Optogenetic targeting of AII amacrine cells restores retinal computations performed by the inner retina

• Published in: Molecular therapy. Methods & clinical development Vol. 31; p. 101107
• Main Authors: Khabou, Hanen, Orendorff, Elaine, Trapani, Francesco, Rucli, Marco, Desrosiers, Melissa, Yger, Pierre, Dalkara, Deniz, Marre, Olivier
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 14-12-2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: gene therapy; optogenetics; Original; retina; vision restoration; gene therapy; vision restoration; retina; optogenetics
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2023.09.003

Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. Here we used a vector that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. AII amacrine cells simultaneously activate the ON pathway and inhibit the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.
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Trapani and colleagues show that targeting specific cells called AII amacrine cells to express optogenetic proteins shows promise in restoring various visual responses, holding potential for better retinal function in those with degenerative retinal conditions.