Long-term functional synaptic integration of genome-edited retinal organoids in a primate model of macular degeneration.

Authors

Atsuta Ozaki, Akihiro Kawai, Ryutaro Akiba, Satoko Okayama, Nobuhiko Ohno, Keisuke Kajita, Tomohiro Masuda, Satoshi Yokota, Shin-Ichiro Ito, Du Peiyan, Kenta Onoue, Shigenobu Yonemura, Mineo Kondo, Yasuo Kurimoto, Yingbin Fu, Michiko Mandai

Published in

Molecular therapy : the journal of the American Society of Gene Therapy. Jun 27, 2026. Epub Jun 27, 2026.

Abstract

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1^-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation nonhuman primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography (FMERG), we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1^-/- graft by up to 21.6% and remained stable for up to 2 years post-transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem cell-derived grafts. Our results highlight ISL1^-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

PMID:
42365435
Bibliographic data and abstract were imported from PubMed on 28 Jun 2026.

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