Abstract

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.

Highlights

  • Choroideremia (CHM) is an X- linked inherited retinal disease characterized by the degeneration of photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris

  • Expression mediated by pAAV2.chicken beta actin promoter (CBAe).hCHM in cultured cells

  • Recombinant AAV2. hCHM -mediated delivery of the CHM gene resulted in a dose-dependent response in Rab Escort Protein-1 (REP-1) protein expression when the multiplicity of infection (MOI) ranged from 16103 to 26105

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Summary

Introduction

Choroideremia (CHM) is an X- linked inherited retinal disease characterized by the degeneration of photoreceptors, retinal pigment epithelium (RPE) and choriocapillaris. Symptoms develop in the 1st or 2nd decade of life with complaints of poor night vision (nyctalopia) and progressive loss of peripheral vision. Visual fields constrict as the disease progresses. This culminates with loss of central vision (visual acuity) and blindness as early as the fourth decade of life [1,2,3,4]. The choroideremia gene, CHM, encodes Rab Escort Protein-1 (REP-1), a 653 amino acid protein thought to be involved in membrane trafficking [5,6]. Since the CHM locus is on the Xchromosome, choroideremia is typically only diagnosed in males

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