Chimeric AAV vectors enabling antibody evasion and redosing for cardiac gene therapy
Unmet Need
Gene therapy using adeno-associated virus (AAV) vectors is severely limited by pre-existing immunity in 30–80% of adults and by the development of neutralizing antibodies after initial treatment, preventing redosing. There is a critical need for AAV vectors that can evade both natural and treatment-induced immunity to expand patient eligibility and enable repeat dosing for chronic conditions.
Technology
Duke inventors have developed chimeric AAV capsids designed to improve AAV-based gene therapy in patients with pre-existing or treatment-induced AAV immunity. Specifically, engineered capsids derived from non-mammalian AAV isolates, including a lead candidate AAV.div3A, demonstrate robust transduction in murine heart, skeletal muscle, and liver following intravenous administration while evading neutralizing antibodies found in human donor sera and passively immunized mice. A next-generation variant, AAV.div3A-M1, was developed through additional peptide surface display, achieving 14-fold higher transduction in murine heart, 11-fold higher transduction in diaphragm, and a 90% reduction in liver targeting. These capsids have been demonstrated in murine models to enable successful re-administration and cumulatively improved expression of a therapeutic transgene in a Pompe disease mouse model following prior AAV exposure.
Other Applications
This platform could also enable gene therapy redosing for other chronic diseases requiring long-term expression or retreatment; enabling treatment of patient populations previously excluded from AAV-based therapies due to seropositivity.
Advantages
- Enables AAV gene therapy in patients with pre-existing antibodies to conventional serotypes.
- Allows redosing after initial AAV treatment without loss of efficacy.
- Achieves up to 14-fold higher cardiac and 11-fold higher diaphragm transduction, with reduced off-target liver delivery.
- Expands therapeutic access by overcoming a key barrier to AAV gene therapy eligibility.