Martin Kang, PhD

Gene therapy using adeno-associated viral (AAV) vectors is a promising therapeutic strategy for genetic pediatric lung diseases. Naturally found in the environment, AAV is a preferred vector for gene therapy as it is not associated with any known diseases in animals or humans. Until recently, few AAV vectors were capable of effectively transducing human lung cells. We recently demonstrated the promising potential of AAV gene therapy for the fatal neonatal respiratory disease surfactant protein-B (SP-B) deficiency in an animal model. However, the effectiveness of viral vectors like AAV is mitigated by our immune response which manifests as a loss in therapeutic efficacy over time, and the inability to redose AAV to prolong its effects. Our current research utilizes a novel strategy to inhibit the innate immune response against AAV to allow for effective long-term gene therapy in the lungs. This approach results in an unprecedented improvement in survival in our SP-B deficient mouse model to nearly 300 days versus 5 days in untreated mice by allowing us to readminister AAV. In this present research plan, we will characterize how this strategy affects the adaptive B and T cell immune response to AAV in the lungs, determine the safety and efficacy of redosing AAV gene therapy in pediatric aged lungs, and attempt to further improve gene therapy efficacy by targeting B and T cells. If successful, this strategy will lead to a long-term therapy for SP-B deficiency, and provide the formative steps of translating this gene therapy into the clinic. This work may also influence how other respiratory AAV gene therapy constructs are designed in the future. There are several genetic pediatric diseases that currently have no treatment options and would benefit from the identification of an effective gene therapy vector that can be redosed in the lungs.

Funded by the ALA/ATS Commemorative 120th Anniversary Joint Research Award