Retina4Future - COST Action CA24105

A new study explores a non-viral approach to gene delivery for choroideremia

Current gene therapies for inherited retinal diseases (IRDs) typically use viral vectors, such as adeno-associated viruses (AAVs), to deliver therapeutic genes. Although these approaches have shown promising results, they can be costly, have limited cargo capacity, and may trigger immune responses. A new study from the Miguel Seabra Lab at the Champalimaud Foundation and NOVA Medical School in Lisbon, Portugal, investigates the potential of lipid nanoparticle (LNP)-mediated mRNA delivery as a non-viral strategy for gene replacement in choroideremia (CHM), a rare X-linked IRD caused by mutations in the CHM gene.

The researchers investigated whether in vitro transcribed human CHM-mRNA packaged in LNPs could restore production of Rab escort protein-1 (REP1), the protein missing in CHM patients. Following subretinal administration, the mRNALNP treatment efficiently targeted the affected cells, the retinal pigment epithelium and choroid, with CHM mRNA expression detectable for up to 15 days. Compared with AAV2 vectors, the treatment induced a lower, transient inflammatory response. Importantly, delivery of CHM-mRNA restored REP1 levels and corrected defects in Rab prenylation, a key cellular process regulated by REP1, in both CHM patient-derived retinal pigment epithelial cells and a mouse model of CHM. Retinal function also improved in CHM treated mice, as measured by electroretinography.

Together, these findings provide proof-of-concept that non-viral mRNA therapies can achieve biologically meaningful gene replacement in the retina and highlight the potential of non-viral mRNA delivery as an alternative platform for developing future therapies for IRDs such as choroideremia.