Gene Therapy for Choroideremia

Abstract

Choroideremia leads to degeneration of the outer retina with a characteristic clinical appearance that may first have been recognised in the nineteenth century. In sufferers, the appearance of the fundus is of a characteristic pale colour caused by the loss of the outer retina, retinal pigmented epithelium and choroidal vessels, leading to exposure of the underlying sclera. Visual symptoms begin with reduction of night vision and gradually progress to blindness by middle age. The choroideremia (CHM) gene was one of the first disease-causing genes to be identified by positional cloning in 1990. As CHM is located on the X chromosome, the disease follows an X-linked (and normally recessive) inheritance pattern. The CHM gene encodes Rab escort protein 1 (REP1), and characterisation of the gene and its protein product has led to better comprehension of the disease and enabled advances in genetic diagnosis. After several decades of research, we now have a clearer understanding of the exact pathogenesis, but despite this, no established treatments currently exist to stop or even slow the progression of retinal degeneration in choroideremia. Fortunately, some specific molecular and clinical features of choroideremia make it an ideal candidate for treatment with gene therapy. This chapter describes the consideration, challenges and early clinical findings in the development of a gene therapy treatment for choroideremia by using an adeno-associated virus (AAV) encoding the CHM gene.