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mRNA delivery to the retina restores REP1 function in choroideremia
Luisa de Lemos1, Pedro Antas1,2,3, Cláudia Carvalho1
1Champalimaud Foundation, Champalimaud Research, 1400-038 Lisbon, Portugal.
Molecular Therapy. Advances
|July 23, 2026
Summary
Non-viral mRNA delivered via lipid nanoparticles offers a safe and cost-effective gene therapy for choroideremia (CHM), a major cause of inherited retinal diseases (IRDs). This approach successfully restored protein levels and vision in preclinical models.
Area of Science:
- Ophthalmology and Genetics
- Gene Therapy and Nanotechnology
Background:
- Inherited retinal diseases (IRDs) cause significant blindness, with current viral gene therapies facing limitations like cost, cargo size, and immunogenicity.
- Choroideremia (CHM) is an X-linked IRD resulting from mutations in the CHM gene, leading to loss of Rab escort protein-1 (REP1) and impaired intracellular trafficking.
Purpose of the Study:
- To evaluate lipid nanoparticle (LNP)-mediated delivery of in-vitro-transcribed mRNA as a non-viral gene augmentation strategy for CHM.
- To assess the safety, efficacy, and durability of mRNA-based gene therapy for retinal delivery in preclinical models of CHM.
Main Methods:
- Subretinal injection of human CHM-mRNA (hCHM-mRNA) encapsulated in LNPs into the Chm± mouse model.
- In vitro delivery of hCHM-mRNA to patient-derived induced pluripotent stem cell (hiPSC)-RPE cells.
- Assessment of REP1 expression, Rab prenylation correction, inflammatory response, and retinal function via electroretinography (ERG).
Main Results:
- Subretinal hCHM-mRNA delivery efficiently targeted RPE and choroid, with detectable expression up to 15 days post-injection.
- mRNA therapy showed lower and transient inflammatory responses compared to AAV2 vectors.
- Successful restoration of REP1 levels, reversal of Rab prenylation defects, and functional rescue of retinal activity in treated mice and patient-derived cells.
Conclusions:
- Lipid nanoparticle-mediated mRNA delivery presents a promising, scalable, and non-viral gene therapy approach for IRDs, including CHM.
- This technology offers a safer and potentially more cost-effective alternative to current viral vector-based therapies for retinal genetic disorders.
