1. CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa.
- Author
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Nolan ND, Cui X, Robbings BM, Demirkol A, Pandey K, Wu WH, Hu HF, Jenny LA, Lin CS, Hass DT, Du J, Hurley JB, and Tsang SH
- Subjects
- Animals, Humans, Retinal Cone Photoreceptor Cells metabolism, Disease Models, Animal, Retinal Rod Photoreceptor Cells metabolism, Retinitis Pigmentosa genetics, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa therapy
- Abstract
Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models independent of the underlying rod-specific gene mutations. Therapeutic editing of the prolyl hydroxylase domain-containing protein gene (PHD2, also known as Egln1) in rod photoreceptors led to the sustained survival of both diseased rods and cones in both preclinical autosomal-recessive and dominant RP models. Adeno-associated virus-mediated CRISPR-based therapeutic reprogramming of the aerobic glycolysis node may serve as a gene-agnostic treatment for patients with various forms of RP., Competing Interests: Declaration of interests S.H.T. receives research support from Emendo. He is on the scientific and clinical advisory board for Emendo, Medical Excellence Capital, and Nanoscope Therapeutics. S.H.T. and X.C. hold a patent related to this work: WO2018232227A1., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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