mRNA delivery to the retina restores REP1 function in choroideremia
Summary
Inherited retinal diseases (IRDs) represent a major cause of blindness, yet current viral vector-based gene therapies are limited by high cost, restricted cargo capacity, and safety concerns related to immunogenicity. We explore here retinal delivery of non-viral, in-vitro-transcribed mRNA using lipid nanoparticles (LNPs) as a safe, cost-effective gene augmentation strategy for choroideremia (CHM). CHM is an X-linked IRD caused by loss-of-function mutations in CHM that encodes Rab escort protein-1 (REP1), which is essential for Rab GTPases prenylation and intracellular trafficking. We demonstrate that subretinal delivery of human CHM-mRNA (hCHM-mRNA) efficiently targets the retinal pigment epithelium (RPE) and choroid, achieving expression that is detectable up to 15 days post-injection, with lower and transient inflammatory response compared to AAV2 vectors. Furthermore, hCHM-mRNA delivery in vitro to human induced pluripotent stem cell (hiPSC)-derived RPE cells from a CHM patient and in vivo via subretinal injection in the Chm ± mouse model successfully restored REP1 levels and reversed Rab prenylation defect. Concordantly, Chm ± treated with hCHM-mRNA showed functional rescue of retinal activity measured by electroretinography 24 h post-injection. Overall, these results provide a strong proof-of-concept for LNP-mediated mRNA technology in the retina, supporting the development of scalable, non-viral gene approaches for IRDs, including CHM. © 2026 The Authors.
| Authors | de Lemos L, Antas P, Carvalho C, Castro M, Bruno D, Fonseca AF, Rakshit S, Seabra MC |
|---|---|
| Journal | Molecular therapy. Advances |
| Publication Date | 2026 Sep 10;34(3):201768 |
| PubMed | 42488178 |
| PubMed Central | PMC13390122 |
| DOI | 10.1016/j.omta.2026.201768 |