With more and more cell therapies entering the market, Dr Maitry Ganatra, global market development director at Thermo Fisher Scientific guides readers on how to comply with regulatory standards to ensure quality and safety, and ultimately make it to commercialisation.

In recent years, sophisticated cell therapies have emerged to treat a broad range of cardiovascular, neurological and autoimmune diseases, among others. The complexity and variability of these therapies present unique challenges for the transition from the research phase to commercialisation. Thorough consideration of current good manufacturing practice (cGMP) requirements and regulatory compliance early in the process, even during the research stage, can help alleviate the challenges involved in scaling up. Additionally, applying quality by design (QbD) principles to the production process can ensure high quality and safety of new therapeutics, making commercialisation easier.

Commercialisation of cell and gene therapies, whether allogeneic or autologous, can be challenging. In allogeneic cell therapy, where a single cell type is mass produced for treating multiple patients, the challenge is that of scaling up a thousand-fold from the research phase, while still maintaining the necessary physiological conditions. When processes get scaled up, laboratory instruments, such as centrifuges and CO2 incubators used during the research phase, may not be compatible with the requirements of the cGMP environment. Typically, when equipment designed for research purposes are used in a cGMP compliant facility without consideration of validation and documentation requirements, this can pose a huge issue during commercialisation.

Scaling up could introduce inconsistencies across multiple factors, including incubator temperature, composition of reagents, such as media or growth factors, as well as cell culture parameters, such as incubation time. Even the slightest change in production conditions upon moving from research level to the multi-liter scale can have an impact on how the cells behave, ultimately affecting the quality and safety of the therapy. In adapting research workflows to meet commercial cGMP requirements, cell therapy manufacturers often realise too late that processes that work well at the research stage are incompatible with the cGMP environment. Furthermore, they often underestimate how involved the regulatory compliance process can be; each piece of equipment needs to be validated to ensure it meets the highest standards and relevant documentation should be produced.

In autologous cell therapy, where each batch of cells is produced for only one patient, modified and re-introduced into the same patient, the challenge is that of scaling out and producing multiple batches corresponding to multiple patients, while maintaining due diligence throughout the process-heavy workflow.

Scaling out in autologous cell therapy demands more space and a large number of instruments, each being compliant with regulatory standards. The challenges here involve managing the complexity of working with multiple sets of equipment, having sufficient space for all these systems and keeping track of which instrument is used for a specific therapy. When processing multiple batches in autologous cell therapy, every patient sample needs to be tracked as it goes from the hospital to the manufacturing site and back to the patient, thereby adding logistical burden to the process. On the whole, scaling out relies on having the operational capacity to accommodate all the equipment as well as the materials, manpower and time involved in the process.

Recognising these challenges, many technology vendors offer advice and guidance around cGMP compatible instrumentation, including centrifuges, biological safety cabinets, cold storage equipment and CO2 incubators. A standard laboratory CO2 incubator, for example, cannot be moved to a cGMP environment without temperature mapping or testing for installation, operational and performance qualifications (IQ, OQ and PQ). To this effect, some vendors even offer customisable solutions to help meet cGMP requirements.

Applying quality by design principles to cell therapy manufacturing

Increased testing does not necessarily improve the quality of the final product. A more robust solution is to build quality into entire production workflows. The US Food and Drug Administration (FDA) encourages implementation of the Quality by Design (QbD) principles into the production, manufacturing and regulation processes.

In adopting the QbD principles, every step of the process, starting from raw materials to the operating plant, clean room, and water and materials used, all should adhere to high-quality standards. Every piece of equipment used in the manufacturing process needs to meet quality requirements, such as being certified by the International Organisation for Standardisation.

Recognising the challenges posed when transitioning from research to commercialisation of cell and gene therapies, many instrument vendors apply the QbD principles and undertake all of the necessary performance testing to deliver equipment that meet the requirements of cGMP compliant facilities. Some of the steps involved in performance testing include temperature testing, ramp up/ramp down testing, sterilisation, and electrical checks. By inspecting the overall safety and configuration of the instrumentation, the required factory end-of-line testing is completed.

Vendors also provide the relevant documentation required in adhering with the cGMP standards, for example, issuing the certificate of conformance and providing instrument calibration documentation, equipment drawing and critical component specifications. To ensure that each piece of equipment is installed per vendor specifications, meets the quality requirements, and offers consistent and reproducible results, IQ, OQ and PQ validation protocols are performed, followed by issuing the respective documentation.

In addition to testing for compliance and offering documentation, some vendors provide user and maintenance training to ensure best practices are upheld in the day-to-day workflow.

As pharmaceutical manufacturers transition cell therapies from the research to the commercialisation phase, they start acknowledging the complexity that comes from scaling up and expanding workflows, while staying compliant with the regulatory requirements. Carefully planning cell therapy production processes beforehand, understanding the needs of cGMP compliance and collaborating with knowledgeable technology vendors who offer solutions adhering to QbD principles, can set cell therapy manufacturers up for successful commercialisation.

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Getting cell therapies to market - EPM Magazine

- First conditional approval of ZYNTEGLOTM (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy for patients 12 years and older with transfusion-dependent -thalassemia who do not have 0/0 genotype in Europe achieved in 2019; Germany launch underway

- Announced positive top-line data from pivotal Phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma

- Presented clinical data across studies of LentiGlobin gene therapy for -thalassemia (betibeglogene autotemcel) and LentiGlobin gene therapy for sickle cell disease (SCD) and bb21217 in multiple myeloma at American Society of Hematology (ASH) Annual Meeting

- Ended quarter with $1.24 billion in cash, cash equivalents and marketable securities

bluebird bio, Inc. (NASDAQ: BLUE) today reported financial results and business highlights for the fourth quarter and full year ended December 31, 2019.

"2019 was truly a transformative year for bluebird, with our first commercial product now launched in Europe and exciting progress across our first four clinical programs and pipeline," said Nick Leschly, chief bluebird. "Notably, our data in SCD continues to build, and at the ASH annual meeting in December we presented data that showed a 99% reduction in the annualized rate of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) in HGB-206 Group C patients with history of VOCs and ACS who had at least six months follow-up. In -thalassemia, the consistency with which patients who do not have a 0/0 genotype in our Northstar-2 (HGB-207) study are achieving transfusion independence is very encouraging and were starting to see indications that we may be able to see similar outcomes with many patients with 0/0 genotypes as well in our Northstar-3 (HGB-212 study). These data put us in a strong position as we progress our European launch, currently underway in Germany. At the end of 2019, we also announced positive top-line data from the pivotal KarMMa study of ide-cel. We and our partners at BMS look forward to submitting these data to the FDA in the first half of this year. Amidst all of our progress in 2019, our birds demonstrated time and again their dedication to patients and ability to meet and learn from the many challenges we have faced along the way. I look forward to facing the challenges of 2020 with this amazing flock."

Recent Highlights:

TRANSFUSION-DEPENDENT -THALASSEMIA

SICKLE CELL DISEASE (SCD)

MULTIPLE MYELOMA

COMPANY

Upcoming Anticipated Milestones:

Fourth Quarter and Full Year 2019 Financial Results

LentiGlobin for -thalassemia Safety

Non-serious adverse events (AEs) observed during the HGB-204, HGB-207 and HGB-212 clinical studies that were attributed to LentiGlobin for -thalassemia were hot flush, dyspnoea, abdominal pain, pain in extremities, thrombocytopenia, leukopenia, neutropenia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

With more than five years of follow-up to date, there have been no new unexpected safety events, no deaths, no graft failure and no cases of vector-mediated replication competent lentivirus or clonal dominance. In addition, there have been no new reports of veno-occlusive liver disease (VOD) as of the data cutoff presented at ASH.

About LentiGlobin for -Thalassemia (betibeglogene autotemcel)

The European Commission granted conditional marketing authorization for LentiGlobin for -thalassemia, to be marketed as ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy, for patients 12 years and older with TDT who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Story continues

LentiGlobin for -thalassemia adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

The conditional marketing authorization for ZYNTEGLO is only valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted LentiGlobin for -thalassemia Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT.

bluebird bio has initiated its rolling BLA submission of LentiGlobin for -thalassemia for approval in the U.S. and is engaged with the FDA in discussions regarding the requirements and timing of certain information to be provided in the BLA, including information regarding various release assays for LentiGlobin for -thalassemia. Subject to these ongoing discussions, the company is currently planning to complete the BLA submission in the second half of 2020.

LentiGlobin for -thalassemia continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of LentiGlobin for -thalassemia. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

The full common name for ZYNTEGLO: A genetically modified autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with lentiviral vector encoding the A-T87Q-globin gene.

Forward-Looking Statements

This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys financial condition, results of operations, as well as statements regarding the plans for regulatory submissions and commercialization for ZYNTEGLO and the companys product candidates, including anticipated regulatory milestones, the execution of the companys commercial launch plans, planned clinical studies, as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; the risk that our collaborations, including the collaborations with Bristol-Myers Squibb and Forty Seven, will not continue or will not be successful; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

bluebird bio, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(in thousands, except per share data)(unaudited)

For the three months endedDecember 31,

For the year endedDecember 31,

2019

2018

2019

2018

Revenue:

Collaboration revenue

$ 7,159

$ 18,382

$ 36,469

$ 52,353

License and royalty revenue

2,838

861

8,205

2,226

Total revenues

9,997

19,243

44,674

54,579

Operating expenses:

Research and development

161,821

119,722

582,413

448,589

Selling, general and administrative

76,202

53,508

271,362

174,129

Cost of license and royalty revenue

1,073

818

2,978

885

Change in fair value of contingent consideration

1,435

2,156

2,747

2,999

Total operating expenses

240,531

176,204

859,500

626,602

Loss from operations

(230,534)

(156,961)

(814,826)

(572,023)

Interest income, net

6,855

6,209

34,761

14,624

Other (expense) income, net

535

1,916

(10,088)

1,961

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bluebird bio Reports Fourth Quarter and Full Year 2019 Financial Results and Highlights Operational Progress - Yahoo Finance

The Global Gene Therapy Market is expected to grow from USD 1,636.49 Million in 2018 to USD 6,436.64 Million by the end of 2025 at a Compound Annual Growth Rate (CAGR) of 21.60%.

The Gene Therapy Market research presents a study by combining primary as well as secondary research. The report gives insights on the key factors concerned with generating and limiting Gene Therapy market growth.

Additionally, the report also studies competitive developments, such as mergers and acquisitions, new partnerships, new contracts, and new product developments in the global Gene Therapy market. The past trends and future prospects included in this report makes it highly comprehensible for the analysis of the market. Moreover, the latest trends, product portfolio, demographics, geographical segmentation, and regulatory framework of the Gene Therapy market have also been included in the study.

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Gene Therapy Market Segment by Manufacturers includes: Achieve Life Sciences, Inc., Adaptimmune, Bluebird bio, Inc., Gilead, Merck & Co., Inc, Abeona Therapeutics, Inc.,, AGTC, Audentes Therapeutics, Biogen, Editas Medicine, Novartis, Orchard Therapeutics, and Spark Therapeutics.

On the basis of Type, the Global Gene Therapy Market is studied across Antigen Gene Therapy, Cancer Gene Therapy, Cytokine Gene Therapy, Suicide Gene Therapy, and Tumor Suppressor Gene Therapy.

On the basis of Vector Type, the Global Gene Therapy Market is studied across Non-viral Vectors and Viral Vectors.

On the basis of Application, the Global Gene Therapy Market is studied across Cardiovascular Diseases, Genetic Diseases, Infectious Diseases, Neurological Diseases, and Oncological Disorders.

Global Gene Therapy market report covers all the major participants and the retailers will be in conscious of the development factors, market barriers & threats, and the opportunities that the market will offer in the near future. The report also features the historical revenue of the market; industry trends, market volume, and consumption in order to gain perceptions about the political and technical environment of the Gene Therapy market share.

This report focuses on the Gene Therapy in Global market, especially in

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The report gives detailed analysis in terms of qualitative and quantitative data pertaining to the projected potential opportunities that influence markets growth for the forecast period. With a major focus on the key elements and segments of the global Gene Therapy market that might affect the growth prospects of the market, making it a highly informative document.

Major Points covered in this Report:

Market Segmentation:

Regional market analysis

The content of the study subjects includes a total of 15 chapters:

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Gene Therapy Market to Witness Considerable Growth Owing to Extensive Demand & Rise in Industrialization by 2025 - Galus Australis

Studies by researchers at University of South Florida Health (USF Health) Morsani College of Medicine have found that a protein known as -arrestin2 increases the accumulation of the neurotoxic tau tangles that cause several forms of dementia, by interfering with the process that cells use to remove excess tau from the brain. The studies demonstrated that an oligomerized form of -arrestin2, but not monomeric -arrestin2, disrupted the process of autophagy, which would normally act to help rid cells of malformed proteins like disease-causing tau.

Encouragingly, in vivo studies showed that blocking -arrestin2 oligomerization suppressed disease-causing tau in a mouse model that develops a form of human frontotemporal lobar degeneration (FTLD) with dementia, a form of neurodegeneration that is characterized by tau accumulation and the formation of neurofibrillary tangles. Our research could lead to a new strategy to block tau pathology in FTLD, Alzheimers disease, and other related dementias, which ultimately destroys cognitive abilities such as reasoning, behavior, language, and memory, said Jung-A (Alexa) Woo, PhD, an assistant professor of molecular pharmacology and physiology and an investigator at the USF Health Byrd Alzheimers Center. Woo is lead author of the teams published paper in theProceedings of the National Academy of Sciences(PNAS), which is titled, -arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.

FTLD, which is also called frontotemporal dementia, is second only to Alzheimers disease (AD) as the leading cause of dementia. This aggressive form of dementia is typically earlier onset, in people aged 4565, and is characterized by atrophy of the front or side regions of the brain, or both. The two primary hallmarks of Alzheimers disease are clumps of amyloid-beta (A) protein fragments known as amyloid plaques, and the tangles of tau protein. Abnormal accumulations of both proteins are needed to drive the death neurons in Alzheimers, although recent research suggests that tau accumulation appears to be required for the toxic effects of A in AD, and correlates better with cognitive dysfunction than A. Indeed, tauopathy correlates significantly better than A with cognitive deficits in AD, the team noted, and drugs targeting A have been disappointing as a treatment.

Like Alzheimers disease, FTLD displays an accumulation of tau, which results in the formation of tau-laden neurofibrillary tangles that destroy synaptic communication between neurons, eventually killing the brain cells. There is no specific treatment or cure for FTLD. However, in contrast with AD, A aggregation is absent in the FTLD brain, in which the key feature of neurodegeneration appears to be the excessive tau accumulation, known as tauopathy. In contrast to AD, where amyloid is an integral part of the tangle, there is no accumulation of A in FTLD neurons , the authors noted.

Previous studies have pointed to an association between G protein-coupled receptors (GPCRs) and AD pathogenesis, and have linked the activation of several, diverse GPCRs with A and/or tau pathogenesis in animal models. While it isnt clear how these very different GPCRs can impact on A and tau pathogenesis, and neurodegeneration in AD, one potential commonality among the receptors is their interaction with arrestins, the researchers noted. Interestingly, previous studies have shown that one of the family of -arrestin proteins known as -arrestin2, is increased in AD brains, and genetic studies have shown that endogenous -arrestin2 promotes A production and deposition, linking -arrestin2 to A pathogenesis. Despite this evidence, the authors acknowledged, prior to the current work, however, it was not known whether, or how, -arrestin2 pathogenically impinges on tauopathy and neurodegeneration in AD, or in FTLD where there is no accumulation of A. As Woo commented, Studying FTLD gave us that window to study a key feature of both types of dementias, without the confusion of any A component.

-arrestin2 in its monomeric form is mostly known for its ability to regulate receptors, but -arrestin2 can also form multiple interconnecting units, called oligomers, and the function of -arrestin2 oligomers is not well understood. While the monomeric form was the basis for the laboratorys initial studies examining tau and its relationship with neurotransmission and receptors, Woo said, we soon became transfixed on these oligomers of -arrestin2.

The teams studies confirmed the presence of elevated -arrestin2 levels, both in cells from the brains of TFLD-tau patients, and in a mouse model. This model expresses disease-associated tau in neurons, and displays FTLD-like pathophysiology and behavior and, like FTLD in humans, doesnt accumulate A.

The researchers also found that -arrestin2 acts to increase tau stability via scaffolding potein:protein interactions. Their results indicated that when -arrestin2 is overexpressed, tau levels also increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau. As the authors commented, the data suggested that increased tau increases -arrestin2, which in turn acts to further potentiate tau-mediated events by stabilizing the protein, thus indicative of a vicious positive pathogenic feedback cycle.

To determine the effects of reducing -arrestin2 levels, the team crossed a mouse model of early tauopathy with genetically modified mice in which the -arrestin2 gene was inactivated. They demonstrated that genetic knockdown of -arrestin2 also reduced tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. Importantly, experiments confirmed that it was oligomerized -arrestin2, and not the proteins monomeric form, which was associated with increased tau. By blocking -arrestin2 molecules from binding together to create oligomerized forms of the protein, the investigators demonstrated that pathogenic tau significantly decreased when only monomeric -arrestin2, which does bind to receptors, was present.

Further experiments indicated that oligomerized -arrestin2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In effect, this reduces the efficiency of the autophagy process that would otherwise clear toxic tau. The resulting accumulation of tau clogs up the neurons. Blocking -arrestin2 oligomerization also suppressed disease-causing tau in the mouse model that develops human tauopathy with signs of dementia.

Specifically, our results indicate that -arrestin2 oligomers increase tau levels by blocking the self-interaction of p62, an initial step essential in p62-mediated autophagy flux, the team commented. Genetic reduction or ablation of -arrestin2 significantly decreased sarkosyl-insoluble tau and mitigated tauopathy in vivo. Furthermore, -arrestin2 mutants incapable of forming oligomersactually reduced insoluble tau.

It has always been puzzling why the brain cannot clear accumulating tau, said Stephen B. Liggett, MD, senior author and professor of medicine and medical engineering at the USF Health Morsani College of Medicine. It appears that an incidental interaction between -arrestin2 and the tau clearance mechanism occurs, leading to these dementias. -arrestin2 itself is not harmful, but this unanticipated interplay appears to be the basis for this mystery We also noted that decreasing -arrestin2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle, erasing the tau tangles like an eraser. This is something the field has been looking foran intervention that does no harm and reverses the disease.

The results point to a potential therapeutic strategy for tauopathies such as FTLD, based on partial inhibition of -arrestin2 oligomerization. For gene therapy of human FTLD-tau, mutants with a somewhat decreased capacity for such inhibition might be desirable, so that some levels of the oligomer are present to carry out other functions Similarly, small molecule inhibitors of -arrestin2 oligomerization, given for treatment or prevention of FTLD-tau, could be designed to spare complete loss of the oligomer in the cell, they suggested. Based on our findings, the effects of inhibiting -arrestin2 oligomerization would be expected to not only inhibit the development of new tau tangles, but also to clear existing tau accumulations due to this mechanism of enhancing tau clearance.

This treatment strategy could be both preventative for at-risk individuals and those with only mild cognitive impairment, and therapeutic in patients with evident FTLD-tau, by decreasing existing tau tangles. Beyond tauopathy, it is conceivable that this strategy could also prove to be beneficial in other neurodegenerative diseases bearing proteinopathies that are cleared via p62, the scientists concluded.

This study identifies beta-arrestin2 as a key culprit in the progressive accumulation of tau in brains of dementia patients, added co-author David Kang, PhD, professor of molecular medicine and director of basic research for the Byrd Alzheimers Center. It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting beta-arrestin oligomerization.

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Protein that Prevents Tau Clearance Linked to AD and Other Tau Tangle Proteinopathies - Clinical OMICs News

TEL AVIV, Israel, Feb. 20, 2020 (GLOBE NEWSWIRE) -- VBL Therapeutics (Nasdaq: VBLT) today announced the launch of a phase 2 clinical trial of VB-111 in combination with nivolumab (Opdivo), an immune checkpoint inhibitor, in the treatment of metastatic colorectal cancer. The National Cancer Institute (NCI) will serve as the Investigational New Drug (IND) sponsor for this study and the IND application has been approved by the U.S. Food and Drug Administration (FDA). This new study will investigate if priming with VB-111 can drive immune cells into the tumor and turn the colorectal tumor from immunologically cold to hot. The addition of nivolumab to VB-111 may further boost the anti-tumor immune response.

This phase 2 study is part of our strategy to broaden the potential indications for VB-111 and to explore its activity as part of combination therapies, said Dror Harats, M.D., Chief Executive Officer of VBL Therapeutics. We look forward to collaborating with NCI on this clinical trial, as we continue to generate data which adds to our understanding of VB-111s mechanism of action and therapeutic potential. We were particularly encouraged by results in ovarian cancer demonstrating the recruitment of infiltrating T cells into a tumor following treatment with VB-111, turning the tumor hot. This important finding suggests that VB-111 may be applied to other cold tumors, in which checkpoint inhibitors show limited or no efficacy, including colorectal cancer, for which there remains a major unmet need.

VBL and the NCI have entered into a Cooperative Research and Development Agreement (CRADA) under the direction of Tim F. Greten, M.D., Deputy Branch Chief & Senior Investigator of the Thoracic and GI Malignancies Branch (TGMB) and Co-Director of the NCI Center for Cancer Research (CCR) Liver Cancer Program. The goal of this open-label, single-arm phase 2 study is to evaluate VB-111 in combination with an anti-PD-1 inhibitor, nivolumab, in patients with metastatic colorectal cancer. In addition to safety and tolerability, this study will evaluate efficacy endpoints including Best Overall Response, as well as immunological and histologic readouts from tumor biopsies. For additional information refer to https://clinicaltrials.gov/show/NCT04166383.

For patients interested in enrolling in this clinical study, please contact NCIs toll-free number 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615) and/or the Web site: https://trials.cancer.gov

About VBLVascular Biogenics Ltd., operating as VBL Therapeutics, is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of first-in-class treatments for cancer. VBLs lead oncology product candidate, ofranergene obadenovec (VB-111), is a first-in-class, targeted anti-cancer gene-therapy agent that is being developed to treat a wide range of solid tumors. It is conveniently administered as an IV infusion once every two months. It has been observed to be well-tolerated in >300 cancer patients and demonstrated activity signals in a VBL-sponsored all comers phase 1 trial as well as in three VBL-sponsored tumor-specific phase 2 studies. Ofranergene obadenovec is currently being studied in a VBL-sponsored phase 3 potential registration trial for platinum-resistant ovarian cancer.

Forward Looking StatementsThis press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as anticipate, believe, could, estimate, expect, goal, intend, look forward to, may, plan, potential, predict, project, should, will, would and similar expressions. These forward-looking statements include, but are not limited to, statements regarding our programs, including VB-111, including their clinical development, such as the timing of clinical trials and expected announcement of data, therapeutic potential and clinical results, and our financial position and cash runway. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with research and development, clinical trials and related regulatory reviews and approvals, the risk that historical clinical trial results may not be predictive of future trial results, that our financial resources do not last for as long as anticipated, and that we may not realize the expected benefits of our intellectual property protection. A further list and description of these risks, uncertainties and other risks can be found in our regulatory filings with the U.S. Securities and Exchange Commission, including in our annual report on Form 20-F for the year ended December 31, 2018, and subsequent filings with the SEC. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. VBL Therapeutics undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.

INVESTOR CONTACT:

Michael RiceLifeSci Advisorsmrice@lifesciadvisors.com(646) 597-6979

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VBL Therapeutics Announces the Launch of a New Clinical Trial of VB-111 Combined with the Checkpoint Inhibitor, Nivolumab, in Metastatic Colorectal...

Viral Vector and Plasmid DNA Manufacturing Market

Facts and Factors Market Researchhas published a new report titled Viral Vector and Plasmid DNA Manufacturing Market By Product (Viral Vectors and Plasmid), By End-User (Biopharmaceutical Companies and Research Institutes), and By Application (Gene & Cancer Therapies, Formulation Development, Viral Infections, and Immunotherapy): Global Industry Perspective, Comprehensive Analysis, and Forecast, 2018 2027. According to the report, the globalviral vector and plasmid DNA manufacturing marketwas valued at approximately USD 418 million in 2018 and is expected to reach a value of around USD 2,237 million by 2027, at a CAGR of around 20.5 % between 2019 and 2027.

Viral vectors are altered viruses that are utilized for inserting genetic material into a cell that can be manipulated for the purpose of healing. These viral vectors prevent the new gene from getting degraded through the delivery of gene castle in the targeted cell. The latter makes use of the new gene to carry out its function. Various kinds of viral vectors include adenoviruses, lentiviruses, and adeno-associated viruses.

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Plasmid DNA gene is utilized for the purpose of cloning, transferring, and manipulating the gene. The key qualities of plasmid include easy working with self-replicating and stability. They are mainly utilized for understanding the gene function and examining RNAs and other genetic material. Plasmid DNA is sectored into conjugative plasmids and non-conjugative plasmids.

Growing occurrence of chronic ailments to drive the market trends

A prominent rise in the aging population prone to chronic disorders along with an increase in incidences of chronic diseases is likely to upsurge the growth of viral vector and plasmid DNA manufacturing industry over the forecast timeline. Moreover, gene therapy offers major treatment facilities for chronic ailments like cancer, inherited diseases, and viral infections.

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Furthermore, the rise in the allocation of funds by private firms on research activities is predicted to drive the market expansion over the forecast timespan. Apart from this, manufacturers are implementing new techniques such as cell line culture development, expression systems, and cell culture system for effectively handling activities related to viral-based vector development. All these factors will upsurge market growth during the forecast period. Nonetheless, the risk of mutagenesis & other obstructions in gene therapy as well as huge costs associated with gene treatment will put brakes on the growth of the market over the forecast period.

Gene & Cancer therapies segment to dominate the application landscape over the forecast period

The growth of the segment is attributed to the rise in the number of gene & cancer therapy subjects along with rapid clinical growth. Apart from this, viral vectors are used for developing gene and T-cell therapies and this will further steer the segmental growth.

Research Institutes to contribute majorly towards the overall market revenue by 2027

The growth of the research institutes segment is attributed to the rise in the research & development activities for launching new therapies to treat chronic ailments like cancer.

North America to dominate the overall regional market growth in terms of revenue by 2027

The growth of the market in the region over the forecast period is due to large-scale government assistance for carrying research activities along with the presence of biopharmaceutical firms in North America. The U.S. is likely to be the regional revenue driver during the forecast timeline.

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Some of the key players in the viral vector and plasmid DNA manufacturing business include Kaneka Corporation (Eurogentec), Cobra Biologics, VGXI, Inc., DNA manufacturing market include Lonza, FUJIFILM Diosynth Biotechnologies Inc., Genzyme Corporation, Vigene Biosciences Inc., Brammer Bio, Oxford Gene Technology, SIRION Biotech GmbH, FinVector Vision Therapies, VIROVEK, Novasep, SPARK THERAPEUTICS, INC., ALDEVRON, and General Electric Company (GE Healthcare).

This report segments the viral vector and plasmid DNA manufacturing market as follows:

Global Viral Vector and Plasmid DNA ManufacturingMarket: By Product Segment Analysis

Global Viral Vector and Plasmid DNA ManufacturingMarket: By End-User Segment Analysis

Global Viral Vector and Plasmid DNA ManufacturingMarket: ByApplicationSegment Analysis

GlobalViral Vector and Plasmid DNA ManufacturingMarket: Regional Segment Analysis

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Facts & Factors is a leading market research organization offering industry expertise and scrupulous consulting services to clients for their business development. The reports and services offered by Facts and Factors are used by prestigious academic institutions, start-ups, and companies globally to measure and understand the changing international and regional business backgrounds. Our clients/customers conviction on our solutions and services has pushed us in delivering always the best. Our advanced research solutions have helped them in appropriate decision-making and guidance for strategies to expand their business.

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Global Viral Vector and Plasmid DNA Manufacturing Market to be Worth $2,237 Million by 2027 | CAGR 20.50% - Global Newspaper 24

A PHOTOGRAPHY exhibition showcasing ground-breaking NHS research taking place across the Thames Valley has been launched in Oxford.

TitledThe Body Unlocked: How Research is Changing Lives, it features life-sized photographs of people who have taken part in studies, researchers at work and microscopic images of cells and bacteria.

Images include surgeons preparing a pioneering gene therapy injection for vision loss, dogs smelling urine to detect cancer, a close-up of cells responsible for controlling blood sugar and a virtual reality headset to treat mental illnesses.

The exhibition can be seen for the next two months at Oxfords Covered Market, in the windows of a unit opposite Wicked Chocolate.

ALSO READ: Scientists working on a coronavirus vaccine in Oxford

Among those featured in the exhibition are dementia study participants Barry and Enid Reeves, of Abingdon, who have been married for 70 years.

The couple, both 91, volunteered for the study at Oxford Health NHS Foundation Trust after Mrs Reeves was diagnosed with Alzheimers disease in 2016. Her husband said: Weve become closer as a consequence of her diagnosis because I have become her carer now. The study is not for our benefit particularly, we took part to help others.

In 2018/19, there were 1,930 studies involving 39,129 participants at Oxford University Hospitals NHS Foundation Trust, which manages the John Radcliffe Hospital, Churchill Hospital and Nuffield Orthopaedic Centre in Oxford and Banburys Horton General Hospital.

Professor Keith Channon, director of research and development at the trust, said: Oxford is one of the UKs leading centres for healthcare research, often leading the world in specialties as diverse as neuroscience, cancer, cardiology, diabetes or surgery and delivering improvements in diagnosis and treatment for NHS patients.

ALSO READ: Scientists to share latest dementia research at open day

That research, and the ability to push forward our knowledge of different health conditions, is critically dependent on the participation of many thousands of patients and members of the public from across the region.

We hope that this exhibition, which showcases examples of the ground-breaking research that takes place here, highlights the contributions of patients and members of the public and encourages them to get involved in research studies.

After the Covered Market, the exhibition will travel around the Thames Valley to be displayed at other venues. To find out more visit thebodyunlocked.info.

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Photo exhibition at Covered Market showcases science research - Oxford Mail

Newark, NJ, Feb. 20, 2020 (GLOBE NEWSWIRE) -- As per the report published by Fior Markets, theglobal veterinary x-ray market is expected to grow from USD 651.07 Million in 2017 to USD 1,167.47 Million by 2025 at a CAGR of 7.81% during the forecast period from 2018-2025.

Radiology systems are the most preferred diagnostic tools a veterinarian uses to diagnose diseases in animals. It contains of diagnostic medical descriptions including ultrasound, magnetic resonance tomography, magnetic resonance imaging and atomic imaging. This is a non-invasive way to diagnose the disease. It is a painless procedure, however, animals are often anesthetized to reduce anxiety and stress during the procedure. The rise in the number of pets and the increase in awareness about the well-being of pets is driving the growth of this sector. According to the American Pet Products Association, in 2016, American families had approximately 35% of cats and 44% of dogs, making them around 85.8 million cats and 78 million dogs owned by the United States

The global market for veterinary X-rays is expected to grow rapidly during the forecast period, due to the increasing incidence of animal bone diseases, the increasing number of pets around the world, and the increase in the number of veterinary practitioners worldwide, as it is the main factor driving the market. The high cost of veterinary X-ray tools and the shortage of skilled veterinary technicians may limit market growth. However, high levels of pet insurance may boost future market opportunities.

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Key players operating in the global veterinary X-ray market are IDEXX Laboratories, Fujifilm, Onex Corporation, Agfa-Gevaert Group, Sound Technologies, Sedecal, Examion, Canon, DRE Veterinary, Heska Corporation, Fovea, Clearvet, Control-X Medical, Allpro Imaging, Vetel Diagnostics, Pixxgen and Konica Minolta among others. To enhance their market position in the global veterinary X-ray market, the key players are now focusing on adopting the strategies such as recent developments, product innovation, joint venture, mergers & acquisitions, collaborations, and partnership. Major firms are increasingly investing on research and development activities and development of newer products.

Computed radiography systems is dominating the segment and was valued around USD 286.44 Million in 2017

The technology segment is classified into computed radiography systems segment, direct radiography systems and film-based radiography systems. Computed radiography systems is dominating the segment and was valued around USD 286.44 Million in 2017. Increasing demand for affordable digital X-ray equipment and benefits offered by CR systems over other technologies are contributing for the growth of the segment.

The digital X-rays segment held the largest share of around 56.31% in 2017

Type section includes digital X-rays and analog X-rays. The digital X-rays segment held the largest share of around 56.31% in 2017. X-ray systems offer various benefits over analog systems, which include less costly, improved efficiency, and patient-centric imaging are some of the factors driving the growth of the segment.

The Stationary X-Ray Systems segment is dominated and expected to witness the highest market share of 56 % in the forecast period

The segment is classified into stationary x-ray systems and portable x-ray systems. The stationary x-ray systems is dominated and expected to witness the highest market share of 56% in the forecast period. While new technology advancement and rising use of portable x-ray systems are boosting this segment.

The small companion animals segment is dominated and is expected to held largest share of 61.17% in 2017

Animal type segment includes small companion animals and large animals. The small companion animals segment is dominated and is expected to held largest share of 61.17% in 2017. Increased adoption of pets, growing companionship and demand of highly accurate diagnostic solutions are boosting the growth of the segment.

The orthopedic & trauma segment is dominating and was valued around USD 214.83 million in 2017

Application segment is bifurcated into orthopedics & trauma, dental applications, oncology and other applications. Orthopedic & trauma segment is dominating and was valued around USD 214.83 million in 2017 due to increase in injuries among animals and availability of animal care facilities are contributing to the growth of the segment.

The veterinary hospitals & academic institutes segment is anticipated to grow with the highest CAGR of 9.14% in the forecast period

End user section includes veterinary hospitals & academic institutes and veterinary clinics. The veterinary hospitals & academic institutes segment is anticipated to grow with the highest CAGR of 9.14% in the forecast period. The growth can be accredited to developments in technologies for cost-effective, fast and precise diagnostic tools for animal healthcare.

Browse full report with TOC athttps://www.fiormarkets.com/report/global-veterinary-x-ray-market-by-technology-type-direct-376062.html

Regional Segment Analysis of the Veterinary X-ray market

The regions analysed for the market include North America, Europe, South America, Asia Pacific, and Middle East and Africa. North America region captured the largest share of global veterinary X-ray market and was valued in USD 318.99 Million in 2017 whereas Asia pacific is expected to attain the lucrative growth in the forecast period. North America region is expected to dominate the market due to pet adoption coupled with increasing healthcare expenditure and increase in R&D with growing demand for veterinary equipment. Asia pacific is expected to register the highest growth in the forecast period owing to growing demand for veterinary products and availability of low-cost animal health products are anticipated to drive the growth. Figured radiography and film-based radiography are inexpensive in this region as compared to industrialised regions.

About the report:

The global veterinary x-ray market is analysed on the basis of value (USD Million). All the segments have been analyzed on global, regional and country basis. The study includes the analysis of more than 30 countries for each segment. The report offers an in-depth analysis of driving factors, opportunities, restraints, and challenges for gaining the key insight of the market. The study includes porters five forces model, attractiveness analysis, raw material analysis, supply, demand analysis, competitor position grid analysis, distribution and marketing channels analysis.

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Global Veterinary X-ray Market is Expected to Reach USD 1,167.47 Million by 2025 : Fior Markets - GlobeNewswire

GlobalSandhoff disease treatment marketis growing at a steady CAGR in the forecast period of 2019-2026. The report contains data of the base year 2018 and historic year 2017. This rise in market value can be attributed to the orphan drug designation to novel drugs, along with the increasing investment of biotechnology and pharmaceutical industries in R&D.

The key market players in the Sandhoff disease treatment market areIntrabio, Axovant Gene Therapies Ltd among others

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With the market info provided in the Sandhoff Disease Treatment Market report, it has become easy to gain global perspective for the international business. Focus groups and in-depth interviews are included for qualitative analysis whereas customer survey and analysis of secondary data has been carried out under quantitative analysis. This market analysis report acts as a very significant constituent of business strategy. It is a definite study of the Healthcare industry which explains what the market definition, classifications, applications, engagements, and global industry trends are. Sandhoff Disease Treatment Market business document proves to be a sure aspect to help grow the business.

Market Definition: Global Sandhoff Disease Treatment Market

Sandhoff diseaseis also known as Beta-hexosaminidase-beta-subunit deficiency is a fatal pediatric lysosomal storage genetic disorder characterized by progressively destruction of neuron in the brain and spinal cord. It is caused by defects in HEXB gene which is responsible for regulation of vital enzyme called beta-hexosaminidase, as a result of accumulation of lipid called G2 gangliosides. This ongoing accumulation of lipid affects the function of the nerve cells and causes other neurological problem.

Segmentation:Global Sandhoff Disease Treatment Market

Sandhoff Disease Treatment Market : By Types

Sandhoff Disease Treatment Market : ByTherapy

Sandhoff Disease Treatment Market : By Treatment

Sandhoff Disease Treatment Market : By Drugs

Sandhoff Disease Treatment Market : ByRoute of Administration

Sandhoff Disease Treatment Market : By Distribution Channel

Sandhoff Disease Treatment Market : By End-Users

Sandhoff Disease Treatment Market : By Geography

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Key Developments in the Sandhoff Disease Treatment Market

Sandhoff Disease Treatment Market Drivers

Sandhoff Disease Treatment Market Restraints

Sandhoff Disease Treatment Market : Competitive Analysis

Global Sandhoff disease treatment market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of Sandhoff disease treatment for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Opportunities in the Sandhoff Disease Treatment Market :-

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Sandhoff Disease Treatment Market 2020-2026 Boosting the Growth Worldwide || Leading Players Intrabio, Axovant Gene Therapies Ltd - News Times

Global CNS Gene Therapy Market From PMRs Viewpoint

Decorated with a team of 300+ analysts, PMR Insights serves each and every requirement of the clients while preparing market reports. With digital intelligence solutions, we offer actionable insights to our customers that help them in overcoming market challenges. Our dedicated team of professionals perform an extensive survey for gathering accurate information associated with the market.

PMR, in its latest business report elaborates the current situation of the global CNS Gene Therapy market in terms of volume (x units), value (Mn/Bn USD), production, and consumption. The report scrutinizes the market into various segments, end uses, regions and players on the basis of demand pattern, and future prospect.

In this CNS Gene Therapy market study, the following years are considered to project the market footprint:

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On the basis of product type, the global CNS Gene Therapy market report covers the key segments,

key players and product offerings

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CNS Gene Therapy market players Player 1, Player 2, Player 3, and Player 4, among others represent the global CNS Gene Therapy market. The market study depicts an extensive analysis of all the players running in the CNS Gene Therapy market report based on distribution channels, local network, innovative launches, industrial penetration, production methods, and revenue generation. Further, the market strategies, and mergers & acquisitions associated with the players are enclosed in the CNS Gene Therapy market report.

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CNS Gene Therapy Market Growth Factors, Applications, Regional Analysis, Key Players and Forecasts by 2026 - Jewish Life News

WASHINGTON, D.C., Feb. 13, 2020 (GLOBE NEWSWIRE) -- via NEWMEDIAWIRE -- The Alliance for Regenerative Medicine (ARM), the international advocacy organization representing the cell and gene therapy and broader regenerative medicine sector, today released the agenda for its second annual Cell & Gene Meeting on the Mediterranean. The event will be held from April 15-17, 2020 in Barcelona, Spain.

The event, modeled after ARMs highly successful Cell & Gene Meeting on the Mesa, is expected to attract more than 500 attendees, including senior executives from leading cell therapy, gene therapy, and tissue engineering companies worldwide, large pharma and biotech representatives, institutional investors, academic research institutions, patient foundations, disease philanthropies, and members of the life science media community.

The agenda includes:

Plenary Session:

Keynote Address:

Panels:

Throughout the two-day event, participants can also attend presentations by more than 50 publicly traded and emerging private companies, highlighting clinical and commercial progress in cell therapy, gene and gene-modified cell therapy, tissue engineering, biomaterials and more. In addition to their presentations, representatives from these organizations will also be available for one-on-one partnering opportunities throughout the conference.

2020 presenting companies include:Adaptimmune, AGTC, Ambys Medicines, AskBio, Aspect Biosystems, Atara Biotherapeutics, Autolus Therapeutics, Avectas, AVROBIO, Axovant Gene Therapies, bluebird bio, Bone Therapeutics, Cabaletta Bio, Caribou Biosciences, Celavie Biosciences, Cellatoz Therapeutics, Cellect Biotherapeutics, CEVEC, Cryoport, Cynata Therapeutics, Flexion Therapeutics, Fraunhofer IZI, Genethon, GenSight Biologics, Healios, Iovance Biotherapeutics, Kiadis Pharma, Kytopen, LogicBio Therapeutics, MeiraGTx, Minerva Biotechnologies, MolMed, Novadip Biosciences, Orchard Therapeutics, Oxford Biomedica, PDC*line Pharma, Polyplus-transfection, Precision BioSciences, Promethera Biosciences, PTC Therapeutics, Recombinetics, REGENXBIO, ReNeuron, Rexgenero, Sangamo, SmartPharm Therapeutics, Standards Coordinating Body for Regenerative Medicine, Theradaptive, ThermoGenesis, Tmunity Therapeutics, Ultragenyx Pharmaceutical, VERIGRAFT, and Vineti.

For full details on the agenda and further information about the event, please visit http://www.meetingonthemed.com.

Registration is complimentary for credentialed members of the media. For members of the media interested in attending, please contact Kaitlyn Donaldson Dupont at kdonaldson@alliancerm.org or Consilium Strategic Communications at ARM@consilium-comms.com.

About the Alliance for Regenerative Medicine

The Alliance for Regenerative Medicine (ARM) is an international multi-stakeholder advocacy organization that promotes legislative, regulatory, and reimbursement initiatives necessary to facilitate access to life-giving advances in regenerative medicine worldwide. Founded in 2009, ARM works to increase public understanding of the field and its potential to transform human healthcare, providing business development and investor outreach services to support the growth of its 350+ member organizations worldwide. ARM represents the interests of therapeutic developers, academic research institutions, major medical centers, investors, and patient groups that comprise the broader regenerative medicine community and is the prominent international advocacy organization in this field.

ARM has 70+ members across 15 countries in Europe. ARM aims to work closely with European stakeholders, leveraging its membership to create a supportive commercial and regulatory environment to create better conditions for the development and commercialization of ATMPs in Europe; develop strong stakeholder support around proposed solutions to improve patient access to ATMPs; promote clear, predictable and efficient regulatory framework across Europe; and promote international convergence of key regulations and guidance. For more information, visit alliancerm.org.

Kaitlyn Donaldson Dupont8037278346kdonaldson@alliancerm.org

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The Alliance for Regenerative Medicine Releases Agenda for 2020 Cell & Gene Meeting on the Mediterranean - Yahoo Finance

The world is watching with alarm as China struggles to contain a dangerous new virus, now being called SARS-CoV-2. It has quarantined entire cities, and the US has put a blanket ban on travellers whove been there. Health officials are scrambling to understand how the virus is transmitted and how to treat patients.

But in one University of North Carolina lab, theres a different race. Researchers are trying to create a copy of the virus. From scratch.

Led by Ralph Baric, an expert in coronaviruseswhich get their name from the crown-shaped spike they use to enter human cellsthe North Carolina team expects to recreate the virus starting only from computer readouts of its genetic sequence posted online by Chinese labs last month.

The remarkable ability to boot up viruses from genetic instructions is made possible by companies that manufacture custom DNA molecules, such as Integrated DNA Technology, Twist Bioscience, and Atum. By ordering the right genes, which cost a few thousand dollars, and then stitching them together to create a copy of the coronavirus genome, its possible to inject the genetic material into cells and jump-start the virus to life.

The ability to make a lethal virus from mail-order DNA was first demonstrated 20 years ago. Its enough of a bioterrorism concern that companies carefully monitor who is ordering which genes. But its also an important way to respond to a sudden outbreak, since synthetic virus recipes give researchers powerful ways to study treatments, vaccines, and how mutations could make it more dangerous.

When a synthetic virus is better than the real thing

Barics North Carolina lab, which specializes in engineering viruses, has previously butted heads with Washington agencies over the work, which has included synthesizing new, never before seen coronaviruses that can infect mice. In 2014, the National Institutes of Health froze funding to several labs, including Barics, over concerns that such research was too risky. The funding was later reinstated.

For the China virus, Baric said in a telephone interview, his team placed an order for matching DNA from a manufacturer last month. Their first step was to go online and look at genetic sequences of the virus. They then compared several available sequences, which differ slightly, and picked a consensus version to have manufactured.

Once Baric gets his DNA, something that could take a month, he plans to inject the genetic instructions into cells. If things go as planned, the cells should begin making actual infectious viral particles.

CDC

By rolling their own germs, scientists can get hold of viruses even if they cant obtain them directly from a country, especially one thats in the grip of an epidemic. Baric says so far samples of the live virus from patients have not been made widely available from China. This is the future in terms of how the medical research community responds to a new threat, says Baric.

The real virus and the synthetic one should be basically identical. But with the synthetic one, we have a DNA copy that we can go back to over and over and over again, to make genetically identical viruses, says Timothy Sheahan, a researcher at UNC who works with Baric. Starting from these copies, scientists can remove genes, add others, and figure out things like what makes the germ spread and how it gains access to human cells. Sheahan wants to try infecting mice with the virus and giving them various drugs to see what stops it.

Artificial copies may also help scientists keep up with the outbreaks unpredictable path. I worry this virus is going to mutate in the course of the epidemic, and this would allow me to study what effects those mutations have, says Stanley Perlman, a microbiologist who works on coronaviruses at the University of Iowa. The synthetic virus is just a substitute for the actual virus, but with the DNA clone you can manipulate it and find the weak points and develop a therapy.

During past outbreaks, scientists would have had to wait months or years to get a look at the germ behind an outbreak. But with SARS-CoV-2 it took only weeks until its genetic sequence was posted online. Immediately, some scientists began analyzing the genetic data, comparing it to viruses from bats, snakes and pangolins; they concluded it could have begun circulating last November.

Biotech companies, governments, and universities also quickly started ordering physical copies of particular genes found in the virus. DNA manufacturers say they have been deluged with orders for virus parts, including those useful for verifying diagnostic tests and others needed to make potential vaccines.

Its been a pretty dramatic uptick, starting with the publication of the genome, says Adam Clore, technical director of synthetic biology at IDT, based in Iowa, and one of the worlds largest sellers of DNA. Its high priority. There are a number of institutions that are devoting nearly all their energy working on detection or vaccines.

Still, most researchers need only one or two genes from the virus to carry forward work on tests and vaccines. Barics lab in North Carolina is the only one in the US known to be trying to re-create the virus completely from ordered DNA parts.

How to keep deadly viruses out of the wrong hands

It was in the early 2000s that scientists first showed that synthetic DNA strands could be used to resurrect viruses just from their genetic code. A team in New York State did it with polio, producing infectious material from DNA they ordered online.

The technology immediately created bio-weapon worries. What if terrorists used the technique to resurrect smallpox? That hasnt happened, but it does mean that scourges like polio, smallpoxand now the Chinese coronaviruscannot now ever be truly wiped out. Researchers at the US Centers for Disease Control and Prevention (CDC) drove that point home in 2005 when they resurrected the influenza virus that killed tens of millions in 1918-1919.

To keep the technology out of the hands of evil-doers, companies that manufacture DNA banded together a few years ago to limit access to dangerous genes. The big US players have all agreed to compare incoming DNA orders to a database of about 60 lethal germs and toxins called select agents so that only authorized labs can ever obtain the DNA needed to resurrect them.

CDC

At our request, Battelle, a scientific R&D company whose software ThreatSEQ can make those comparisons, ran the scenario of someone trying to order a copy of SARS-CoV-2. According to Craig Bartling, a senior research scientist at Battelle, the software flagged both the entire virus, and most of its genes individually, at the highest threat level. Bartling says the alerts went off because the virus is highly similar to the original SARS, a related virus that sparked a global outbreak starting in 2002.

Research into the new virus is seen as risky enough that manufacturers of DNA hurried last week to meet and formulate a policy about who should be able buy complete versions of the new germs genome. In a statement released on February 11, the International Gene Synthesis Consortium, a trade group, struck a cautious position. It said it would treat the new Chinese virus as if it were SARS, a germ added to the select agent list in 2012 and whose possession is tightly monitored by the US government.

That means anyone who wants a complete synthetic copy of SARS-CoV-2 would need to undergo specific and detailed vetting and prove they are already registered by the CDC to work with SARS, as the North Carolina researchers are.

However, companies that manufacture DNA still have discretion over what they sell and to whom, and not all of them think they should make the whole genome of this virus. Claes Gustaffson, founder and chief commercial officer of Atum, a DNA supplier in California, says hes gotten orders from eight companies for parts of the virus genome and has personally approved a request by a US government agency to make 90% of its geneslikely to create an attenuated (i.e., harmless) version of it.

They probably want to figure out how to make a vaccine as quickly as possible, says Gustaffson. But if someone wanted the whole thing, I wouldnt make it. Some things, like polio, you dont want to make, no matter who is asking.

UNC Gillings School of Public Health

Not everyone thinks synthesizing the new coronavirus is particularly dangerous. I dont really see a huge amount of risk, says Nicholas G. Evans, who studies biothreats at the University of Massachusetts, Lowell. Right now, a lot of people are spending a lot of time on how this coronavirus works. I think the risks are outweighed by the benefits.

The outbreak, which appears to have begun in a live animal market in the city of Wuhan, had caused more than 64,000 cases and 1,350 deaths in China by February 14, so its even worse than SARS, which killed 774 people.

Still, the US has not yet declared the new virus to be a select agent. According to Baric, the decision to add a new virus to the most-dangerous list is not made in the expanding outbreak, because it slows down research.

Scaring people

For now, only a very few sophisticated centers can actually re-boot a virus; theres no chance a nut working from a garage could do it. We are at the point where the best of the best can start to synthesize this new virus contemporaneously with the outbreak. But that is just a few labs, says Evans. Fortunately, we are still far from the point when lots of people can synthesize anything.

The advanced state of synthetic virus research, and the ability to genetically engineer germs, inevitably feeds fears, and conspiracy theories. Social media and some blog sites have been full of groundless speculation that the new virus was accidentally released from a Chinese bioweapon lab located outside of Wuhan. Theres no evidence that is the case, and substantial evidence it is not, but the rumor caused a diplomatic breach with China after it was repeated in the US Congress by a senator, Tom Cotton of Arkansas.

Baric says he doesnt see a particular danger to synthesizing the new virus at this stage of the outbreak, especially because the virus is still circulating in the wild. The important thing is to figure out what it does and stop it. Whether you get it from a cell or synthesize it, it ends up the same thing, says Baric.

Continued here:
Biologists rush to re-create the China coronavirus from its DNA code - MIT Technology Review

Global Viral Vector & Plasmid DNA Manufacturing Market 2019 by Company, Regions, Type and Application, Forecast to 2024 is the most recent research report launched by MarketsandResearch.biz breaks major business segments and highlights wider level geographies to get deep-dive analysis on market data. The report incorporates comprehensive data along with type, end-use industry, and region. The report is a perfect balance that comprises bridging both qualitative and quantitative information of the global Viral Vector & Plasmid DNA Manufacturing market. The study provides valuable market size data for historical (Volume & Value) from 2014 to 2019 which is estimated and forecasted till 2024.

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Market Fragmentation:

The report helps with terms of the emerging patterns and odds of advancement in the business. It also assists in deciding every one of the remarkable obstacles to improvement alongside identifying the patterns inside different utilization areas of the Global Viral Vector & Plasmid DNA Manufacturing market. Further, the report presents a graphical proportion of the market condition just as the compound yearly development rate (CAGR). Based on the type of product, the market report displays the production, income, price, market share, and growth rate of each type. On the basis of end users/applications, the market report focuses on the status and prospects of the main applications/end users, sales volume, market share, and growth rate of each application.

An outline of the manufacturers active in the global Viral Vector & Plasmid DNA Manufacturing market, consisting of Merck, Cobra Biologics, Waisman Biomanufacturing, uniQure, Novasep, The Cell and Gene Therapy Catapult, Creative Biogene, Addgene, Aldevron,

This research report also states import/export data, industry supply, and consumption figures as well as cost structure, price, industry revenue (Million USD) and gross margin by regions like North America (United States, Canada and Mexico), Europe (Germany, France, UK, Russia and Italy), Asia-Pacific (China, Japan, Korea, India and Southeast Asia), South America (Brazil, Argentina, Colombia etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa)

Most important types of products covered in this report are: Adenovirus, Retrovirus, Plasmid DNA, Others

Most widely used downstream fields of market covered in this report are: Biopharmaceutical Companies, Research Institutes,

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The report delivers comprehensive information on the major competitors formally developed as well as development associations with a significant market value in terms of sales, size, share, demand, forecast, supply, manufacture analysis, and demand ratio. Industry players are planning to introduce new products to launch around the globe considering applications/end-use.

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Global Viral Vector & Plasmid DNA Manufacturing Market 2019 Industry Research, Segmentation, Key Players Analysis and Forecast to 2024 - Nyse...

Millions of people are affected by blood disorders, and the prevalence is expected to grow as our population ages.

It is not surprising that, according to the American Society of Hematology, the FDA approved several new therapies or new indications for previously approved therapies in 2019 for people living with non-malignant blood disorders. Those included two disease-modifying treatments for sickle cell disease and the first anticoagulant for venous thromboembolism management in children.

In the wings and poised to reshape the treatment landscape for hematologic disorders are two potential blockbuster drugs - Valrox (valoctocogene roxaparvovec) for hemophilia A and vadadustat for anemia related to chronic kidney disease - that are among the 11 included in the Cortellis Drugs to Watch analysis predicted to achieve annual sales of $1 billion by 2024.

Hemophilia A

Hemophilia A, also called factor VIII (FVIII) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. People with that disorder are at risk for painful and/or potentially life-threatening bleeds from even modest injuries. According to the U.S. CDC, the condition occurs in approximately one in 5,000 live births, and about 20,000 people are living with hemophilia in the U.S. Accurate data on the worldwide incidence of hemophilia is estimated at more than 400,000.

People suffering from the most severe form of hemophilia A often experience painful, spontaneous bleeds into their muscles or joints and that group makes up approximately 43% of the hemophilia A population. The standard of care (SOC) for such individuals is a prophylactic regimen of replacement factor VIII infusions administered intravenously up to two to three times per week or 100 to 150 infusions per year. Despite those treatments, many people continue to experience bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

One and done treatment

San Rafael, Calif.-based Biomarin Pharmaceutical Inc. has submitted a BLA to the FDA for its investigational AAV gene therapy, Valrox, for adults with hemophilia A. The therapy is designed to deliver functional copies of the FVIII gene into patients cells, enabling them to make the previously missing or defective FVIII protein. If approved, Valrox would be the first potentially curative (one and done) approach to hemophilia A, eliminating the need for blood transfusions and FVIII replacement therapy after a single infusion. Subject to completion of the agency's filing review, the company anticipates the BLA review to start in February.

The FDA has granted breakthrough therapy and orphan drug designations; and the EMA has validated the company's marketing authorization application with the review under accelerated assessment.

According to the Cortellis Drugs to Watch analysis, the filings were based on interim data from the phase III GENEr8-1 study as well as three-year phase I/II trial data. In GENEr8-1, Valrox met the prespecified criteria for U.S. and EU regulatory review, with eight patients in a 20-patient cohort achieving FVIII levels of at least 40 IU/dl at 23 to 26 weeks; the ongoing trial has the goal of evaluating superiority of Valrox to the current standard of care, prophylactic therapy. The high-dose cohort in the phase I/II study showed 100% resolution of target joints, a 96% reduction in mean annualized FVIII usage, and all patients remained off FVIII prophylaxis. No thrombotic events or development of FVIII inhibitors have been reported to date.

Transformative for patients

"People with severe hemophilia A continue to experience clinically relevant breakthrough bleeds despite the current standard of care and can be limited in their physical activities," noted John Pasi, chief investigator for the phase I/II study and a principal investigator for the phase III study. "Valoctocogene roxaparvovec represents a potentially transformative investigative therapy that could improve patients' quality of life, including consequences of bleeding, physical functioning, role functioning, emotional impact, treatment concern and worry."

In January, the company published three years of follow-up data in the phase I/II study showing the median use of exogenous factor VIII at the 6e13-vg/kg dose was reduced from 138.5 infusions per year to zero infusions per year in year three. In the year before study entry, the mean annualized number of factor VIII infusions per participant was 136.7+22.4; at the end of year three, the mean annualized use of exogenous factor VIII decreased by 96% to a mean of 5.5+9.4 infusions.

"As a treating physician, I am excited about the potential of the field of gene therapy to make a meaningful difference in the lives of people with hemophilia A," Pasi noted on the results.

First-mover advantage

In a presentation at the annual J.P. Morgan Healthcare Conference in January 2020, Biomarin Chairman and CEO Jean-Jacques Bienaime was excited to reveal that the company is ramping up productivity at its Novato, Calif., plant, more than doubling its capacity to 10,000 doses annually. He noted that the capacity upgrade is important as the firm wants to be able to supply the gene therapy market as quickly as possible "because first-mover advantage in gene therapy is fundamental in a sense that every time you treat a patient that patient is off the market."

Gene therapy certainly has the potential to revolutionize treatment for patients with hemophilia A. However, according to the Canadian Hemophilia Society, Never have so many coagulation therapies been in development. In addition to the large number of therapies recently introduced, we have identified another 18 new therapies in development or soon to be marketed, including six clotting factor concentrates, four bypassing therapies to treat patients with inhibitors, two non-factor coagulation products and five gene therapy products.

If approved, Valrox will certainly face competition from well-established FVIII replacement therapies, in addition to those that are nearing the market, the Cortellis analysis suggests.

Recently approved therapies such as Roche Holding AG's Hemlibra (emicizumab) and Bayer AG's Jivi (antihemophilic factor [recombinant] pegylated) are improving the options available to those patients. The hemophilia market is conservative in adopting new therapies, the analysis notes, and patients may be reluctant to switch to new products if their current replacement therapy works well. However, an unmet need remains, as approximately 75% of hemophilia A patients do not respond adequately to their treatment or even do not receive treatment at all. Despite a relatively low worldwide prevalence of patients, with orphan pricing, hemophilia A represents a large market.

In addition, Valrox is not without its own challenges, the Cortellis analysis notes. The drug fell short in the initial cohort of the phase III GENEr8-1 trial: of 17 evaluable patients, three failed to achieve FVIII levels above 5 IU/dl. The mean and median FVIII levels across the cohort were also lower than seen in phase I/II, at 33 and 36 IU/dl, respectively. Failure to improve the response once full data are available may impact the potential commercial uptake

The market

The global market for hemophilia A last year was estimated to be close to $10 billion, and Bienaime in his presentation said that an estimated 121,000 patients are located in the territories covered by the company. Although no pricing has yet been set for the gene therapy, the company has done a lot of payer research. He indicated that payers attribute a high value to the physiological correction of hemophilia A, and it appears the U.S. payer community would be comfortable with a price between $2 million and $3 million.

Given the fact that wholesale acquisition pricing for Hemlibra in non-inhibitor adult patients is between $600,000 to $800,000 per year, Biomarin has looked at pricing of between $1 million and $5 million. Since by launch date it will have four years of data on Valrox, the price could be set at four times the average price of Hemlibra ($700,000), establishing a price of $2.8 million. That would make it the most expensive one-time therapy, topping spinal muscular atrophy gene therapy Zolgensma (onasemnogene abeparvovec-xioi) from Novartis AG at $2.1 million. The company says that this first gene therapy for any form of inherited hemophilia could save health care systems more than $20 million over a typical patients lifetime.

For that reason, even if the penetration is modest, Valrox could post significant revenue. The Cortellis analysis predicts sales of $17.45 million forecast for this year, rising to $1.297 billion in 2024. However, while Biomarin is in the pole position with its gene therapy, potential competition in the pipeline from FVIII gene therapies in development may temper sales forecasts in the mid- to long term. Spark Therapeutics Inc.'s SPK-8011 entered phase III development in February 2019, having shown a 94% reduction in bleeds and a 95% reduction in FVIII infusions in a previous phase I/II study. Other direct competitors in phase I/II development include Ultragenyx Pharmaceutical Inc.s DTX-201, Sparks SPK-8016, Shire plcs SHP-654 and University College London (UCL)/St. Jude Children's Research Hospitals AAV2/8-HLP-FVIII-V3.

Anemia in chronic kidney disease

Anemia is one of the many complications of chronic kidney disease (CKD), which worsens as kidney disease progresses; most patients whose CKD has progressed to kidney failure have significant anemia. It is estimated that CKD affects 200 million people worldwide. The anemia in CKD is currently treated with injectable recombinant erythropoiesis-stimulating agents (ESAs), which are often associated with inconsistent hemoglobin responses and safety risks.

The need for more effective and safer therapies has led to the discovery of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) enzyme inhibitors, a new class of agents for the treatment of anemia in CKD (see sidebar story). Those agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease.

Several HIF-PH enzyme inhibitors are currently in development targeting the estimated $3.5 billion renal anemia market, including Cambridge, Mass.-based Akebia Therapeutics Inc.s vadadustat, which has advanced to late-stage clinical trials. In July, its strategic partner, Osaka-based Mitsubishi Tanabe Pharma Corp., filed an NDA with the Japanese Ministry of Health, Labour and Welfare, seeking approval for the product as a treatment for anemia due to CKD.

The filing is based on data from four studies in Japanese patients: an active-controlled study in non-dialysis-dependent CKD anemia (J01), another active-controlled study but in dialysis-dependent patients with CKD anemia (J03), and two single-arm studies in patients with peritoneal and hemodialysis-dependent CKD anemia (J02 and J04). Vadadustat demonstrated non-inferiority with respect to hemoglobin level versus the active comparator (darbepoetin alfa) in both dialysis- and non-dialysis-dependent patients (J01 and J03 studies; 11.66 vs 11.93 g/dL, and 10.61 vs 10.65 g/dL, respectively) and showed therapeutic effect in the single-arm studies.

If approved, the company expects commercial launch during mid-2020, and filings in the U.S. and the EU are planned, those territories covered by Akebias alliance with Otsuka Pharmaceutical Co., Ltd.

Competitors

Within the HIF-PH inhibitor class itself, and particularly from Fibrogen Inc.s Evrenzo (roxadustat), the first-in class HIF-PH inhibitor, vadadustat will face direct competition. Fibrogen has partnered with Astellas Pharma Inc. and Astrazeneca plc for the development and marketing of Evrenzo, which has been approved in Japan (in dialysis patients) and China (in dialysis- and nondialysis-dependent patients) in the third quarter of 2019. An additional filing in Japan in non-dialysis patients is expected in the short term upon completion of a second pivotal study in that setting. The drug has also been filed in the U.S (for both patient populations) and filings in the EU are expected by March, according to Cortellis, following positive top-line data from the ALPS (nondialysis-dependent) and HIMALAYAS (dialysis-dependent) studies.

The analysis indicates vadadustat would also face competition from other well-established therapeutic approaches in CKD such as intravenous iron replacement products and blood transfusions that offer rapid increases in Hb levels.

Future direct competition will also come from Glaxosmithkline plcs HIF-PH inhibitor daprodustat, which was submitted for approval in Japan in August last year.

The Cortellis analysis cites sales forecasts in 2024 of $1.188 billion for Evrenzo and $286 million for daprodustat. For vadadustat, sales of $2 million are forecast for this year, rising to $1.589 billion in 2024.

See a related article:

Out of basic science, a blockbuster: Vadadustat

To read more about the Cortellis Drugs to Watch potential blockbusters, visit BioWorlds collection of articles which are freely available.

More:
Therapies poised to reshape the treatment landscape for hematologic disorders - BioWorld Online

Novato Feb 14, 2020 (Thomson StreetEvents) -- Edited Transcript of Ultragenyx Pharmaceutical Inc earnings conference call or presentation Thursday, February 13, 2020 at 10:00:00pm GMT

Ultragenyx Pharmaceutical Inc. - Senior Director of IR & Corporate Communications

* Emil D. Kakkis

Ultragenyx Pharmaceutical Inc. - President, CEO & Director

Ultragenyx Pharmaceutical Inc. - CFO & Executive VP

* Andrea R. Tan

Sanford C. Bernstein & Co., LLC., Research Division - VP

Ladies and gentlemen, thank you for standing by. And welcome to the Ultragenyx Fourth Quarter and Full Year 2019 Financial Results Conference Call. (Operator Instructions)

I would now like to hand the conference to your speaker today, Danielle Keatley. Please go ahead.

Danielle Keatley, Ultragenyx Pharmaceutical Inc. - Senior Director of IR & Corporate Communications [2]

Thank you. Good afternoon, and welcome to the Ultragenyx Pharmaceutical financial results and corporate update conference call for the fourth quarter and full year 2019. We've issued a press release detailing our financial results, which you can find on our website at ultragenyx.com.

I'm Danielle Keatley, Senior Director of Investor Relations. And with me today are Emil Kakkis, Chief Executive Officer and President; and Shalini Sharp, Chief Financial Officer.

I'd like to remind investors that this call will include forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the types of statements identified as forward-looking in our quarterly report on Form 10-Q that was filed on November 6, 2019, our annual report on Form 10-K that will be filed soon; and our subsequent periodic reports filed with the SEC, which will all be available on our website in the Investors section.

These forward-looking statements represent our views only as of the date of this call and involves substantial risks and uncertainties, including many that are beyond our control.

Please note that actual results could differ materially from those projected in any forward-looking statement.

For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements as well as risks relating to our business, see our periodic reports filed with the SEC.

I'll now turn the call over to Emil.

Emil D. Kakkis, Ultragenyx Pharmaceutical Inc. - President, CEO & Director [3]

Thank you, Daniel. I'll start with our commercial performance in the fourth quarter of 2019. Shalini will then summarize our financial results for the quarter and the year. I'll come back at the end to discuss the progress across our clinical and preclinical programs and our outlook for the rest of the year.

Starting with Crysvita, which has been the main focus of our commercial efforts and the primary driver of revenue in 2019. Performance in the fourth quarter built on the momentum in the first 5 quarters of launch, this was reflected by continued increases in depleted start forms and the number of patients on reimbursed therapy.

In the U.S., we ended the year with approximately 1,590 completed start forms, 160 more than the third quarter. We also ended the year with approximately 1,330 patients on reimbursed therapy, a 200 patient increased versus the end of the third quarter.

As the commercial team continues to work to penetrate the adult market, we believe Crysvita will continue to be one of the most successful rare disease programs launched.

Our 2020 Crysvita revenue guidance of $125 million to $140 million further reflects the confidence we have in Crysvita and our commercial team's ability to execute. Now that the early launch period is over, going forward, we do not plan on providing specific launch metrics, but we'll focus on revenue for Crysvita. To put our launch progress in perspective, we mapped out the top rare disease launches through their first 6 quarters over the last 15 years. We found that Crysvita is one of the top rare disease launches based on top line total product sales. We've also generated a substantial revenue of setting a price that is substantially lower than any of the other top rare disease drugs. As a result, we have successfully ensured that payer view our pricing as responsible, allowing us to reach more patients, especially adult and achieve a positive financial outcome for the company. This approach is core to our philosophy about improving access and total revenue by moderating rare disease pricing.

Turning to Canada, we are seeing continued prescribing interest from physicians and the number of reimbursed patients with private insurance has exceeded our expectations. More than half of Canadians have supplemental private insurance today and the number of pediatric and adult patients were receiving Crysvita through their private insurance drug plans continues to grow. We also continue to pursue public reimbursement in Canada, which will take more time.

Moving to Latin America. In Argentina and Colombia, the number of patients are reimbursed, named patient treatment continues to increase, and the feedback has been very positive.

In Brazil, the demand has been strong, with a significant number of patients successfully navigating the cumbersome legal process and a few receiving reimbursed treatment to date. We're also seeking pricing and full reimbursement approval by the Ministry of Health to enable more rapid access for patients in Brazil. Ultimately, we believe there is significant potential for Crysvita in Latin America, with growing demand in multiple countries for the product.

Briefly turning to Mepsevii. The therapy approved in the United States, Europe and Brazil, and demand continues to build gradually as typical for enzyme replacement therapies. We are also continuing reimbursement discussions with various government health authorities throughout the world.

With that, I'll turn the call over to Shalini, who will provide a financial update.

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Shalini Sharp, Ultragenyx Pharmaceutical Inc. - CFO & Executive VP [4]

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Thank you, Emil. And good afternoon, everyone. Earlier today, we issued a press release that included a financial update, which I will briefly summarize.

Ultragenyx's total net revenue for the 12-month period ending December 31, 2019, was $103.7 million. And for the fourth quarter of 2019 was $35.6 million. The following is a product-by-product breakdown of these figures.

For Crysvita, during the year ended December 31, 2019, we recognized total revenue of $87.3 million. This includes $74.9 million in collaboration revenue in the U.S. profit share territory in Canada and $8.1 million in royalty revenue in the European territory from our collaboration and license agreement with our partner, Kyowa Kirin or KKC. Net product sales for Crysvita in other regions totaled $4.3 million. Total Crysvita revenue recognized Ultragenyx for the 3 months ended December 31, 2019, was $29.9 million. This includes $26.1 million in collaboration revenue in the North American profit share territory, $2.2 million in royalty revenue on KKC sales in the European territory and $1.6 million in net product revenue in other regions.

Recall, there was a significant order that was placed on the last day of the third quarter of 2019, which was recognized in the fourth quarter due to shipping terms. Depending on ordering patterns, we continue to expect fluctuations in our quarter-to-quarter revenue recognition from time to time.

In Latin America, full reimbursement takes place on a country-by-country basis and can take some time, which can be further complicated by economic and political instability. Total 2019 Crysvita sales in North America, Europe and Latin America, which are shared with KKC were approximately $104 million for the fourth quarter and approximately $316 million for the full year 2019.

Mepsevii product revenue for the fourth quarter of 2019 was $4.4 million and was $12.6 million for the year. Due to the rarity of MPS 7, we expect revenues for this product to be somewhat irregular from quarter-to-quarter and to build very gradually as is typical for enzyme replacement therapies.

UX007 named patient revenue in the fourth quarter was $1.2 million and was $3.3 million for the year. We also recognized $0.1 million in revenue this quarter and $0.5 million for the year from our research agreement with Bayer.

As we have stated previously, we continue to expect revenues from this agreement to be minimal going forward. Our total operating expenses were $130 million for the fourth quarter of 2019. For the past several quarters, up to 20% of our operating expenses, excluding expenses related to business development transactions like genetics and Arcturus has consisted of noncash items.

Our research and development costs were $83.1 million. We expect our R&D cost to increase moderately over the time as we continue advancing product candidates from early preclinical development into early and pivotal clinical studies.

Our SG&A costs in Q4 were $41.9 million. We expect SG&A to increase moderately over time as we support our commercial programs simultaneously launching across multiple geographies.

Our cost of sales were $5.1 million for the fourth quarter of 2019. This includes a $3.8 million reserve on Mepsevii inventory that did not meet our quality standards.

Recalling the third quarter of 2019, there was a $1.9 million reserve for a similar issue. We expect that a majority of these reserves will be recovered from our supplier, and we do not currently anticipate any supply interruptions or future reserves related to this issue.

Net loss for the fourth quarter of 2019 was $93.8 million or [$1. 62] per share, basic and diluted compared with a net loss of $87.8 million or $1.73 per share basic and diluted for the fourth quarter of 2018. For the year ended December 31, 2019, net loss was $402.7 million or $7.12 per share, basic and diluted, compared with a net loss for the same period in 2018 of $197.6 million or $3.97 per share basic and diluted.

The net loss for the fourth quarter of 2019 and for the year ended December 31, 2019, includes unrealized gains of $1.4 million and $13.4 million, respectively, from their fair value adjustment on the investment in our Arcturus equity securities.

The net loss for the full year ended 2018 was reduced by $170.3 million due to sales of priority review vouchers.

For the year ended December 31, 2019, cash used in operations was $345.4 million. This includes $20 million for the GeneTx upfront payment in the third quarter of 2019, $15.6 million for the amended Arcturus license rights in the second quarter of 2019 as well as adjustments for significant noncash charges, including stock-based compensation expense of $82 million.

We ended the fourth quarter of 2019 with $760.4 million in cash, cash equivalents and available for sale investments. This includes proceeds of $320 million we received from the sale of the company's royalty interest in Crysvita in the European territory.

Moving to our guidance for 2020. We continue to expect the Crysvita revenue to Ultragenyx in our territories to be between $125 million and $140 million. Those territories include North America, Latin America and Turkey and exclude the EU royalty, as this was monetized in the transaction that was completed with Royalty Pharma that was announced in December 2019. We expect the pace of our revenue growth to significantly exceed the pace of expense growth. And therefore, we are projecting a greater than 20% decrease in net cash burn, which includes net cash used in operations as well as capital expenditures.

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Emil D. Kakkis, Ultragenyx Pharmaceutical Inc. - President, CEO & Director [5]

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Thank you, Shalini. I'll spend a few minutes on our clinical and preclinical programs before turning to the upcoming catalysts. I'll start with Crysvita for tumor-Induced Osteomalacia a rare disease for which approximately half of the patients have tumors that cannot be surgically removed and leading them with no other current treatment options.

In December of last year, we submitted a supplemental biologic license application ahead of our anticipated timing. We expect to hear back from FDA on submission acceptance and review designation later this month.

Turning to UX007 for LC-FAOD. A devastating set of diseases with a high mortality rate despite newborn screening and current use of MCT oil. The FDA is currently reviewing the new drug application and set a PDUFA date for July 31, 2020. As we've discussed before, the FDA does not currently plan to hold an advisory committee meeting to discuss the application. The review process continues on track, and we expect to review decision by the PDUFA date.

In addition to progress in U.S., we've also submitted a marketing authorization application to regulatory authorities in Brazil, and we continue discussion with other regulatory authorities in the EU and Canada.

Based on our experiences, we know that there are a lot of patients with LC-FAOD, who are not doing well on current treatment of MCT oil and are seeking new treatment options. In France alone, for example, there were originally only a few doctors requesting UX007 via the ATU named patient program. Now there are approximately 20 physicians treating 34 patients for the LC-FAOD, who are using UX007 through that named patient program. We expect there to be significant interest in the product, if approved, but as with many inborn air products, we believe, will build steadily and will take time.

In the developed world, there are approximately 8,000 to 14,000 patients with LC-FAOD and we own the worldwide rights to the product.

Moving to DTX301, our gene therapy program for ornithine transcarbamylase deficiency or OTC deficiency. OTC deficiency is an X-linked urea cycle disorder that limits the body's ability to detoxify ammonia into urea. These patients can quickly deteriorate into full metabolic crisis, causing neurologic deficits, hospitalization, coma, in some cases, death.

In January, we reported positive data from dose Cohort 3 and longer-term data from the first 2 cohorts of our OTC study.

In Cohort 3, we are seeing responses from all 3 patients. 2 of the patients are confirmed responders, and the third patient appears to be responder as well, but we will wait until we have longer-term data to confirm this.

In total, up to 6 of the 9 patients have responded. Importantly, 3 patients have come off their ammonia scavenger medications and liberalize their diet. We consider these patients complete responders and these patients appear to be metabolically cured.

Based on these data and the favorable safety profile, we believe the Cohort 3 1e13 GC per kilogram dose is the appropriate dose level. We're seeing a more consistent response across the patients, and we believe this higher dose has achieved the adequate level of therapeutic effect. From here, we will enroll a fourth cohort at the same dose of Cohort 3, this time using prophylactic steroids rather than reactive steroids. We believe this will enhance the level of expression, also provide more consistent expression. We expect data in the second half of 2020 from this cohort. If positive will proceed to dose 3 more patients and simultaneously discuss the design of the Phase III study and end points with regulators.

Based on our ongoing conversation with FDA, we expect that ammonia will be a primary endpoint. The FDA considers ammonia validated clinical endpoint, and they've approved other products based on ammonia.

Switching to DTX401, our gene therapy program in glycogen storage disease type Ia, a disease that leads to severe and sometimes life-threatening hypoglycemia. Patients with GSDIa today have to take cornstarch every 3 to 4 hours, which can keep glucose levels up. But it does not address the disease and its long term consequences. While cornstarch therapy has same lives and improved health, it is not a normal life by any measure and patients or their parents live in fear of death, if they miss a single dose of cornstarch.

Today, we've shown data from the first 2 cohorts of all 6 patients demonstrating a meaningful clinical response to the therapy at the 2e12 and 6e12 dose levels. This includes improvement in glucose control, shown by timed hypoglycemia reductions in cornstarch requirements for all patients. In the second dose cohort, all patients showed a meaningful reduction in glycogen storage and improvements in metabolism. These days data indicate that Cohort 2 dose is showing greater transgene expression and our view that these patients have greatly improved glucose control. They are weighing down their starch requirements, and we think we have a treatment that could change the future of GSDIa patients.

We've now moved to a confirmatory cohort of 3 patients at the same dose and are simultaneously having discussions with the FDA about the Phase III study. We expect to have data from the confirmatory cohort in the first half of 2020. And we could be in a position then to begin Phase III in the second half of 2020.

I will also touch on our agreement with the [gene genetics] Biotherapeutics to advance GTX-102, an antisense oligonucleotide for the treatment of Angelman syndrome. Angelman is a devastating neurologic disease that affects approximately 60,000 patients worldwide, and there are no approved treatment options today. Disease is not neurodegenerative. So there is potential to reverse some disease symptoms, which include speech, cognitive impairment, seizures, ataxia and sleep dysfunction. As a result, we think Angelman's one of the disease in neurology that could benefit most from a treatment. The disease mechanism is well understood, and ASOs (inaudible) can target the disease directly. We believe that the team at GeneTx has developed a very potent and specific differentiated antisense oligonucleotide. We are excited to partner with this group.

The IND for this program is now active, and GeneTx has received IRB our Institutional Review Board approval for the first study site. We expect enrollment in the Phase I/II study to begin in the coming months. Following the acceptance of IND, we paid a $25 million milestone to obtain the option to maintain the option to acquire the company until the earlier of 30 months after the first patient's dose or 90 days after the results are available from the Phase I/II study.

The last product I'll discuss is DTX201 for hemophilia A. Our program is partnered with Bayer and used in material for our proprietary HeLa manufacturing platform.

At the European Association of Hemophilia and Allied Disorders meeting last week, Bayer presented data on first 2 low dose cohorts of the Phase I/II study. All 4 patients showed a response with 3 of the 4 patients showing clinically meaningful increase in Factor VIII levels. One patient Cohort 1 achieved clinically meaningful Factor VIII levels and has experienced only 4 bleeds posttreatment compared to 99 bleeds the prior year. Both patients in dose Cohort 2 achieved clinically meaningful Factor VIII levels up to 24 and 30 weeks.

Patient 4 on Cohort 2 has been bleed-free and treatment-free for up to 7 months of the data cutoff. The same patient had a mild ALT/AST elevations that were managed with a short tapering course of steroids. And the other patients have not required steroids at all. A third high-dose cohort has been dosed, and we expect to see additional updates this year.

While Bayer is responsible for the clinical execution of the program, we are pleased to see that our HeLa manufacturing platform validated and looked forward to continued progress with the program. As a reminder, we are eligible to see milestones and royalty payments from Bayer for this program.

I'll spend a few minutes now discussing a number of important milestones in the coming months that will continue to drive our progress, and then we can move to Q&A.

For Crysvita, in 2020, we expect revenue between $125 million to $140 million across North America, Latin America and Turkey, representing a 58% to 77% increase versus 2019 in the same territories. This will be driven by continued strong performance in the U.S. and expansion of our reach in Latin America through named patient sales and pending regulatory decisions as well as growth in Canada. With our Rare transmission for Crysvita for the treatment of TIO, we are looking to expand procedures in this additional patient population, while there are fewer patients with TIO, there's often a very urgent need for treatment. If approved in this indication, we believe Crysvita therapy will be adopted over phosphate therapy.

For UX007, we will continue to work with the FDA, to view our NDA, working towards the PDUFA date of July 31, 2020. The review is progressing well, and we look forward to being able to provide the stream to many more patients with LC-FAOD. For the gene therapy programs, we have shown strong data for our 2 programs in GSDIa and OTC. In the both phase, we believe we had found the appropriate dose.

The GSDIa program will have a data readout from the confirmatory cohort in the first half, and the OTC program will read out in the second half. We are simultaneously having discussions with FDA about the Phase III studies for both programs.

The Bayer hemophilia A program is writing us with the first clinical data using material from our proprietary HeLa platform, our Wilson disease program will use this HeLa manufacturing system when it enters the clinic, and we are targeting an IND for this program by the end of 2020. We'll also provide more updates on the GTX102 ASO program for Angelman as the program begins to enroll patients.

To summarize briefly, our commercial team continues to execute at an extremely high level, making Crysvita one of the top rare disease launches. The continued efforts with Crysvita and Mepsevii as well as 2 more potential launches this year set us up to grow -- substantially grow our commercial business.

In 2019, we had annual revenue exceeding $100 million for the first time, with substantial growth expected in 2020. We're now well capitalized with $760 million in cash and equivalents, we combined with the financial discipline we are applying and expect to reduce net cash burn in 2020. This puts us in good position to drive our clinical programs forward.

Our gene therapy programs are advancing to a confirmatory dose cohorts through Phase III studies and the Angelman, Wilson disease programs are both large indication opportunities that are nearing clinic with diverse set of early-stage product candidates to follow. We have become a diversified rare disease company, we'll continue to grow. We're constantly innovating, adapting where disease drug developments, strategies, trial designs, and endpoints, working with regulators, establish a more efficient model for rare disease drug development as well as evolving the way we commercialize product in these indications and efficiently manage the cost structure. These are just some of the things we do each day, and we have the foundation while we build an exceptional rare disease company.

With that, let's move to your questions. Operator, can you please provide the instructions for the Q&A portion of the call.

================================================================================

Questions and Answers

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Operator [1]

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(Operator Instructions) And our first question will come from the line of Gena Wang from Barclays.

--------------------------------------------------------------------------------

Huidong Wang, Barclays Bank PLC, Research Division - Research Analyst [2]

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I wanted to congratulate you on the great quarter. I have 2 questions. The first one is regarding the Crysvita 2020 revenue guidance. Just wondering the 58% to 77% growth is mainly driven by U.S. growth or geographic expansion? How much growth assumption was building for Latin America.

My second question is regarding the Angelman Syndrome. Could you walk through the Phase I trial design in terms of initial dose? And how would your dose escalate? And what kind of data will lead your decision to acquire GeneTx?

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Emil D. Kakkis, Ultragenyx Pharmaceutical Inc. - President, CEO & Director [3]

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Great. So on the Crysvita launch growth, Shalini do you want to answer that particular one, how the numbers...

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Shalini Sharp, Ultragenyx Pharmaceutical Inc. - CFO & Executive VP [4]

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Link:
Edited Transcript of RARE earnings conference call or presentation 13-Feb-20 10:00pm GMT - Yahoo Finance

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Extraordinary growth in Gene therapy market is expected to reach US$ 5,609.9 million by 2027, growing at an estimated CAGR of 8.2% over the forecast...

The incidence of cancer has increased tremendously in the past few years. With advancements in science and technology, the treatment for cancer has become efficient and affordable. However, there are some rare and complicated forms of cancer that require better treatments to increase success rates. Recently, cancer gene therapy has showed promising results in preclinical trials. This is a promising trend for the global cancer gene therapy market.

Gene therapy is a method of adding or replacing a gene in an organisms DNA. In some forms of cancer, there is a defective or malfunctioning gene. Nucleic acid is administered to an individual like a drug to correct the gene sequence. Globally, there is a huge thrust on gene therapy research, and it is boosting the growth in the cancer gene therapy market.

Key driving factors of the global cancer gene therapy market

Chemotherapy and radiation, along with surgery are some of the prominent treatments available for cancer today. In cases of early detection, doctors recommend surgery along with chemotherapy or radiation. But, if the cancer has metastasized (spread to other organs), then surgery is difficult. This calls for advanced treatments, a positive factor for the global cancer gene therapy market

While chemotherapy has its own advantages, it has several side effects on the patients. It causes weight loss, vomiting, hair loss, nausea, and other complications in the body. That is the reason why doctors are better treatment options. This is a boost for the global cancer gene therapy market

Radiation also has severe impact on the body. It may cause hair loss, nausea, vomiting, fatigue and skin problems depending on the area of radiation. It also results in lung and heart problems. These factors are favorable for the global cancer gene therapy market

The survival rate of some cancers like lung, pancreatic, and liver is very less. Their chemotherapy treatments have severe side effects. Researchers feel that cancer gene therapy can improve the quality of the treatment. These findings are pushing the demand in the global cancer gene therapy market

With promising in vivo (laboratory) results, many pharmaceutical companies have embarked upon research to develop cancer gene therapy. Investments in R&D have soared in the past few years, a welcoming trend for the global cancer gene therapy market

Cancer has become more prevalent than ever today. With rising number of people seeking treatment for this disease, the demand for quality treatment is expected to grow in the coming years. This is a prime growth factor for the global cancer gene therapy market

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Global Cancer Gene Therapy Market: Key Segments

Based on type, the cancer gene therapy market is segmented into gene transfer immunotherapy and oncolytic virotherapy. Immunotherapy uses genetically modified cells and viral particles to stimulate the immune system to destroy cancer cells. Immunotherapy include treatment with either cytokine gene delivery or tumor antigen gene delivery.

Oncolytic virotherapy uses viral particles, which replicate within the cancer cell causing the death of the cell. It is an emerging treatment modality that is expected to shows great promise, particularly in metastatic cancer treatment. It includes treatment with adenovirus, retrovirus, lentivirus, herpes simplex virus, adeno-associated virus, simian virus, alphavirus, and vaccinia virus.

Gene transfer is the newest treatment modality that is expected to introduce new modified genes into cancerous cell or associated tissue for destruction of cell or to slow down cancer growth. This technique is flexible as a wide variety of vectors and genes are used for clinical trials with positive outcomes. As gene therapy advance, they could be used alone or in combination with other treatments to control the disease. Gene transfer or gene replacement is performed using naked/plasmid vectors, electroporation, sonoporation, magnetofection, and gene gun.

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Global Cancer Gene Therapy Market: Regional Analysis

Based on region, the global cancer gene therapy market is segmented into North America, Europe, Asia Pacific, Latin America and Middle East & Africa. North America is anticipated to hold the largest market share. The U.S. dominates the cancer gene therapy market owing to its increase in funding for research & development and other government initiatives.

Key players in the biotech industry are engaging in research & development of gene therapy products. Moreover, rising demand for DNA vaccines and growing interest of venture capitalists to investment in commercialization of gene-based cancer therapies are likely to propel the market. The cancer gene therapy market in Asia Pacific is anticipated to expand at a rapid pace as in China cancer gene therapy is anticipated to attribute for largest revenue, due to the recent launch of Gendicine and rising healthcare expenditure with strong R&D facilities.

Global Cancer Gene Therapy Market: Key Players

Key players operating in the global cancer gene therapy market are Adaptimmune, ZioPharm Oncology Altor Bioscience, MolMed, bluebird bio, Shanghai Sunway Biotech Company limited, MultiVir, Shenzhen SiBiono GeneTech, and Corporation.

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Original post:
Promising In Vitro Results to Fillip Global Cancer Gene Therapy Market - BioSpace

Researchers at the University of Pennsylvania and Childrens National Hospital in Washington, DC utilized a hybrid approach that combined gene therapy with gene editing to treat a rare genetic disease in animal models, making it convert into a milder, more treatable form of the disease. The disease was ornithine transcarbamylase deficiency (OTCD), which is the most common type of a family of illnesses called urea cycle disorders.

Urea cycle disorders affect about 1 in 30,000 individuals. It causes problems in how the body metabolizes proteins in food. Normally, proteins are broken into individual amino acids. The body then recycles those amino acids to create new proteins for the body to use. Extra proteins are metabolized for energy, which requires a chemical category called amines to be removed, which are converted into ammonia. Ammonia is toxic to cells. In healthy people, urea cycle enzymes from the liver convert ammonia into urea, which is harmlessly excreted in urine.

When people have urea cycle disorders, ammonia builds up, causing vomiting and lethargy. If untreated, it can cause coma and death.

The various urea cycle disorders are caused by various genetic mutations. The researchers, led by James M. Wilson at the University of Pennsylvania and Mark L. Batshaw at Childrens National, originally attempted a typical form of gene therapy in animal models, inserting a properly functioning version of the OTC gene into a virus that carries the code for the missing enzyme, ornithine transcarbamylase.

This approach worked in older animals but did not last long in newborn animals because of rapid liver growth. CRISPR/Cas9 gene editing, on the other hand, can be used to modify the genes. Alone, this is a problem for OTCD because there are more than 400 different known mutations that cause it.

For their new approach, which they described in the journal Science Advances, they developed a viral vector that carried an enzyme that creates a targeted break in DNA. This step is typical in standard gene editing. But, instead of correcting the mistake, a second vector that carried a copy of the correct OTC gene sequence was used simultaneously.

In their experimental animal models of newborn animals, the gene integrated into cells and spread in patches in the animals livers as they grew. They produced more and more of the necessary detoxifying enzyme as they grew. They then tested nitrogen loads on the animals, and the ones who had been treated with the combined strategy had approximately 60% lower ammonia levels in their blood compared to untreated animals. All of the treated animals survived a seven-day test, while only a quarter of the untreated animals survived.

Theoretically, this could be a curative approach for OTCD, Batshaw said. And if it worked for that, we could create similar templates to treat other related disorders.

Currently, treatment for the disease includes a very low protein diet, drugs that scavenge nitrogen from the blood or a liver transplant in the most serious cases. Through these therapies, weve turned this fatal disease into a chronic one for most patients, Batshaw said. But theres still no curative approach other than liver transplantation.

The research isnt quite ready for human studies, but it is promising.

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Hybrid Gene Therapy Approach Shows Promise in Treating Metabolic Diseases - BioSpace