AAV Viral Vector Designs For Therapeutic Application

Recombinant adeno-associated viral vectors (AAV) have emerged as the most preferred gene delivery modality for long-term therapy. A key component of successful gene therapy is the design of the vector. The vector design has two primary components: A) the transgene design with sequence variations and regulatory elements; and B) the AAV capsid. These two elements of vector design are critical for the expression efficacy, safety, and specificity of AAV-mediated gene therapy. In terms of the therapeutic gene of choice, a single AAV virion can only carry about 4.7KB of cargo DNA; therefore, for large genes, dual AAV vector designs are a necessity. We have developed several unique methods of split gene approaches to accommodate large therapeutic genes, including the hybrid dual-AAV vector system. Additionally, the tissue-specific promotors allow for targeted expression of the transgene in the disease tissues. Transgene organization can be optimized for maximal expression and safety during the vector production process. Finally, the selection of the appropriate AAV capsid serotype allows for high level expression in the disease affected tissues, preferentially.

Presented by Dr. Arkasubhra Ghosh, Director of GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore

Dr. Arkasubhra Ghosh obtained his PhD in Molecular Medicine from the University of Missouri-Columbia, School of Medicine, where he focused on developing AAV vectors for gene therapy. He subsequently worked on discovering how inflammation is regulated by telomeric proteins at the IMCB in Singapore. His current research focuses on understanding the genetic and molecular signalling mechanisms driving the pathogenesis of ocular disorders and cancers, determining the course and severity of the disorders for applications in early clinical diagnosis, and identification of novel therapeutic targets. A database of mutations and genes associated with genetic diseases within the Indian population has been established for future recombinant vector-based gene therapy and cell replacement modalities. His Gene Therapy platform focuses on recombinant Adeno-associated virus (AAV) as the transfer vehicle, utilizing multiple pseudotyped capsids for efficient delivery and targeted therapy. Further, transgene engineering tools and a clinical-grade gene therapy vector production platform have now been developed, and various functional genetics studies are being done with the aim of starting human clinical gene therapy trials in India. He is actively involved in mentoring graduate scholars, clinical fellows, and post-doctoral fellows. He has published over a hundred research articles and serves on numerous research committees and journal editorial boards