Search

Inherited retinal diseases (IRDs) are characterized by progressive vision loss. There are over 270 causative IRD genes, and variants within the same gene can cause clinically distinct disorders. One example is RLBP1, which encodes CRALBP. CRALBP is an essential protein in the rod and cone visual cycles that take place primarily in the retinal pigment epithelium (RPE) but also in Müller cells of the neuroretina. RLBP1 variants lead to three clinical subtypes: Bothnia dystrophy, retinitis punctata albescens, and Newfoundland rod-cone dystrophy. We modeled RLBP1-IRD subtypes using patient-specific induced pluripotent stem cell (iPSC)-derived RPE and identified pathophysiological markers that served as pertinent therapeutic read-outs. We developed an AAV2/5-mediated gene-supplementation strategy and performed a proof-of-concept study in the human models, which was validated in vivo in an Rlbp1 -/- murine model. Most importantly, we identified a previously unsuspected smaller CRALBP isoform that is naturally and differentially expressed both in the human and murine retina. This previously unidentified isoform is produced from an alternative methionine initiation site. This work provides further insights into CRALBP expression and RLBP1-associated pathophysiology and raises important considerations for successful gene-supplementation therapy., Competing Interests: Declaration of interests V.K. is scientific co-founder of Horama (now Coave Therapeutics and eyeDNA Therapeutics). V.K. and M.P. are inventors of the patent WO/2015/082690 concerning AAV-mediated gene transfer into the RPE., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Low-threshold mechanoreceptor neurons (LTMs) of the dorsal root ganglia (DRG) are essential for touch sensation. They form highly specialized terminations in the skin and display stereotyped projections in the spinal cord. Functionally defined LTMs depend on neurotrophin signaling for their postnatal survival and functioning, but how these neurons arise during development is unknown. Here, we show that specific types of LTMs can be identified shortly after DRG genesis by unique expression of the MafA transcription factor, the Ret receptor and coreceptor GFRalpha2, and find that their specification is Ngn2 dependent. In mice lacking Ret, these LTMs display early differentiation defects, as revealed by reduced MafA expression, and at later stages their central and peripheral projections are compromised. Moreover, in MafA mutants, a discrete subset of LTMs display altered expression of neurotrophic factor receptors. Our results provide evidence that genetic interactions involving Ret and MafA progressively promote the differentiation and diversification of LTMs., (2009 Elsevier Inc. All rights reserved.)