Engineering adeno-associated viral vectors to evade immune responses

Gene therapy works by transferring genetic materials (cargo, the FXN gene) in a vector to FA-damaged tissues. Adeno-associated virus vectors (AAVs) are the leading vectors used in gene therapy, given their safe clinical record, robust delivery efficiency, specificity, and superior ability to enter the brain. There are also extensive studies to package regulatory elements into AAVs to make the cargo gene only active in FA-affected tissues, thus minimizing unnecessary harm to other tissues. There are two typical ways to deliver AAVs to human bodies: direct injection and intravenous (IV) injection. Direct injection involves delivering the AAVs directly into the target organ, but its downside is that it will not treat all affected tissues. IV injection, on the other hand, allows the AAVs to circulate in the bloodstream and reach all therapeutic targets throughout the body. However, IV injections bring the risk of immune toxicity. Up to 70% of human populations have neutralizing antibodies (NAbs) against AAVs, which trigger severe immune responses and body damage. For this reason, many clinical treatments have opted to exclude patients with NAbs from AAV-based gene therapy. This proposal aims to engineer AAVs to escape from these Nabs, enabling the treatment of all FA patients. Dr. Lin aims to (1) develop NAb-based selection assays and screen AAV variants to discover new AAVs that don’t bind to NAbs and retain the desired delivery function in model animals; (2) develop novel AAVs targeting newly identified receptors important for AAVs to enter the human brain, in order to enhance brain delivery.