By its very nature, gene therapy of genetic diseases is a technology of tremendous potential in relieving human suffering, but it is at the same time a massive and dauntingly complex scientific endeavor. That we currently stand on the threshold of successfully curing genetic diseases is a monument to the unprecedented scientific breakthroughs achieved in recent years, in mapping the genetic mutations underlying inherited metabolic diseases and in precisely defining the pathophysiology of the resulting cellular defects. These accomplishments have required the concerted effort of scores of dedicated clinical and basis science researchers, many of whom are faculty members at the University of Iowa. However, despite the recent advances, the science for gene therapy of human genetic diseases is still currently in its infancy and much work remains to be done. The Iowa Center for Gene Therapy has a particular emphasis on cystic fibrosis, but extends as well to other areas in which the University of Iowa has particular strengths. Historically, the academic culture at The University of Iowa has been one of collaboration and the sharing of resources and expertise, and gene therapy research for CF has benefited from the active gene therapy programs directed at other target organs and diseases. It is the goal of this Center to further facilitate such interactions among researchers investigating gene therapy for diseases affecting the CNS, muscle, vessels, skin, liver, and lung.

Steps for Gene Therapy Research

There are three broad research areas underlying the development of successful gene therapy approaches for the treatment of inherited metabolic diseases:

(1) The first is the identification of disease-causing gene mutations.

(2) The pathophysiology arising from the genetic mutation must then be studied in the context of gene function and the basic cell biology of the affected organ system(s), so that the appropriate cellular targets for gene therapy can be identified.

(3) Lastly, suitable and effective gene therapy vector systems for targeting the specific affected system and providing long-term amelioration of the disease must be developed.

Cystic Fibrosis: The Disease

Cystic Fibrosis is the most common fatal genetic disease in the Caucasian population, with a frequency of about one in 2,500 live births a year. Currently, the median age of survival for a patient with CF is 31 years. Although disseminated throughout other organs, the most life-threatening clinical feature of CF is pulmonary obstruction caused by abnormally thick mucus secretions and chronic infection by opportunistic bacteria, such as Pseudomonas and Staphlococcus, which lead to respiratory failure. Treatment today consists of a comprehensive approach, including postural drainage and percussion, replacement of pancreatic enzymes and proper nutrition, administration of antibiotics, mucus-thinning and anti-inflammatory drugs, and newer drugs aimed at symptomatic correction. In 1989, the defective gene underlying CF was identified as Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), opening a new era of investigation into the pathophysiological mechanisms of CF disease, and leading to the promise of gene transfer as the ultimate therapeutic intervention. CFTR is a cAMP-regulated Cl- channel and also has been implicated in the regulation of other ion channels localized in the apical membranes of airway epithelial cells. Mutations in CFTR result in defective ion transport, leading to thick mucus, impaired mucociliary clearance and decreased bacterial killing. Despite recent progress in associating CF defects with CFTR dysfunction, there remain many unanswered questions concerning the roles of CFTR in normal airway biology and CF pathology, and the identification of the relevant cellular targets for gene therapy.

The University of Iowa has a long-standing history as a leader in the field of CF research and applied gene therapies for this disorder. In this regard the University of Iowa has several funded CF research programs, including a Research Development Program (RDP) funded by the Cystic Fibrosis Foundation, a CF Scientific Center of Research (SCOR) funded by NHLBI, and a Gene Therapy for Cystic Fibrosis program project grant (PPG) funded by NIH, all under the direction of Michael Welsh. These programs are an integral part of the CF research base involved in the Iowa Center for Gene Therapy of Cystic Fibrosis. In three Clinical Trials for gene therapy of CF, Dr. Michael Welshs group and colleagues in the CF Clinical Center have evaluated the safety and efficacy of CFTR gene delivery to the nasal mucosa of CF patients with recombinant adenoviral vectors and cationic liposomes (1, 2, 3, 4, 5). Importantly, the CF research community at the University of Iowa has also made significant contributions to increase understanding of lung development and the identification of putative stem cell targets for gene therapy, as well as the recent identification of new hypotheses regarding the pathogenesis of bacterial infection in CF airways. This group of investigators has also been instrumental in developing animal and in vitro model systems critical for studying disease pathogenesis and for testing treatment strategies and surrogate endpoints. Ongoing research programs in vector development, vector-host interactions and virology have aided in understanding some of the present limitations in current vectors. Studies are now directed toward improving the efficacy of several vector systems (adenoviruses, adeno-associated viruses [AAV], retroviruses, and non-viral vectors) for gene transfer to multiple organs. Development of an effective gene therapy for cystic fibrosis (CF) requires further advancement in areas of basic research on airway biology, CF pathophysiology, CFTR function, and vector design and evaluation.

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Center for Gene Therapy - Research - University of Iowa

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