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Published April 27, 2021 | Published
Journal Article Open

Targeted Gene Therapy with Engineered Systemic AAVs for the Central and Peripheral Nervous Systems Prevents Motor Coordination Phenotypes in a Mouse Model of Friedreich's Ataxia


Friedreich's Ataxia (FA) is a genetic disease characterized by progressive ataxia and cardiomyopathy. In FA, insufficient expression of frataxin (FXN) increases cell susceptibility to damage from oxidative stress. Neuronal degeneration in the deep cerebellar nuclei and dorsal root ganglia (DRGs) cause loss of motor coordination, while cardiomyopathy in FA contributes to early death. Systemically delivered AAVs can non-invasively target genetic cargo to diverse sites throughout the body, with some serotypes able to reach the CNS. However, at high doses, these vectors can cause severe toxicity, emphasizing the need for targeted, efficient gene delivery vectors. In this study, we used engineered AAVs to target FXN to cell types of pathophysiologic relevance to FA, while de-targeting the liver and cell types typically spared in human disease. A DNA plasmid containing FXN and its putative gene regulatory elements and control constructs were packaged into AAV.CAP-B10[1] and AAV-PHP.PNS2, two next generation systemic AAVs that have demonstrated transduction biases toward CNS and PNS respectively. A cocktail of both capsids packaging either the FXN or control cargo were delivered intravenously to a pilot cohort of young adult FA model mice (inducible shRNA-based FXN knockdown mice (FXNiKD)[2], n=7 per group) 12 weeks prior to doxycycline-induction of the disease phenotype. Motor, sensory and cardiac function was assessed using the beam traversal test, gait analysis, weightlifting and electrocardiography before quantitative tissue analysis was performed to assess FXN levels and pathologic hallmarks. Exogenous FXN expression mimicked the endogenous patterns of non-diseased mice in the CNS and DRGs, with reduced liver expression. Importantly, prophylactic AAV-FXN expression prevented induction of motor and coordination deficits as measured by foot slips and time to traverse the narrowing beam, compared to controls, with performance resembling wildtype littermates. We are investigating whether it is also possible to reverse existing motor deficits and pathology in mice using targeted AAV-FXN intervention after induction of the disease phenotype. These findings demonstrate the utility of engineered AAVs for pre-clinical research to test precision gene therapies in neurodegenerative disease models.

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© 2021 American Society of Gene & Cell Therapy. Available online 27 April 2021.

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