Choroideremia (CHM) is a rare inherited retinal degeneration resulting from mutation of the CHM gene, which results in absence of functional Rab escort protein 1 (REP1).
Sustained improvement or maintenance of BCVA is achievable in choroideremia with high-dose AAV2-REP1, indicating BCVA is a viable primary outcome in advanced choroideremia.
However, the choroideremia (CHM) gene is expressed in all retinal layers, and a previous study on a small cohort of choroideremia patients suggested possible thinning of the retinal nerve fibre layer (RNFL).
Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.
To assess the safety and efficacy of retinal gene therapy with an adeno-associated virus vector (AAV2) designed to deliver a functional version of the CHM gene (AAV2-REP1) for treatment of patients with choroideremia.
Choroideremia (CHM) is an x-linked recessive chorioretinal dystrophy, with 30% caused by nonsense mutations in the CHM gene resulting in an in-frame premature termination codon (PTC).
In this paper, we reviewed the pathogenic effects of synonymous hotspot mutation in the CHM gene and the genotypic-phenotypic associations in families with CHM.
We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia.
As gene therapy of choroideremia is becoming a clinical reality, there is a need for reliable and sensitive assays to determine the expression of exogenously delivered Rab Escort Protein-1 (REP1), in particular to test new gene therapy vectors and as a quality control screen for clinical vector stocks.
Despite ubiquitous expression of the CHM gene, the primary defect in choroideremia is driven by retinal pigment epithelium (RPE) and photoreceptors degeneration.
The results confirm that AAV-mediated delivery of the REP1-encoding gene can rescue defects in CHM iPSC-RPE regardless of the type of disease-causing mutation.
Here, the recovery of retinal structure and function over the first month following iatrogenic retinal detachment for the delivery of adeno-associated viral vector encoding Rab Escort Protein 1 is described as a part of gene therapy for choroideremia.
In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia.