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AGTC and the University of Massachusetts Medical School Report Promising Phase II Gene Therapy Clinical Data

Study published in the Journal of Clinical Investigation shows sustained therapeutic protein expression detected for up to one year following a single dose

November 15, 2013 - AGTC, a clinical stage biotechnology company developing adeno-associated virus (AAV)-based systems to deliver human therapeutics, today reported encouraging results from a phase II clinical trial using the Company’s proprietary AAV gene therapy vector system. Data from the study demonstrate that intramuscular administration of AAV-based therapies supports sustained expression of a therapeutic protein for up to a year following a single dose. The data also provide insight into the mechanism by which AAV vectors can persist in patients’ cells in the presence of an immune response to the vector. The results were published in the current online issue of the Journal of Clinical Investigation. Review the Full Study

The ongoing phase II trial from which these data were compiled is designed to evaluate the safety and efficacy of AAV-based gene therapy in patients with alpha-1 antitrypsin (AAT) deficiency, an inherited genetic condition. Patients in the study received intramuscular injections of an AAV vector encoding wild-type AAT. The amount of AAT protein expression increased proportionally with the dose of vector administered and was sustained for more than one year following a single treatment. Importantly, sustained expression was achieved without the need for treatment to suppress immune responses against the vector surface protein. This is an important finding that supports intramuscular administration as a potentially effective method for delivering AAV-based therapies. This finding also provides important insight into variations in immune responses to AAV vectors based on the route of administration.

“Although this is a small study, these findings support the safety and efficacy of AAV-based therapies manufactured using our proprietary processes, and provide additional evidence that AAV vectors can support sustained expression of therapeutic proteins,” said Sue Washer, president and chief executive officer of AGTC. “The finding that regulatory T cells may limit the immune response to AAV vectors delivered intramuscularly should enhance our efforts to optimize the design and delivery methods of our product candidates. We are currently evaluating a standard limb infusion method to deliver our AAV-ATT clinical candidate, which may help to increase AAT expression beyond what has been described in this publication. The strategy of optimizing each aspect of gene therapy, including vector design, gene and promoter selection, and delivery method, is an essential part of our approach to realizing the potential of AAV-based gene therapy for patients with few or no treatment options.”

In muscle biopsy specimens taken one year after AAV-ATT administration, cells with characteristics of regulatory T cells were found adjacent to muscle cells expressing AAT protein. These analyses also showed that AAV capsid was still present in transduced cells up to one year following administration. Further analyses demonstrated that the T cells were stimulated by AAV capsid protein. Given that some chronic viral infections have been shown to induce regulatory T cells that limit the immune response to the virus, it is possible that the persistence of AAV capsid may help to limit the immune response to AAV-based therapies administered intramuscularly. This is a key finding because previous studies of AAV vectors delivered to the liver have shown immune responses that lead to decreased expression of the delivered gene over time.

“This study shows that persistent anti-capsid T cell immune responses did not cause any safety concerns and did not inhibit sustained transgene expression,” said Terence R. Flotte, MD, dean of the School of Medicine and provost & executive deputy chancellor of the University of Massachusetts Medical School.  “Moreover, these findings provide a potential mechanism that accounts for the sustained presence of transduced cells even in the absence of immune suppression strategies.  These data support a role for regulatory T cells in limiting the immune response to transduced cells following intramuscular administration of AAV vectors. These results are highly encouraging for the future of muscle-directed AAV gene therapy.”

Alpha-1 antitrypsin deficiency is an inherited, genetic condition characterized by reduced levels of a required protein leading to increased risk of developing emphysema and liver disease. It affects approximately 50,000 people in the US.  The current therapy, requiring weekly intravenous infusions, is in short supply and not all patients are able to receive treatment.

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