Small-Molecule-Directed Endogenous Regeneration of Visual Function in a Mammalian Retinal Degeneration Model

Degenerative retinal diseases associated with photoreceptor loss are a leading cause of visual impairment worldwide, with limited treatment options. Phenotypic profiling coupled with medicinal chemistry were used to develop a small molecule with proliferative effects on retinal stem/progenitor cells...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-02, Vol.25 (3), p.1521
Main Authors: Mokady, Daphna, Charish, Jason, Barretto-Burns, Patrick, Grisé, Kenneth N, Coles, Brenda L K, Raab, Susanne, Ortin-Martinez, Arturo, Müller, Alex, Fasching, Bernhard, Jain, Payal, Drukker, Micha, van der Kooy, Derek, Steger, Matthias
Format: Article
Language:English
Subjects:
Animals
Cell growth
Disease
Disease Models, Animal
functional recovery
Genetic engineering
Humans
inherited retinal diseases
Investigations
Kinases
Mammals
Methylnitrosourea
Mice
Morphology
Photoreceptor Cells
Photoreceptors
Regeneration
regenerative medicine
Retina
Retina - metabolism
Retinal degeneration
Retinal Degeneration - metabolism
small molecule
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Summary:Degenerative retinal diseases associated with photoreceptor loss are a leading cause of visual impairment worldwide, with limited treatment options. Phenotypic profiling coupled with medicinal chemistry were used to develop a small molecule with proliferative effects on retinal stem/progenitor cells, as assessed in vitro in a neurosphere assay and in vivo by measuring Msx1-positive ciliary body cell proliferation. The compound was identified as having kinase inhibitory activity and was subjected to cellular pathway analysis in non-retinal human primary cell systems. When tested in a disease-relevant murine model of adult retinal degeneration (MNU-induced retinal degeneration), we observed that four repeat intravitreal injections of the compound improved the thickness of the outer nuclear layer along with the regeneration of the visual function, as measured with ERG, visual acuity, and contrast sensitivity tests. This serves as a proof of concept for the use of a small molecule to promote endogenous regeneration in the eye.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25031521