Expression of NMNAT1 in the Photoreceptors is Sufficient to PreventNMNAT1-Associated Disease

Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a ubiquitously expressed enzyme involved in nuclear NAD + production throughout the body. However, mutations in the NMNAT1 gene lead to retina-specific disease with few reports of systemic effects. We have previously demonstrated that AAV-mediated gene therapy using self-complimentary AAV (scAAV) to ubiquitously express NMNAT1 throughout the retina prevents retinal degeneration in a mouse model of NMNAT1 -associated disease. We aimed to develop a better understanding of the cell types in the retina that contribute to disease pathogenesis in NMNAT1 -associated disease, and to identify the cell types that require NMNAT1 expression for therapeutic benefit. To achieve this goal, we treated Nmnat1 V9M/V9M mice with scAAV using cell type-specific promoters to restrict NMNAT1 expression to distinct retinal cell types. We hypothesized that photoreceptors are uniquely vulnerable to NAD + depletion due to mutations in NMNAT1 . Consistent with this hypothesis, we identified that treatments that drove NMNAT1 expression in the photoreceptors led to preservation of retinal morphology. These findings suggest that gene therapies for NMNAT1 -associated disease should aim to express NMNAT1 in the photoreceptor cells.