Expression of NMNAT1 in the Photoreceptors is Sufficient to Prevent NMNAT1-Associated Disease
Brown, E. E.; Scandura, M.; Pierce, E. A.
Show abstract
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 Nmnat1V9M/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.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia 97%
- Limited time window for retinal gene therapy in a preclinical model of ciliopathy 97%
- MCOLN1 gene-replacement therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV. 94%
Similar papers in this journal
- Evaluation of subretinally delivered Cas9 ribonucleoproteins in murine and porcine animal models highlights key considerations for therapeutic translation of genetic medicines 95%
- Ccr2 suppression by minocycline in Cx3cr1/Ccr2-visualized inherited retinal degeneration 94%
- A Cell Penetrating Peptide from Type I Interferon Protects the Retina in a Mouse Model of Autoimmune Uveitis 92%
Similar papers in this journal
- RPE-specific MCT2 expression promotes cone survival in models of retinitis pigmentosa 97%
- Targeting ON-bipolar cells by AAV gene therapy stably reverses LRIT3-congenital stationary night blindness 94%
- Transcriptomic Analysis Of The Ocular Posterior Segment Completes A Cell Atlas Of The Human Eye 94%
Similar papers in this journal
- C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function 96%
- Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease 95%
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology 94%
Similar papers in this journal
- Dual CRALBP isoforms unveiled: iPSC-derived retinal modelling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy 96%
- AAV NRF2 Gene Therapy Preserves Retinal Structure and Function in Rodent Models of Oxidative Damage 95%
- A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.