FDA & ASGCT's Immune Responses to AAV Vectors

Shari Gordon, PhD, from AskBio, spoke about the immunogenicity of empty capsids in healthy volunteers and modulating the immune response. Preview below and watch the full talk and Q&A on demand. 

Building on the concept 'the product is the process', this presentation provided an overview of the quality attributes of AAV based vectors that contribute to innate and adaptive immune responses in human gene therapy, and how they are affected by vector and manufacturing process design. Preview below and watch the full talk and Q&A on demand. 

Systemic gene replacement therapy of adeno-associated virus (AAV) is attractive as a potential treatment for a variety of genetic disorders. However, therapeutic use of high-dose AAV is associated with activation of both adaptive and innate immune responses, which pose ongoing concern about patient safety as well as efficacy of gene transfer and expression. Our data, suggests that targeted immune modulation therapy, as an adjunctive therapy, is a successful approach to prevent complement mediated immune response triggered by systemic AAV. In addition, our data suggests that immune suppression can allow for repeated AAV dosing. Preview below and watch the full talk and Q&A on demand. 

During the talk, Dr. Thorne covered the definition of a companion diagnostic (CDx) as specified in FDA guidance and how CDx are indicated for use with gene therapies. Dr. Thorne also covered the regulation of CDx, from use as an investigational device in a clinical study to commercialization, and gave an overview of the studies recommended to support a premarket submission. Preview below and watch the full talk and Q&A on demand. 

This talk provided an overview of the complement system and thrombotic microangiopathy, summarized the clinical experience with thrombotic microangiopathy associated with AAV gene therapy, considered possible contributing factors, and reviewed practical risk mitigation approaches in the clinical trial setting. Preview below and watch the full talk and Q&A on demand. 

Preview below and watch the full talk and Q&A on demand. 

GM2 Gangliosidosis (Tay-Sachs and Sandhoff diseases, due to defects in HEXA and HEXB genes, respectively) are severe, progressive single gene disorders causing global injury to the central nervous system because of accumulation of toxic GM2 gangliosides. A rAAVrh8-based gene therapy has been administered to 8 GM2 patients (2 in an expanded access trial, and 6 in a phase 1-2 trial) by a combination of bilateral intrathalamic, intracisterna magna and intrathecal gene therapy. Patients were immune suppressed with B-cell ablation, systemic corticosteroids (for 3 months) and sirolimus (for 6 months). Innate and adaptive immune responses, including Treg responses were measured up to 2 years after the initial therapy. The complexities of these responses were discussed. Preview below and watch the full talk and Q&A on demand. 

Preview below and watch the full talk and Q&A on demand.