Targeting Innate Immunity to Allow Redosing of AAV Viral Vectors
Abstract
Scientific Objective: The proposed studies are designed to improve the safety and efficacy of AAV-microdystrophin gene therapy for Duchenne muscular dystrophy. This goal will be achieved by our study, which is designed to improve our understanding of the parts of the human immune system that cause rejection of AAV-microdystrophin. Applicability to patients: AAV-microdystrophin is a therapy designed to replace the missing dystrophin protein in Duchenne muscular dystrophy. There are currently three ongoing phase I/II clinical trials testing this therapy in patients, and in a few patients, serious adverse events have been observed, related to the immune response. Because of this immune response, there is currently no way to re-administer AAV-microdystrophin once a patient has been dosed or exposed to AAV during their lifetime. This is because when patients are dosed with AAV-microdystrophin, they are being immunized against the gene therapy and their body thinks it is foreign. Our goal is to interfere with the parts of immunity that are causing this response so that AAV-microdystrophin can be re-administered. To know what parts of the immune system to target, we need to study the response to AAV exposure. Potential Clinical Applications: These studies have the potential to impact three aspects of AAV-microdystrophin treatment for DMD. First, by blocking the immune response, the therapy will be safer. Second, if the therapy can be re-dosed, then lower doses can be used and this will improve the safety. Third, by administering multiple doses, the efficacy of this therapy will be increased and more long-lasting. Time line: At the end of the 2-year period, we anticipate that we will have an improved understanding of the human immune response to AAV. Impact: The proposed investigation describes the steps that are necessary for us to gather pre-clinical translational data to support the therapeutic development path to use immune suppressant drugs to accompany AAV-microdystrophin. If successful, these inhibitors have great potential to improve the safety and efficacy of AAV-microdystrophin and other AAV-mediated delivery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010450
Entities
People
- Melissa J Spencer
Organizations
- United States Army
- University of California, Los Angeles