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Pasqualina Colella, Ph.D. - "Developing improved AAV gene therapy approaches for Pompe disease"

Immunology and Liver gene therapy, Genethon, Evry, France
When Jul 10, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Short CV

In vivo gene therapy with adeno-associated-virus (AAV) vectors has recently shown to provide persistent therapeutic efficacy in several human inherited diseases, upon a single administration. This result, together with the marketing approval of the first AAV-based drugs, has the potential to change the standard of care of many human genetic diseases. Yet, the development of efficient AAV-based strategies is crucial to reach the therapeutic threshold in diseases requiring high/widespread transgene expression and/or transgene persistence during growth. The improvement of AAV gene therapy approaches is relevant especially considering that vector doses administered in humans correlate not only with efficacy but also with potentially detrimental immune responses. Finally, avoiding immune responses against therapeutic transgene products is key to the success of all AAV gene therapies. Based on these considerations, I will present the work we have done in the past years to develop improved AAV gene therapy strategies for the effective treatment of pediatric diseases requiring multi-organ targeting and the induction of immune tolerance to the therapeutic transgene product. To validate the improved AAV strategies we used Pompe disease (PD) as prototype disease model and provided proof-of-concept of efficacy in the PD mouse and in non-human primates. PD is caused by the lack the ubiquitous enzyme acid-alpha-glucosidase (GAA) and presents with multi-organ manifestations and frequent anti-GAA immunity that hampers the efficacy of enzyme replacement therapy (ERT). PD shows signs of both lysosomal storage disease and neuromuscular disease and its effective treatment would require the restoration of GAA activity virtually whole-body. In our studies, we found that the rational design of both transgene and regulatory elements allowed the development of improved AAV-GAA vectors. This allowed to restore GAA activity in multiple affected tissues long-term and to provide sustained immune tolerance to the transgene product. Interestingly, using improved AAV-GAA vectors, we observed whole-body therapeutic efficacy at low vector doses. Notably, this approach could potentially be translated to other diseases sharing similar therapeutic needs. 

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