Immunomodulation Approaches to Improve Safety And Efficacy of Gene Therapy Treatment in Friedreich’s Ataxia

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Project Summary / Abstract Friedreich’s ataxia (FA) is the most common form of hereditary ataxia, affecting ~1 in every 50,000 people in the US. FA is an autosomal recessive condition caused by the inheritance of a GAA trinucleotide repeat expansions in the frataxin (FXN) gene, which results in reduced levels of FXN in mitochondria. Clinical manifestations appear between the ages of 8 and 16 as a multisystem disorder, primarily affecting cardiac and nervous system. FA is steadily progressive and is characterized by diminished quality of life (QOL) and premature death, usually caused by ventricular arrhythmia. There is currently no effective treatment. Gene replacement using recombinant adeno-associated viral vectors (rAAV) carrying the human FXN gene is a promising therapeutic strategy for FA as shown by our group and others. Our group has conducted toxicology and biodistribution studies in support of the first-in-human gene therapy study for the treatment of FA. The IND will be submitted in 2020 Q2 and we expect to enroll the first patient immediately after approval. However, a critical unresolved challenge for the success of gene therapy is the host immune response to the vector capsid. Administration of rAAV vectors carrying a transgene elicits cellular and adaptive immune responses against the vector capsid. Exaggerated immune responses can lead to safety concerns and impact longevity of expression, as well as contribute to loss of the therapeutic effect. In addition, preclinical data from our lab and others suggest that prior natural exposure to AAV (pre-existing immunity), can lead to severe infusion reactions and diminished therapeutic efficacy with subsequent AAV exposure. Current AAV-mediated gene therapy trials must consider a single exposure to the therapeutic vector at a dose below the toxic level and exclude subjects with pre-existing AAV immunity. Our hypothesis is that a more effective dose could be achieved safely by incremental dosing of AAV with multiple lower AAV doses over time. Our extensive preclinical and clinical data demonstrate that B-cell depletion with rituximab and sirolimus in association with AAV delivery prevents formation of antibodies and confirm our hypothesis. However, prolonged use of rituximab has been associated with rare but devastating adverse events. In this U01 application, we propose to improve the overall efficacy and safety of the planned FA gene therapy program by identifying an optimal immunomodulation regimen to prevent immune responses against the AAV capsid, which will allow for safe repeated administration of AAV (Aim 1) and therapeutic AAV administration in subjects’ with pre-existing immunity (Aim 2). We anticipate that the proposed studies will have a major impact on the application of gene therapy approaches not only for FA, but for a wide array of neuromuscular genetic disorders.