Molecular Therapy for Choroideremia: Pre-clinical and Clinical Progress to Date.

ABSTRACT

Choroideremia is an inherited retinal disease characterised by a degeneration of the light-sensing photoreceptors, supporting retinal pigment epithelium and underlying choroid. Patients present with the same symptoms as those with classic rod-cone dystrophy (1) night blindness early in life; (2) progressive peripheral visual field loss, and (3) central vision decline with a slow progression to legal blindness. Choroideremia is monogenic and caused by mutations in CHM. Eight clinical trials (three phase 1/2, four phase 2, and one phase 3) have started (four of which are already finished) to evaluate the therapeutic efficacy of gene supplementation mediated by subretinal delivery of an adeno-associated virus serotype 2 (AAV2/2) vector expressing CHM. Furthermore, one phase 1 clinical trial has been initiated to evaluate the efficiency of a novel AAV variant to deliver CHM to the outer retina following intravitreal delivery. Lastly, a non-viral-mediated CHM replacement strategy is currently under development, which could lead to a future clinical trial. Here, we summarise the rationale behind these various studies, as well as any results published to date. The diversity of these trials currently places choroideremia at the forefront of the retinal gene therapy field. As a consequence, the trial outcomes, regardless of the results, have the potential to change the landscape of gene supplementation for inherited retinal diseases.