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AAV-Engineering For Advanced Gene Therapy

Identifying variants of adeno-associated virus (AAV) that can address current challenges in gene delivery

Gene therapy with AAV (adeno-associated virus) as a delivery vehicle is a leading therapeutic modality for genetic disorders that is approved in Europe for the metabolic disease Familial Lipoprotein Lipase Deficiency. It is currently being tested in clinical trials in the U.S. to treat other rare conditions like the retinal Leber Congenital Amaurosis and the hereditary bleeding disorder Hemophilia B. AAV serotypes, or variants, are favored over other viral vectors because they are non-pathogenic, relatively safe due to their inability to integrate into the genome of targeted cells, and because, in principle, they can reach cells in different tissues.

Red and yellow denote regions of capsid protein that can be changed without viral loss of function. Blue shades denote regions pertaining to the capsid core that cannot be mutated without loss of viral function). Credit: Eric Kelsic/Wyss Institute at Harvard University

However, to be able to harness the full power of AAV gene delivery, biomedical researchers and clinicians must overcome several challenges that are related on one hand to the limited efficiency and cell-type and tissue specificity of existing AAV serotypes, and on the other to the immune responses triggered in the patients in response to a viral vector. This AAV-induced immunogenicity is responsible for the acquisition of resistance to gene therapy with the variant to which a body had prior exposure, and damaging inflammatory reactions in patients after administration of large therapeutic doses.

Our platform is built on bringing together all central AAV research nodes to provide an improved therapeutic vector to treat disease and our universal affliction, aging.

George Church

Wyss Institute researchers are taking a new data-driven, rapid evolution approach towards overcoming these barriers.  Using methods that allow the synthesis and testing of many variants at a time, and combining those with comprehensive in vivo tissue-screening protocols and machine learning, they are selecting AAV variants with better cell-type and tissue specificities as well as improved immune-evasion potential. The Wyss scientists are also engineering existing AAV vectors to prevent damaging inflammatory and immune responses.

In addition, the Wyss team employs AAV-mediated gene delivery to fight skin aging and disease.

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