Adeno-associated virus (AAV)-based vectors are the leading platform for the delivery of gene therapy in vivo, but have a limitation in that they need to avoid neutralizing and potentially dangerous immune response to the AAV capsids.
AAV9 is one of the most used AAV serotypes for therapeutic applications due to its ability to transduce multiple tissues and organs, such as cardiac and skeletal muscle, liver, pancreas and the eye, and its ability to cross the blood-brain-barrier, crucial for reaching the central nervous system. However, approximately 40% of the population presents pre-existing neutralizing antibodies against AAV9, making them ineligible for AAV9-based treatments. Additionally, the common occurrence of cross-reactivity between variants often results in the neutralization of more than one AAV serotype by the same antibody. The presence of these neutralizing antibodies in a patient receiving AAV-based gene therapy can decrease treatment effectiveness and have detrimental immunogenic responses.
Researchers at the University of Florida have engineered the AAV9 capsid, based on the binding profile of anti-AAV9 antibodies derived from patients who received a commercially available AAV9 biologic therapy. Common binding regions in the AAV9 capsids are modified to circumvent the detection of the new capsid variant by pre-existing neutralizing antibodies and enhance the therapy's effectiveness. By incorporating one or more mutations on the AAV capsid, these AAV particles can escape neutralizing human antibodies to treat patients who would otherwise be unable to receive treatment.
Recombinant AAV9-based vectors escaping neutralizing antibodies for more efficient and safer gene therapies
Adeno-associated virus 9 (AAV9)-based vectors are the main gene therapy delivery vehicle, and several AAV9-based therapies hold FDA approval. However, the presence of neutralizing human antibodies in a significant portion of the population limits their use. These antibodies target and neutralize specific AAV serotypes, and in some instances, several AAV serotypes, greatly decreasing the number of patients able to receive therapy.
Researchers at the University of Florida engineered the AAV9 capsid, harboring one or more mutations in VP1, VP2 and/or VP3. These mutations modulate reactivity to neutralizing antibodies, while maintaining or even increasing their infectivity and production and transduction efficiency. Evasion of neutralizing antibodies decreases immunogenic responses and improves efficacy. This can enable delivery of AAV9-based therapies to subjects testing positive for these antibodies, allowing more patients to receive gene therapy and participate in clinical trials.
