Immune activation and subject-specific risk in ocular gene therapies

Project summary Gene therapies for heritable eye disorders are being developed at an unprecedented rate, but the immune response, despite being a known reaction to gene therapies, is poorly characterized. Side effects to ocular gene therapies do not affect individuals to the same degree clinically, despite receiving similar dosing and treatments, underscoring the need for understanding subject-specific risk. In this proposal, I will 1) determine the effect of immunosuppression on toxicity risks after intraocular gene therapy, 2) discover genetic variants that modify susceptibility to gene therapy-related toxicity, and 3) test if subject-specific risks can be estimated before treatment using blood. Genotype-phenotype correlations will be performed to map genetic loci associated with toxicity phenotypes in mice with a diverse genetic background. To estimate risk specific to an individual animal, biomarkers in blood will be measured and analyzed by machine learning. The overall objective of the research is to use subject-specific characteristics to predict and mitigate toxicity risks. The long-term goal is to achieve precision medicine via individualized risk assessment for ocular and for all gene therapies. Though the proposed research uses mice as a model organism, the outcomes are highly clinically relevant and have immense potential for making a positive clinical impact. The proposed work will advance personalized design and optimization of ocular gene therapies.