Gene therapy for choroideremia - a Phase II clinical trial

Choroideremia is an X-linked inherited retinal degeneration first described in 1872 that causes blindness and is currently incurable. The purpose of this proposed study is to assess the efficacy of a new gene therapy treatment which we have tested in a recent Phase 1 clinical trial. Gene therapy is a process of replacing a defective gene in order to restore function to cells which would otherwise undergo a pathological process, such as cell death. In choroideremia the CHM gene encodes a protein known as Rab escort protein-1 (REP1). The CHM gene is normally expressed in the pigmented lining of the eye, known as the retinal pigment epithelium. It also has an important function in the light sensing cells known as photoreceptors. In the absence of REP1 the retina in choroideremia undergoes a slow but progressive degeneration which begins in childhood and results in blindness by the fourth decade. Our research focuses on a viral vector known as adeno-associated virus serotype 2 (AAV2). This virus has considerable advantages for transduction of the non-dividing cells in the retina and research over the last 15 years has shown that the expression of the gene product can be indefinite. For our Phase 1 study, we tested safety using an AAV2 vector encoding REP1. Our AAV2 vector was constructed with a strong ubiquitous promoter producing sustained long-term gene expression as demonstrated by AAV vectors used in earlier retinal gene therapy trials, as well as a post-transcriptional regulatory element shown to augment gene expression in an AAV vector used in a gene therapy trial to treat Parkinson’s disease. We now have one year follow-up data from the first six patients from our Phase 1 clinical trial and we have observed improvements in vision which have been sustained to date. Two patients experienced significant gains in visual acuity. We have also observed a correlation of dose and treatment effect at around 1010 genome particles per mm2 of retina. These results are all the more remarkable because each patient had to undergo detachment of the fovea in order to receive the gene therapy treatment, which ordinarily would result in a loss of visual function. Having shown safety and efficacy (in terms of preservation of visual function) in one centre, we wish to replicate with a larger number of patients across two sites in order to estimate the therapeutic dose more accurately. We can now randomise treatment to one or the other eye. We also need to know if the underlying retinal degeneration can be slowed or stopped by the gene therapy. To do this we need to assess retinal area changes over a minimum two year period in those patients who show a definite treatment effect, as evidenced by improved visual function in the short term. In the proposed trial we have widened our entry criteria to include patients in whom the fellow eye cannot be used as a control. This is because we have noted improvements in maximal sensitivity (the dimmest stimulus that can be seen) after surgery in the treated eyes of patients in the Phase 1 study. Hence we can compare visual function to the pre-operative level in the same eye. This allows us also to include patients in the terminal stages of sight loss who would otherwise be completely blind by the time this becomes an approved treatment. For assessment of the anatomical rate of degeneration however we would ideally need the fellow eye as an internal control and in these patients we would need fairly symmetrical disease. We would also need to randomise treatment to one eye or the other to avoid selection bias. Hence we shall have two cohorts of patients. Cohort 1 will include all patients and will make comparisons of visual function in the treated eye before and after surgery in relation to vector dose per unit area of retina. Cohort 2 will be the subset of patients in whom treatment has been randomised and will make comparisons to the control eye with regard to the rate of anatomical degeneratio