Title: Gene therapy for choroideremia - a Phase II clinical trial
Funder: Department of Health and Social Care

Abstract: 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 degeneration. Once we have sufficient information on the vector’s efficacy and safety, we would be able to set up a pivotal study for regulatory approval by the Food and Drug Administration (FDA) and the Medicines & Healthcare Products Regulatory Agency (MHRA), with the ultimate goal of developing this gene therapy as a licensed and approved medicinal treatment for choroideremia. Moreover, the technique and vector we are developing for choroideremia would be applicable for the treatment of other genetic retinal diseases such as retinitis pigmentosa. The results from this trial, despite being for a relatively rare single gene disorder, will provide us with valuable information that could have a potentially huge impact for developing gene therapies for many genetic retinal diseases in the future.

Lay abstract: Gene therapy is a new medical technology in which a disease is treated at the genetic level. Potentially a gene therapy treatment might be performed only once in the lifetime of an affected patient to permanently correct the underlying problem. Many eye diseases that are currently incurable and cause blindness have a genetic cause. In other words, the genetic code, or DNA, has a mutation somewhere which leads to the disease. Often there is a family history with an affected parent from whom a child might inherit the disease. Choroideremia is a genetic disease that causes blindness due a mutation in a gene known as ‘CHM’, which has an important role in the retina, the light sensitive ‘film’ at the back of the eye. It usually always affects males. In choroideremia, the CHM gene does not work and the concept of gene therapy is to put a normal copy of the CHM gene back into the retinal cells. Since genes are very fragile, it is not possible just to inject them into cells – they need some sort of carrier vehicle to deliver them to the nucleus of the cell, which is where genes are normally kept. Once in the nucleus the gene is generally safe and can begin to function. In our research we use a virus to carry the gene into the cells of the eye. We have genetically modified the virus so that it only contains the missing CHM gene. We have recently completed a preliminary trial that shows that the gene therapy treatment is safe and can improve vision in some patients with choroideremia. What we do not yet know however is what dose to use and this might be different at different stages of the disease process. We have recently received funding from the Wellcome Trust to develop a gene therapy product that could be used like a prescription medicine. This could take several years to develop and in the meantime we propose to find out more about the gene therapy treatment for choroideremia through this extended study with an extra 30 patients. Specifically we are interested to know how much virus to inject in order to get the best result. We also need to know if we can expect to improve vision as well as stop the retinal degeneration that leads to eventual blindness. The results from this study will help patients with choroideremia, but may also lead to technology advancements for other blinding genetic diseases such as retinitis pigmentosa, for which gene therapy may also have a role.

Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: EYE