Archive for the ‘Gene Therapy Research’ Category

Public release date: 20-Jul-2012 [ | E-mail | Share ]

Contact: Jenny Eriksen Leary jenny.eriksen@bmc.org 617-638-6841 Boston University Medical Center

(Boston) A research study led by Boston University School of Medicine (BUSM) and the University of Exeter in the United Kingdom, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating estrogen and testosterone levels in the bloodstream. The results, published online in PLoS Genetics, also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.

Andrea D. Coviello, MD, assistant professor of medicine at BUSM and an endocrinologist at Boston Medical Center, is one of the paper's lead authors. This study was done in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.

Sex hormone-binding globulin (SHBG) is the key protein that carries testosterone and estrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.

Previous family studies have demonstrated that approximately 50 percent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.

Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. However, these SNPs combined explain only 16 percent of the variation of SHBG in men and eight percent in women, respectively, indicating that SHBG levels are affected by many other factors as well.

The results also showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.

"These findings underscore the connection between the reproductive system and metabolism in both men and women, and may help explain sex differences observed in some metabolic diseases, particularly type 2 diabetes," said Coviello.

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BUSM researchers identify genetic markers for testosterone, estrogen level regulation

Public release date: 20-Jul-2012 [ | E-mail | Share ]

Contact: Andrew Gould andrew.gould@pcmd.ac.uk 44-188-438-346 The Peninsula College of Medicine and Dentistry

A research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.

The results, published online in PLoS Genetics, also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.

The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.

Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.

Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.

Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.

The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.

"These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation," said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter.

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Genetic markers for testosterone and estrogen level regulation identified

Salt Lake City-based Myriad Genetics expressed confidence Friday it would prevail in defending its patents of genes related to breast and ovarian cancer in a case being closely watched nationally by researchers and the biotech industry.

Myriad attorneys appeared for the second time before a three-judge panel of a federal appeals court in Washington, D.C., to defend patents related to the two genes after the U.S. Supreme Court sent the case back for reconsideration of an earlier decision that upheld most of Myriads patents. That came after the Supreme Court struck down patents in a case revolving around some of the same questions.

The American Civil Liberties Union, which represents breast cancer patients, researchers and professional groups that sued Myriad, argued before the U.S. Court of Appeals for the Federal Circuit that the Utah company cannot patent works of nature such as genes.

But Myriad said the materials it patents are taken out of their naturally occurring context and isolated from the body and, therefore, are not works of nature.

Richard Marsh, Myriad executive vice president and general counsel, said the Supreme Court decision in the related case was distinct from Myriads situation because it involved a process for testing drug levels versus Myriads claim over DNA material isolated from the body.

"In our case, isolated DNA, isolated from the human genome, is not found in nature," Marsh said in an interview after the court hearing.

But the ACLU argues that even out of the body, isolated DNA materials remain a product of nature and are ineligible for patenting. By patenting the materials, Myriad can deny other researchers the opportunity to do research on them and develop different tests for measuring the risk a woman carries of gene-related breast and ovarian cancer, the group said.

"We need to be sure that natural things and all natural laws are available to all mankind," Chris Hansen, an ACLU lawyer, told the appeals court, according to Bloomberg News. The Myriad claims "cover every conceivable form of DNA."

The ACLU position was backed by the Justice Department, which represented the government in place of the U.S. Patent and Trademark Office, which normally appears in such cases.

Justice Department lawyer Melissa Patterson said that isolation of a specific gene was insignificant. She likened it to extracting coal from the ground.

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Utah’s Myriad Genetics defends gene patent claims

BOTHELL, Wash.--(BUSINESS WIRE)--

Seattle Genetics, Inc. (SGEN) today announced that its collaborator, Millennium: The Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for the conditional marketing authorization of ADCETRIS (brentuximab vedotin) for two indications: (1) the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30.

The positive opinion from CHMP and broad label recommendation is a key step in the European regulatory process for ADCETRIS and brings us closer to our goal of making this important new therapy globally available to patients with relapsed Hodgkin lymphoma or systemic ALCL, said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. If approved in the European Union, ADCETRIS will represent the first new therapeutic advance for relapsed Hodgkin lymphoma patients in several decades and further validates the potential of ADCs in the treatment of cancer.

The European Commission, which has the authority to approve medicines for use in the European Union, generally follows the recommendations of the CHMP and typically renders a final decision within three months of the CHMP opinion. If the CHMP recommendation is formally adopted by the European Commission, ADCETRIS would be approved for marketing in all 27 member states of the European Union.

European Commission approval will trigger two milestone payments, one for each indication, totaling $25 million to Seattle Genetics under the collaboration agreement between Seattle Genetics and Millennium: The Takeda Oncology Company. Seattle Genetics is also entitled to tiered double-digit royalties with percentages starting in the mid-teens and escalating to the mid-twenties based on net sales of ADCETRIS within Millenniums territories, subject to offsets for royalties paid by Millennium to third parties.

About ADCETRIS

ADCETRIS (brentuximab vedotin) is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS received accelerated approval from the U.S. Food and Drug Administration (FDA) in August 2011 for relapsed HL and sALCL.

Seattle Genetics and Millennium are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and the Takeda Group has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and the Takeda Group are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where the Takeda Group will be solely responsible for development costs.

About Seattle Genetics

Originally posted here:
Seattle Genetics Announces ADCETRIS® Receives Positive CHMP Opinion for Conditional Approval in European Union

By Naomi Kresge - 2012-07-20T19:16:23Z

Europe is on the cusp of approving the first gene therapy to be sold on the market in a western nation, a product from UniQure BV designed to treat a rare disease that disrupts fat production in the body.

The drug, called Glybera, won the backing of an advisory panel to the European Commission on its fourth attempt, the group said in a statement today. The Commission, which makes the final decision, usually follows the committees recommendation.

The move comes after 20 years of experimentation into a technology that in the past has been haunted by highly- publicized failures, including the death of 16-year-old Jessie Gelsinger in the U.S. in 1999. More recently, success in trials by Amsterdam-based UniQure and the U.S.-based companies Sangamo BioSciences Inc. (SGMO) and Neurologix Inc. (NRGXQ) are reviving the field.

This is good news for the field, definitely, said Savio Woo, a professor of genetics and genomic sciences at the Mount Sinai School of Medicine in New York. The technology has been really making a lot of progress, and a positive approval was more or less expected to come sometime.

UniQure began preparations a few weeks ago for meetings with the U.S. Food and Drug Administration to seek approval for Glybera, said Jorn Aldag, UniQures chief executive officer.

The treatment targets lipoprotein lipase deficiency, or LPLD, a rare fat-processing disorder that spurs severe or multiple pancreatitis attacks in about one or two people among every million in the population. The therapy is administered only once to be effective.

Glybera may have peak annual sales between 50 million euros ($61.1 million) and 300 million euros, depending on how its priced, Aldag said in an interview.

Its phenomenal because its the first gene therapy the EMA has approved, he said.

While two gene therapy products are sold in China, none are approved in Europe or the U.S., according to Mount Sinais Woo.

See the article here:
UniQure’s Glybera Wins EU Backing as First Gene Therapy

The European Medicines Agency is recommending the first-ever approval of a gene therapy treatment in the EU, in a significant move for a type of treatment that has so far failed to deliver on its promise to cure diseases.

In a statement on Friday, the EMA said Glybera, made by Dutch company uniQure, should be approved across Europe for the treatment of an extremely rare disorder that leaves people unable to digest fat. The treatment consists of a gene that makes a protein to break down fat.

Gene therapy is an experimental technique that tries to cure diseases by replacing genes that don't work. It has never been approved in the U.S. and most trials over the past two decades have failed. China was the first country to approve a gene therapy treatment in 2003 for cancer.

Scientists have struggled to find ways to deliver the genes safely, often by using a harmless virus. There are also concerns that inserting a gene at the wrong spot could cause cancer or that the body's immune system might attack the new gene and the virus used to deliver it.

The EMA previously rejected Glybera three times but it was reconsidered at the request of the European Commission. The agency recommended approval under tough restrictions and will require the company to set up a registry to closely track patients. Previous trials of the treatment only tested it in 27 patients.

"It is only meant for patients with the greatest need," said Monika Benstetter, an EMA spokeswoman, explaining the gene therapy is intended for people with no other treatment options. She said only a handful of gene therapy treatments had been considered before one was recommended for approval but its manufacturer withdrew it before it was finalized.

Recommendations by the EMA are usually given final approval by the European Commission.

Patients with lipoprotein lipase deficiency, the inherited disease Glybera is intended to treat, often cannot eat a normal meal because it can lead to an extremely painful inflammation of the pancreas. Many patients with the disorder have a very restricted diet and only eat a fraction of their daily recommended calories. The condition affects only one to two people per million.

Jorn Aldag, CEO of uniQure, said the company was developing similar treatments for other diseases beyond rare conditions, including Parkinson's. "We believe that just like antibodies, gene therapy will one day be a mainstay in clinical practice," he said in a statement.

Benstetter said there are no other gene therapy treatments currently under consideration by the EMA and was unsure if the agency would get more applications based on Glybera's approval.

Go here to read the rest:
Gene therapy for rare disease OK'd by EU regulator

20 July 2012 Last updated at 11:11 ET By James Gallagher Health and science reporter, BBC News

Europe is on the cusp of approving a gene therapy for the first time, in what would be a landmark moment for the field.

Gene therapies alter a patient's DNA to treat inherited diseases passed from parent to child.

The European Medicines Agency has recommended a therapy for a rare genetic disease which leaves people unable to properly digest fats.

The European Commission will now make the final decision.

The idea of gene therapy is simple: if there is a problem with part of a patient's genetic code then replace that part of the code.

The reality has not been so easy. In one gene therapy trial a US teenager, Jesse Gelsinger, died, and other patients have developed leukaemia.

There are no gene therapies available outside of a research lab in Europe or the US.

The European Medicines Agency's Committee for Medicinal Products for Human Use has considered the use of Glybera to treat lipoprotein lipase deficiency.

One in a million people have the deficiency. They have damaged copies of a gene which is essential for breaking down fat.

More here:
Europe nears gene therapy first

The European Medicines Agency is recommending the first-ever approval of a gene therapy treatment in the EU, in a significant move for a type of treatment that has so far failed to deliver on its promise to cure diseases.

In a statement on Friday, the EMA said Glybera, made by Dutch company uniQure, should be approved across Europe for the treatment of an extremely rare disorder that leaves people unable to digest fat. The treatment consists of a gene that makes a protein to break down fat.

Gene therapy is an experimental technique that tries to cure diseases by replacing genes that don't work. It has never been approved in the U.S. and most trials over the past two decades have failed. China was the first country to approve a gene therapy treatment in 2003 for cancer.

Scientists have struggled to find ways to deliver the genes safely, often by using a harmless virus. There are also concerns that inserting a gene at the wrong spot could cause cancer or that the body's immune system might attack the new gene and the virus used to deliver it.

The EMA previously rejected Glybera three times but it was reconsidered at the request of the European Commission. The agency recommended approval under tough restrictions and will require the company to set up a registry to closely track patients. Previous trials of the treatment only tested it in 27 patients.

"It is only meant for patients with the greatest need," said Monika Benstetter, an EMA spokeswoman, explaining the gene therapy is intended for people with no other treatment options. She said only a handful of gene therapy treatments had been considered before - one was recommended for approval but its manufacturer withdrew it before it was finalized.

Recommendations by the EMA are usually given final approval by the European Commission.

Patients with lipoprotein lipase deficiency, the inherited disease Glybera is intended to treat, often cannot eat a normal meal because it can lead to an extremely painful inflammation of the pancreas. Many patients with the disorder have a very restricted diet and only eat a fraction of their daily recommended calories. The condition affects only one to two people per million.

Jorn Aldag, CEO of uniQure, said the company was developing similar treatments for other diseases beyond rare conditions, including Parkinson's. "We believe that just like antibodies, gene therapy will one day be a mainstay in clinical practice," he said in a statement.

Benstetter said there are no other gene therapy treatments currently under consideration by the EMA and was unsure if the agency would get more applications based on Glybera's approval.

Continued here:
First ever gene therapy treatment recommended by European regulator

The long-frustrated field of gene therapy is about to reach a major milestone: the first regulatory approval of a gene therapy treatment for disease in the West. The European Medicine Agency's Committee for Medicinal Products for Human Use said Friday that it is recommending approval of Glybera, a treatment for lipoprotein lipase deficiency manufactured by uniQure of Amsterdam. The European Commission generally follows the recommendations of the agency, and if it does so this time, the product could be available in all 27 members of the European Union by the end of the year.

Lipoprotein lipase deficiency is a rare disease, a so-called orphan disease, that affects one or two of every million people. As the name suggests, it is the result of a deficiency of an enzyme called lipoprotein lipase. This enzyme breaks down large, fat-carrying molecules, called chylomicrons, that circulate in the blood following meals. When the enzyme is defective, the chylomicrons accumulate, turning the blood almost milky white and blocking small blood vessels, producing severe inflammation of the pancreas -- called pancreatitis. The severe pain typically requires hospitalization. There is currently no treatment for the disease other than regulation of the diet.

Glybera is an active form of lipoprotein lipase that is injected into the patient's legs in a series of shots at one sitting. Clinical trials conducted in 27 people by Dr. Daniel Gaudet of the University of Montreal show that the injections are long-lasting and provide at least partial control of lipoprotein lipase deficiency with no apparent adverse effects. Bouts of pancreatitis are fewer and less severe following treatment.

The European agency had rejected Glybera three times in the past year, citing insufficient evidence of benefit, before unexpectedly reversing its decision and recommending approval. The approval decision was for patients with the most severe form of the disease, and the agency said that the company would be required to monitor patients and provide data to regulators.

UniQure said it will apply for approval in the United States, but is not sure when.

The only previous approval of a gene therapy product is a cancer treatment that has been approved in China.

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First gene therapy in West, for a rare disease, on the horizon

LONDON (AP) -- The European Medicines Agency is recommending the first-ever approval of a gene therapy treatment in the EU, in a significant move for a type of treatment that has so far failed to deliver on its promise to cure diseases.

In a statement on Friday, the EMA said Glybera, made by Dutch company uniQure, should be approved across Europe for the treatment of an extremely rare disorder that leaves people unable to digest fat. The treatment consists of a gene that makes a protein to break down fat.

Gene therapy is an experimental technique that tries to cure diseases by replacing genes that don't work. It has never been approved in the U.S. and most trials over the past two decades have failed. China was the first country to approve a gene therapy treatment in 2003 for cancer.

Scientists have struggled to find ways to deliver the genes safely, often by using a harmless virus. There are also concerns that inserting a gene at the wrong spot could cause cancer or that the body's immune system might attack the new gene and the virus used to deliver it.

The EMA previously rejected Glybera three times but it was reconsidered at the request of the European Commission. The agency recommended approval under tough restrictions and will require the company to set up a registry to closely track patients. Previous trials of the treatment only tested it in 27 patients.

"It is only meant for patients with the greatest need," said Monika Benstetter, an EMA spokeswoman, explaining the gene therapy is intended for people with no other treatment options. She said only a handful of gene therapy treatments had been considered before one was recommended for approval but its manufacturer withdrew it before it was finalized.

Recommendations by the EMA are usually given final approval by the European Commission.

Patients with lipoprotein lipase deficiency, the inherited disease Glybera is intended to treat, often cannot eat a normal meal because it can lead to an extremely painful inflammation of the pancreas. Many patients with the disorder have a very restricted diet and only eat a fraction of their daily recommended calories. The condition affects only one to two people per million.

Jorn Aldag, CEO of uniQure, said the company was developing similar treatments for other diseases beyond rare conditions, including Parkinson's. "We believe that just like antibodies, gene therapy will one day be a mainstay in clinical practice," he said in a statement.

Benstetter said there are no other gene therapy treatments currently under consideration by the EMA and was unsure if the agency would get more applications based on Glybera's approval.

Excerpt from:
European regulator: Gene therapy treatment OK

With the new tools, researchers can compare patterns of drug activity and gene expression, not only to each other but also to other patterns of interest.

The newly updated software, called CellMiner, was built for use with the NCI-60, one of the most widely utilized collections of cancer cell samples employed in the testing of potential anti-cancer drugs. The tools, available free, provide rapid access to data from 22,379 genes catalogued in the NCI-60 and from 20,503 previously analyzed chemical compounds, including 102 U.S. Food and Drug Administration-approved drugs.

The study, written by the scientists that developed the tools at the National Cancer Institute (NCI), part of the National Institutes of Health, appeared in the July 16, 2012, issue of Cancer Research.

"Previously you would have to hire a bioinformatics team to sort through all of the data, but these tools put the entire database at the fingertips of any researcher," explained Yves Pommier, M.D., Ph.D., of the NCI's Center for Cancer Research. "These tools allow researchers to analyze drug responses as well as make comparisons from drug to drug and gene to gene."

Genomic sequencing and analysis have become increasingly important in biomedicine, but they are yielding data sets so vast that researchers may find it difficult to access and compare them. As new technologies emerge and more data are generated, tools to facilitate the comparative study of genes and potentially promising drugs will be of even greater importance. With the new tools, researchers can compare patterns of drug activity and gene expression, not only to each other but also to other patterns of interest. CellMiner allows the input of large quantities of genomic and drug data, calculates correlations between genes and drug activity profiles, and identifies correlations that are statistically significant. Its data integration capacities are easier, faster, and more flexible than other available methods, and these tools can be adapted for use with other collections of data.

Researchers looking at a particular drug can use the tools to access data from previous experiments done on that drug and analyze how the drug relates to other drugs and various gene profiles. As a case example for this study, the researchers compared drug activity levels and gene expression patterns from previous research to identify an investigational compound, called NSC732298, which is not currently being studied for colon cancer, but could be a potential therapy for the disease based on a CellMiner gene-drug match. In the same exercise, the researchers were able to identify that a second investigational drug that is being tested for colon cancer, called selumetinib, might also be effective against melanoma.

"We're looking forward to seeing how other people are going to use this tool to look at gene co-regulation, regulation of gene expression, and the relationship between gene expression and cancer," said Pommier.

This work was supported by NCI's Center for Cancer Research and Division of Cancer Treatment and Diagnosis under intramural project number ZIA BC 006150.

Related Tool Link http://discover.nci.nih.gov/cellminer

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Matching Cancer Drugs with Gene Targets

ScienceDaily (July 19, 2012) The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete -- the only cells that become a child and through which parents pass on physical traits.

"This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. "We now have devices that will allow us to routinely amplify and sequence to a high degree of accuracy the entire genomes of single cells, which has far-ranging implications for the study of cancer, infertility and many other disorders."

Quake is the senior author of the research, published July 20 in Cell. Graduate student Jianbin Wang and former graduate student H. Christina Fan, PhD, now a senior scientist at ImmuMetrix, share first authorship of the paper.

Sequencing sperm cells is particularly interesting because of a natural process called recombination that ensures that a baby is a blend of DNA from all four of his or her grandparents. Until now, scientists had to rely on genetic studies of populations to estimate how frequently recombination had occurred in individual sperm and egg cells, and how much genetic mixing that entailed.

"Single-sperm sequencing will allow us to chart and understand how recombination differs between individuals at the finest scales. This is an important proof of principle that will allow us to study both fundamental dynamics of recombination in humans and whether it is involved in issues relating to male infertility," said Gilean McVean, PhD, professor of statistical genetics at the Wellcome Trust Centre for Human Genetics. McVean was not involved in the research.

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," said study co-author Barry Behr, PhD, HCLD, professor of obstetrics and gynecology and director of Stanford's in vitro fertilization laboratory. "Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems."

Most cells in the human body have two copies of each of 23 chromosomes, and are known as "diploid" cells. Recombination occurs during a process called meiosis, which partitions a single copy of each chromosome into a sperm (in a man) or egg (in a woman) cell. When a sperm and an egg join, the resulting fertilized egg again has a full complement of DNA.

To ensure an orderly distribution during recombination, pairs of chromosomes are lined up in tight formation along the midsection of the cell. During this snug embrace, portions of matching chromosomes are sometimes randomly swapped. The process generates much more genetic variation in a potential offspring than would be possible if only intact chromosomes were segregated into the reproductive cells.

"The exact sites, frequency and degree of this genetic mixing process is unique for each sperm and egg cell," said Quake, "and we've never before been able to see it with this level of detail. It's very interesting that what happens in one person's body mirrors the population average."

Here is the original post:
Entire genetic sequence of individual human sperm determined

RYE BROOK, NY--(Marketwire -07/19/12)- As part of a fundamental commitment to support physicians in the management of cancer, CBLPath announces today its launch of in-house NRAS Mutation Analysis testing. This molecular assay screens for clinically relevant genetic mutations that may be present in cases of colorectal cancer, melanoma and thyroid cancer, thus helping oncologists make an accurate diagnosis and the most appropriate treatment decisions for affected patients.

"Our new polymerase chain reaction, or PCR-based test uses the latest sequencing technology to detect NRAS genetic aberrations in a timely and accurate manner, aiding molecular classification of disease and consequently impacting patient prognosis and therapeutic efficacy," said Co-CEO and Chief Medical Officer, Dr. Carlos D. Urmacher, FCAP, FASCP.

"We're pleased to add NRAS to our powerful arsenal of biomarker-centered diagnostics that are advancing the practice of personalized medicine. It's truly a 'win-win' for oncologists, who can provide better medicine, faster with our testing and for their patients who receive customized care and targeted treatment based on their individual molecular profiles."

The NRAS gene (Neuroblastoma RAS Viral Oncogene Homolog Gene) encodes the NRAS enzyme, which is member of RAS family of proteins. (RAS is an abbreviation for Rat sarcoma, where these proteins were first found.) RAS family members belong to a class of proteins called small GTPases, which carry out a pivotal role in many vital biological processes within the human body, acting as molecular switches to transmit signals within cells. NRAS itself plays a key part in the MAPK (mitogen-activated protein kinase) cellular signaling pathway, which is involved in the regulation of cell growth, differentiation and survival.

CBLPath's NRAS sequencing assay detects variation in codons 12, 13 and 61 of the NRAS oncogene that may be present in colorectal cancer, melanoma and thyroid cancer patients.

In patients with metastatic colorectal cancer, the occurrence of NRAS mutations may be predictive of non-response to anti-EGFR (epidermal growth factor receptor) therapies such as cetuximab and panitumumab. The presence of activating mutations in the cell signaling pathway has been shown to impact the body's ability to respond to these cancer treatments.

In melanoma patients, NRAS mutations may indicate that a tumor will respond favorably to drugs that target genes downstream of NRAS in the MAPK cell signaling pathway, including RAF and MEK.

In thyroid cancer patients, RAS genetic mutations -- particularly NRAS -- have been detected in up to 40% of follicular thyroid carcinomas and up to 10% of papillary thyroid carcinomas. These genetic variants are also found frequently in follicular adenomas. Accordingly, a patient's RAS mutation status must be correlated with morphologic and clinical findings. This is especially important for patients with follicular thyroid tumors, as RAS mutations may be associated with more aggressive disease.

To speak with your local CBLPath representative about ordering NRAS Mutation Analysis testing, call 877.225.7284. To see the company's entire array of tests, visit http://www.CBLPath.com and click Test Menu.

About CBLPathCBLPath is a national specialty lab with a unique leadership position in the convergence of anatomic, molecular and digital pathology. Beginning from a clinical perspective, we harness molecular testing and digital pathology on an anatomic pathology foundation. CBLPath is committed to helping our clients deliver better medicine, faster. At our core are pathologists; excited about technology and innovation and its promise of helping patients. Through the Best Practice Partnership Program we help our pathologist-clients effectively compete against centralized reference laboratories, grow their Practice and remain independent -- Keeping Medicine Local. We provide our subspecialty physician clients comprehensive diagnostics and timely, accurate reports enabling the best patient care. For more about the company, please visit http://www.CBLPath.com.

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CBLPath Bolsters Cancer Management With New NRAS Gene Mutation Analysis Assay

* Glybera recommended for lipoprotein lipase deficiency

* First (OTC BB: FSTC.OB - news) gene therapy drug to reach market in West

* Green light follows three previous rejections

* Decision is victory for private Dutch biotech firm uniQure (Adds EMA comment, uniQure investors, more background on gene therapy)

LONDON, July 20 (Reuters) - European regulators have recommended approval of the Western world's first gene therapy drug -- after rejecting it on three previous occasions -- in a significant advance for the novel medical technology.

More than 20 years since the first experiments with the ground-breaking method for fixing faulty genes, scientists and drug companies are still struggling to apply gene therapy in practice.

Friday's decision by the European Medicines Agency (EMA) is a win for the drug's maker, the small Dutch biotech company uniQure, and a potential lifeline for patients with the ultra rare genetic disorder lipoprotein lipase deficiency (LPLD).

It comes too late, however, for investors in the previous listed firm Amsterdam Molecular Therapeutics (AMT (Taiwan OTC: 8271.TWO - news) ).

After the earlier rebuffs for its Glybera medicine, AMT was taken private by newly created uniQure in April because it could no longer fund itself in the public markets.

Patients with LPLD are unable to handle fat particles in their blood plasma and are afraid of eating a normal meal because it can lead to acute inflammation of the pancreas.

More:
UPDATE 1-European regulators back first gene therapy drug

AMSTERDAM, The Netherlands, July 20, 2012 /PRNewswire/ --

uniQure announced today that the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion that recommends marketing authorization of Glybera (alipogene tiparvovec) as a treatment for lipoprotein lipase deficiency (LPLD) under exceptional circumstances. LPLD is a very rare, inherited disease. Patients with the disease are unable to handle fat particles in their blood plasma, which leads to recurring severe abdominal pain and pancreatitis.

The European Commission (EC) generally follows the recommendations of the CHMP. "We expect final approval from the EC within 3 months after the CHMP decision," says Jrn Aldag, CEO of uniQure. "After today's positive recommendation, Glybera is poised to become the first in a class of gene therapy products approved in Europe to treat orphan diseases, rare conditions with a very high unmet medical need." Marketing authorization covers all 27 European Union member states.

Mr. Aldag continued: "Patients with LPLD are afraid of eating a normal meal because it can lead to acute and extremely painful inflammation of the pancreas, often resulting in a visit to intensive care. Now, for the first time, a treatment exists for these patients that not only reduces this risk of getting severely sick, but also has a multi-year beneficial effect after just a single injection. The positive recommendation from the CHMP for Glybera therefore represents a major breakthrough for both LPLD patients and for medicine as a whole. Restoring the body's natural ability to break down fat particles in the blood in order to prevent pancreatitis and excruciating abdominal pain suffered by patients, is what gene therapy is all about: curing disease at the genetic level."

"At uniQure we are developing treatments for a number of other rare diseases as well, such as acute intermittent porphyria and Sanfilippo B. But the potential of gene therapy stretches far beyond rare diseases. As shown recently in a publication in the New England Journal of Medicine (N Engl J Med 2011; 365:2357-2365, December 22, 2011), hemophilia patients treated with our proprietary gene are showing a sustained clinical effect over several years, which has allowed prophylaxis treatment to be stopped. In addition, we are advancing programs in degenerative diseases such as Parkinson's. We believe that just like antibodies, gene therapy will one day be a mainstay in clinical practice," Mr Aldag added.

As part of the approval, treatment with Glybera will be offered through dedicated centers of excellence with expertise in treating LPLD and by specially trained doctors to ensure ongoing safety of this novel treatment paradigm. uniQure has also committed to building a patient registry for continued understanding of this devastating, under-researched disease. The Company is now preparing to apply for regulatory approval in the US, Canada, and other markets.

Glybera has been tested in three interventional clinical studies conducted in the Netherlands and in Canada, in which a total of 27 LPLD patients participated. In all three clinical trials, Glybera was well tolerated, with no relevant safety issues observed. Data from these clinical trials indicate that a single dose administration of Glybera resulted in a long-term biological activity of the LPL protein.

About Glybera

uniQure has developed Glybera as a therapy for patients with the genetic disorder lipoprotein lipase deficiency. LPLD is an orphan disease for which no treatment exists today. The disease is caused by mutations in the LPL gene, resulting in highly decreased or absent activity of LPL protein in patients. This protein is needed in order to break down large fat-carrying particles that circulate in the blood after each meal. When such particles, called chylomicrons, accumulate in the blood, they may obstruct small blood vessels. Excess chylomicrons result in recurrent and severe acute inflammation of the pancreas, called pancreatitis, the most debilitating complication of LPLD. Glybera has orphan drug designation in the EU and US. LPL Deficiency affects 1-2 persons per million. For further information on LPLD visit http://www.lpldeficiency.com.

About uniQure

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First Gene Therapy in Western World Receives Positive Opinion in Europe from CHMP

Richard Knox/NPR

Timothy Ray Brown, widely known in research circles as the Berlin patient, was cured of his HIV infection by a bone marrow transplant, doctors say. His story inspired scientists to look for new ways to vanquish the disease in other patients.

Ask AIDS researchers why they think a cure to the disease is possible and the first response is "the Berlin patient."

That patient is a wiry, 46-year-old American from Seattle named Timothy Ray Brown. He got a bone marrow transplant five years ago when he was living in Berlin.

Brown, who now lives in San Francisco, is something of a rock star in the AIDS community. He has made himself endlessly available to researchers, who regularly bleed and biopsy him to learn as much as possible about his amazing cure.

"I have sort of a guilt feeling about being the only person in the world who's been cured so far," Brown said in an interview with NPR. "I'd like to dispel that guilt feeling by making sure that other people are cured."

The transplant was to cure leukemia unrelated to his HIV infection. The German doctors gave Brown a new immune system from a bone marrow donor who is immune to HIV by virtue of a genetic mutation shared by 1 percent of Caucasians.

Brown stopped taking his HIV drugs at the time of the transplant. Five years later, he's still free of HIV drugs and apparently free of HIV. And he's still the only person to be cured of HIV, doctors say, although everyone acknowledges that bone marrow transplantation is not something that could be used routinely for this purpose.

Dr. Steven Deeks at San Francisco General Hospital is following Timothy Brown closely. He's an organizer of a two-day symposium on curing HIV this week in advance of the International AIDS Conference in Washington, D.C.

Until recently, Deeks says, it was virtually taboo to use "HIV" and "cure" in the same sentence.

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HIV Cure Is Closer As Patient's Full Recovery Inspires New Research

We like to think of the Olympics as a level playing field thats why doping is banned. But scientific research complicates this view: There are numerous genetic factors known to confer advantages in athletic contests, from mutations that increase the oxygen carrying capacity of blood to gene variants that confer an incredible increase in endurance, and these mutations appear to be especially common in Olympic athletes. In other words, we may want an egalitarian Olympic games, but it probably isnt in the cards.

In the latest issue of the journal Nature, Juan Enriquez and Steve Gullans, a duo of forward-thinking biotech leaders at the firm Excel Venture Management in Boston, propose an alternative: Push the limits even further. They understand this may be unpalatable to the average fan, but they argue that the games are already full of biological competitive advantages.

They write that almost every male Olympic sprinter and power athlete ever tested carries the 577R allele a version of a gene that enhances performance. And thats just the beginning. There are endurance-related genetic variants in some athletes that have been shown to be far more likely to occur in those who successfully summit high mountains, and less likely to occur in those who fail to. These genes, they argue, are quite common, and athletes probably need a subset of them to achieve elite status.

There are also spectacular examples of extreme abilities that are conferred from genetic mutations. In the 1960s, the Finnish skier Eero Mntyranta won seven Olympic medals in cross-country skiing. Tests later revealed that he had a mutation in his EPOR gene, which improved his bloods oxygen-carrying capacity by somewhere between 25% and 50%. This almost certainly contributed to his remarkable streak of medals; taking supplements that mimic his mutation is strictly banned as doping.

In the face of all these variants, Enriquez and Gullans write that we are already watching a cohort of the genetically elite when we tune in to the Olympics: a showcase of athletes born with genetic advantages, they write. But, of course, some athletes' genetics confer more advantage than others.

In the future, they argue, there are only two ways the playing field could ever truly be level. One would be to handicap individual athletes based on their genetics, a la Kurt Vonneguts story Harrison Bergeron. But the approach that is favored by the authors would be to allow for what is called gene doping to allow athletes who did not win the genetic lottery to upgrade through gene therapy.

In gene therapy, genes are generally ferreted into cells by way of viruses, which allows them to integrate into a persons own DNA and begin producing new proteins. In the case of endurance athletes, one might introduce the coveted variant of the EPOR gene to improve oxygen-carrying capacity.

Given the clear genetic advantages of many athletes, they argue, removing relative genetic disabilities just may be the only way to finally make the Olympics fair while still keeping them fun to watch.

After all, they write, we watch the Games today to marvel at athletes who are faster, higher, stronger whether man or woman, amateur or professional, disabled or not.

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Is gene doping coming to the Olympics?

Public release date: 19-Jul-2012 [ | E-mail | Share ]

Contact: Vicki Cohn vcohn@liebertpub.com 914-740-2100 x2156 Mary Ann Liebert, Inc./Genetic Engineering News

New Rochelle, NY, July 19, 2012To enable greater reliance on renewable biomass resources for power generation, combination approaches such as co-firing of high percentages of biomass with coal offer unique advantages, but also significant challenges. A comprehensive review of the strategies currently available and in development to improve the characteristics of biomass is presented in Industrial Biotechnology, a peer-reviewed journal from Mary Ann Liebert, Inc.. The article is available free online at the Industrial Biotechnology website.

"Comprehensive and precise characterization of biomass feedstock is important for the development of biotechnology approaches to bioenergy and bioproducts development," says Larry Walker, PhD, Co-Editor-in-Chief and Professor, Biological & Environmental Engineering, Cornell University, Ithaca, NY.

Jaya ShankarTumuluru and colleagues, Idaho National Laboratory (Idaho Falls), describe and compare formulation, pretreatment, and densification options intended to overcome issues related to physical and chemical composition and storage of biomass and the logistics for successful co-firing of <40% mixtures with coal. The Review is entitled "Formulation, Pretreatment, and Densification Options to Improve Biomass Specifications for Co-Firing High Percentages with Coal."

The current issue of Industrial Biotechnology also features a Commentary by Rina Singh, PhD, Senior Policy Director in the Industrial Biotechnology section at the Biotechnology Industry Organization (BIO) on "The National Bioeconomy Blueprint: Meeting Grand Challenges," followed by highlights of the Blueprint.

Gauri Dhavan, Irene Hudson, and J. Peter Fasse, attorneys at Fish & Richardson PC (Boston, MA and New York, NY) take an in-depth look at the impact for the industrial biotechnology community of the Supreme Court's recent decision on patent eligibility of method claims in the Mayo Collaborative Services v. Prometheus Laboratories, Inc. case in the article "Patent Eligibility of Method Claims: What Is the Impact of the Supreme Court's Prometheus Decision?"

A new feature in Industrial Biotechnology, entitled Catalyzing Innovation, in this issue focuses on the application of zinc finger nuclease technology in the aquaculture food industry. Xavier Lauth, John Buchanan, and Keith Hansen, Center for Aquaculture Technologies (San Diego, CA) and Sigma Life Science (St. Louis, MO), describe this innovative technology in the article "Efficient Targeted Genome Editing for Finfish Aquaculture and Other Industries."

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About the Journal

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Strategies to improve renewable energy feedstocks

New approach sorts cancer driver mutations from abundant but irrelevant passengers

Newswise HOUSTON Its been a burning question in melanoma research: Tumor cells are full of ultraviolet (UV)-induced genetic damage caused by sunlight exposure, but which mutations drive this cancer?

None have been conclusively tied to melanoma. The sheer abundance of these passenger mutations has obscured the search for genetic driver mutations that actually matter in melanoma development and progression.

By creating a method to spot the drivers in a sea of passengers, scientists at the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute and The University of Texas MD Anderson Cancer Center have identified six genes with driving mutations in melanoma, three of which have recurrent hotspot mutations as a result of damage inflicted by UV light. Their findings are reported in the July 20 issue of the journal Cell.

Those three mutations are the first smoking gun genomic evidence directly linking damage from UV light to melanoma, said co-senior author Lynda Chin, M.D., Professor and Chair of MD Andersons Department of Genomic Medicine. Until now, that link has been based on epidemiological evidence and experimental data.

This study also is exciting because many of the recent large-scale genomic studies have not discovered new cancer genes with recurrent hot-spot mutations, a pattern strongly indicative of biological importance, said Chin, who also is scientific director of MD Andersons Institute for Applied Cancer Science.

The six new melanoma genes identified by the team are all significantly mutated and provide potential targets for new treatments.

Puzzle has thousands of potential pieces, but only requires a few dozen A number of important mutations had previously been identified as melanoma drivers. These include BRAF (V600) mutations, present in half of all melanomas, and NRAS (Q61) mutations. However, the vast majority of these mutations do not appear to be caused by direct damage from UV light exposure.

Those known mutations are important, but dont tell the whole story. Melanoma, the authors note, has higher genetic mutation rates than most other types of solid tumors. The majority are attributable to passenger mutations caused by UV light damage resulting in a DNA alteration called a cytidine (C) to thymidine (T) transition.

Chin together with Levi A. Garraway M.D, Ph.D., associate professor at Dana-Farber Cancer Institute and Harvard Medical School and senior associate member at the Broad Institute, sequenced the exons active portions of DNA involved in protein synthesis in 121 melanoma samples paired with normal DNA and found 86,813 coding mutations. The resulting mutation rate was higher than that ever reported in any other tumor type.

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Scientists Discover Melanoma-Driving Genetic Changes Caused by Sun Damage

Public release date: 19-Jul-2012 [ | E-mail | Share ]

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center

STANFORD, Calif. The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete the only cells that become a child and through which parents pass on physical traits.

"This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering and of applied physics. "We now have devices that will allow us to routinely amplify and sequence to a high degree of accuracy the entire genomes of single cells, which has far-ranging implications for the study of cancer, infertility and many other disorders."

Quake is the senior author of the research, which will be published July 20 in Cell. Graduate student Jianbin Wang and former graduate student H. Christina Fan, PhD, now a senior scientist at ImmuMetrix, share first authorship of the paper.

Sequencing sperm cells is particularly interesting because of a natural process called recombination that ensures that a baby is a blend of DNA from all four of his or her grandparents. Until now, scientists had to rely on genetic studies of populations to estimate how frequently recombination had occurred in individual sperm and egg cells, and how much genetic mixing that entailed.

"Single-sperm sequencing will allow us to chart and understand how recombination differs between individuals at the finest scales. This is an important proof of principle that will allow us to study both fundamental dynamics of recombination in humans and whether it is involved in issues relating to male infertility," said Gilean McVean, PhD, professor of statistical genetics at the Wellcome Trust Centre for Human Genetics. McVean was not involved in the research.

The Stanford study showed that the previous, population-based estimates were, for the most part, surprisingly accurate: on average, the sperm in the sample had each undergone about 23 recombinations, or mixing events. However, individual sperm varied greatly in the degree of genetic mixing and in the number and severity of spontaneously arising genetic mutations. Two sperm were missing entire chromosomes. The study has long-ranging implication for infertility doctors and researchers.

"For the first time, we were able to generate an individual recombination map and mutation rate for each of several sperm from one person," said study co-author Barry Behr, PhD, HCLD, professor of obstetrics and gynecology and director of Stanford's in vitro fertilization laboratory. "Now we can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems."

Most cells in the human body have two copies of each of 23 chromosomes, and are known as "diploid" cells. Recombination occurs during a process called meiosis, which partitions a single copy of each chromosome into a sperm (in a man) or egg (in a woman) cell. When a sperm and an egg join, the resulting fertilized egg again has a full complement of DNA.

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Stanford researchers first to determine entire genetic sequence of individual human sperm

More than 200 researchers investigating colon cancer tumors have found genetic vulnerabilities that could lead to powerful new treatments. The hope is that drugs designed to strike these weak spots will eventually stop a cancer that is now almost inevitably fatal once it has spread.

Scientists increasingly see cancer as a genetic disease defined not so much by where it starts colon, liver, brain, breast but by genetic aberrations that are its Achilles' heel. And with a detailed understanding of which genetic changes make a cancer grow and thrive, they say they can figure out how best to mount an attack. They caution that most of the drugs needed to target the cancer mutations have yet to be developed.

The colon cancer study, published Wednesday in Nature, is the first part of a sweeping effort that is expected to produce a flood of discoveries for a wide range of cancers.

"There are so many different ways that you can attack this tumor type," said Raju Kucherlapati, the principal investigator for the colon cancer project and a professor of genetics and of medicine at Harvard Medical School. "We have an opportunity to completely change the landscape."

Researchers have studied colon cancer before and have identified mutations that seemed critical, but their work lacked the scope of the new project and provided more limited information on genetic changes, said Dr. Sanford Markowitz, a colon cancer and genomics expert at Case Western Reserve University.

He, like nearly every other leading scientist in colon cancer genomics, is an author of the study.

About 150,000 Americans receive a diagnosis of colon or rectal cancer each year, and about 50,000 die annually from the disease.

The hope now is that the genetic alterations driving tumors are operating through only a limited number of genetic pathways that can be targeted by a more manageable number of drugs.

Those drugs have yet to be developed, said Dr. S. Gail Eckhardt, the head of the division of medical oncology at the University of Colorado and another author of the study. But, she added, the work "confirms where some of the drug development should be going."

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Colon cancer researchers find genetic vulnerabilities

An Otago University genetics student wants to have his genetic coding mapped and put onto a disk.

Steve Anderson approached genetics service New Zealand Genomics, in the hope of being able to study his DNA and genes as he ages.

Mr Anderson is a student in his 50s at Otago University, and has asked New Zealand Genomics to map his DNA for him.

He says there are over four and a half thousand genetic disorders.

"I'm sure most people in the future may be five- 10 years down the track will have their genome sequenced. it will be part of their medical records and then they'll be able to follow through with any disorders or various things that they find."

But he says there are numerous ethical and privacy issues which surround this - for example family members will have similar coding, which could reveal certain genetic disorders.

"Also I think there's issues with insurance companies and various things like this. If you have a problem coming up in the future and you yourself have been able to work that out then what's the chances of insurance and can they discriminate against you?"

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Otago University student wants a copy of his genetic coding

In a lecture at the Royal Institution in London, Nobel Prize-winning biologist Sir Paul Nurse said that, on the whole, biologists tend to leave grand ideas and theories to physicists and concentrate more on details. "What we like to do is count things and list things," Nurse said, adding that a 19th century biologist might count the numbers of hairs on a beetle's leg, while an ecologist might count and list the number and type of species in a habitat and a molecular biologist would sequence genes and count the numbers of proteins and RNAs in a cell. But biology also has great ideas, Nurse said. His lecture, presented in a series of videos at The Guardian, concentrates on five of these ideas the cell, the gene, natural selection, life as chemistry, and biology as an organized system, the latter of which, he added, has "yet to be fully formulated."

In his lecture on the gene, Nurse started with Gregor Mendel and his peas and traced how that one idea gave rise to heredity, James Watson and Francis Crick's discovery of the double helix, and to what is now known about the genome. The idea of the gene as the basis of heredity can explain the link between genotype and phenotype, he said, adding, "It has tremendous implications for what we are."

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Genetics' 'Tremendous Implications'

SAN MARINO, Calif.--(BUSINESS WIRE)--

The first patient has now been enrolled into the Phase 1 clinical trial sponsored by Viral Genetics (OTC Pink: VRAL) and supported by a donation from Scott and White Foundation. The trial will study Metabolic Disruption Technology (MDT) compounds in combination with an existing cancer therapy to treat drug-resistant ovarian cancer. A total of up to 24 patients will receive combination treatment of hydroxychloroquine and sorafenib (marketed as Nexavar) under primary investigator, Tyler Curiel, M.D., MPH, a medical oncologist affiliated with The Cancer Therapy and Research Center (CTRC) of The University of Texas Health Science Center at San Antonio. This clinical trial is the first sponsored by Viral Genetics based on the licensed research of Dr. M. Karen Newell-Rogers, the Companys Chief Scientist, and represents a milestone in the transition of the Company from preclinical- to clinical-stage. Patient enrollment is also expected to commence at Scott and White Hospital as soon as internal review procedures there are finalized.

Patient enrollment marks the formal beginning of a clinical trial and so we are quite happy to get underway after much preparation and hard work by our team members, and Dr. Curiels group, said Haig Keledjian, President of Viral Genetics. I want to emphasize that we would not have proceeded with this choice of one MDT compound if we and our advisors were not confident that it held real promise for patients, but one should also appreciate the severity of the illnesses we are attempting to treat in this study. We advise optimistic but cautious and restrained expectations.

Because of the staggered nature of patient enrollment which calls for a few patients to be enrolled and treated at low doses prior to enrolling additional patients at higher doses, full enrollment of the study could take up to a few months. Follow up and patient observation will continue post-treatment for up to 12 months. The study can be stopped at any time for safety reasons.

Study Design

Title: A Phase I Dose-Escalation Trial of Oral Hydroxychloroquine Plus Oral Sorafenib to Treat Epithelial Ovarian Cancer FIGO Stage III or Stage IV, or Extraovarian Peritoneal Carcinoma, or Fallopian Tube Carcinoma Failing or Ineligible for First-Line Therapy (HSO1)

The HSO1 study will examine the safety and efficacy of one of the MDT compounds, hydroxychloroquine (HCQ), in combination with an existing cancer drug, sorafenib (marketed as Nexavar) in the treatment of resistant or otherwise untreatable Stage III or IV ovarian cancer including related carcinomas. Viral Genetics is sponsoring the HSO1 study, which is taking place at the Cancer Therapy and Research Center and, eventually at Scott and White Hospital system.

The primary endpoints of the HSO1 study are related to safety and reflect the dose-escalation design of the trial, which is intended to find a maximum tolerated dose of different combinations of HCQ and sorafenib in patients while being alert to any potential toxicities. The study can be stopped in the event of significant adverse events, including toxicity. Both HCQ and sorafenib have separately been extensively studied in humans for safety and toxicity, and they have fairly well-understood individual safety profiles. This will be the first study to examine them in combination using the MDT research suggesting that such a dual-pronged approach would significantly enhance results of single agents alone.

Efficacy will also be evaluated through secondary endpoints in three ways: objective tumor responses (defined under the global Response Evaluation Criteria in Solid Tumors standard), progression-free survival, and certain immune system blood markers. A positive response would generally be characterized by shrinkage in tumor, lesion, or lymph nodes and/or patient survival without advancement of their existing cancer. Additional signs of efficacy include improvement or normalization in certain blood markers (including CA-125 and immunological tests) that are linked to successful treatment responses in ovarian cancer, although this would not generally be considered as a successful outcome on its own without other improvements as well.

There will be up to four separate groups or cohorts in the HSO1 study, each of which will have up to 6 patients. Each cohort will be given a combination of doses of HCQ and sorafenib over a treatment cycle of 28 days. Presuming low levels of toxicity following dosing, additional patients will be added and higher doses of the combination will be given. Depending on the outcome of the primary, and to a lesser extent, secondary endpoints, the study will enroll between 2 and 24 patients in total. Treatment will generally continue for as long as toxicity results remain within acceptable limits and patients experience clinical benefit. Results will be available throughout the course of each 28 day cycle, and will be reviewed by a Data Safety Monitoring Board.

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Viral Genetics Begins Phase 1 Clinical Trial for Ovarian Cancer

(Phys.org) -- New research at the Hebrew University of Jerusalem sheds light on pluripotencythe ability of embryonic stem cells to renew themselves indefinitely and to differentiate into all types of mature cells. Solving this problem, which is a major challenge in modern biology, could expedite the use of embryonic stem cells in cell therapy and regenerative medicine. If scientists can replicate the mechanisms that make pluripotency possible, they could create cells in the laboratory which could be implanted in humans to cure diseases characterized by cell death, such as Alzheimer's, Parkinson's, diabetes and other degenerative diseases.

To shed light on these processes, researchers in the lab of Dr. Eran Meshorer, in the Department of Genetics at the Hebrew Universitys Alexander Silberman Institute of Life Sciences, are combining molecular, microscopic and genomic approaches. Meshorer's team is focusing on epigenetic pathwayswhich cause biological changes without a corresponding change in the DNA sequencethat are specific to embryonic stem cells.

The molecular basis for epigenetic mechanisms is chromatin, which is comprised of a cell's DNA and structural and regulatory proteins. In groundbreaking research performed by Shai Melcer, a PhD student in the Meshorer lab, the mechanisms which support an open chromatin conformation in embryonic stem cells were examined. The researchers found that chromatin is less condensed in embryonic stem cells, allowing them the flexibility or "functional plasticity" to turn into any kind of cell.

A distinct pattern of chemical modifications of chromatin structural proteins (referred to as the acetylation and methylation of histones) enables a looser chromatin configuration in embryonic stem cells. During the early stages of differentiation, this pattern changes to facilitate chromatin compaction.

But even more interestingly, the authors found that a nuclear lamina protein, lamin A, is also a part of the secret. In all differentiated cell types, lamin A binds compacted domains of chromatin and anchors them to the cells nuclear envelope. Lamin A is absent from embryonic stem cells and this may enable the freer, more dynamic chromatin state in the cell nucleus. The authors believe that chromatin plasticity is tantamount to functional plasticity since chromatin is made up of DNA that includes all genes and codes for all proteins in any living cell. Understanding the mechanisms that regulate chromatin function will enable intelligent manipulations of embryonic stem cells in the future.

"If we can apply this new understanding about the mechanisms that give embryonic stem cells their plasticity, then we can increase or decrease the dynamics of the proteins that bind DNA and thereby increase or decrease the cells differentiation potential," concludes Dr. Meshorer. This could expedite the use of embryonic stem cells in cell therapy and regenerative medicine, by enabling the creation of cells in the laboratory which could be implanted in humans to cure diseases characterized by cell death, such as Alzheimer's, Parkinson's, diabetes and other degenerative diseases.

More information: The research appears in the journal Nature Communications as Melcer et al., Histone modifications and lamin A regulate chromatin protein dynamics in early embryonic stem cell differentiation. go.nature.com/9B33Ue

Journal reference: Nature Communications

Provided by Hebrew University of Jerusalem

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Researchers identify mechanisms that allow embryonic stem cells to become any cell in the human body