Gene Therapy for Choroideremia Using an Adeno-Associated Viral (AAV) Vector

Genetic manipulation for inherited neurodegenerative diseases: myth or reality?

“…Another form of inherited retinal degeneration where significant progress has been achieved recently is choroideremia, which has an estimated prevalence of 1 in 50 000 40. It is an X-linked disorder caused by null mutations in the CHM gene and the lack of the encoded Rab escort protein-1 (REP1) accounts for the neurodegenerative process 41…”

“…The pathological hallmark of choroideremia is the progressive degeneration of the choriocapillaris, the RPE and the outer retina. Patchy areas of chorioretinal atrophy begin in the mid-periphery of the fundus and the foveal region is spared until the end stages of the disease, affording an attractive window of opportunity for therapeutic intervention 40. Nearly all reported cases of choroideremia have been attributed to functionally null CHM mutations and because the gene has a relatively small protein coding sequence (1.9 kb), it can easily be packaged in an AAV delivery vector.…”

“…40 It is an X-linked disorder caused by null mutations in the CHM gene and the lack of the encoded Rab escort protein-1 (REP1) accounts for the neurodegenerative process. 41 42 Loss of night vision begins in the first decade of life and there is gradual loss of peripheral vision leading to legal blindness by the fifth decade of life.…”

“…Patchy areas of chorioretinal atrophy begin in the mid-periphery of the fundus and the foveal region is spared until the end stages of the disease, affording an attractive window of opportunity for therapeutic intervention. 40 Nearly all reported cases of choroideremia have been attributed to functionally null CHM mutations and because the gene has a relatively small protein coding sequence (1.9 kb), it can easily be packaged in an AAV delivery vector. Based on promising preclinical work that confirmed the effectiveness and safety of an AAV-based strategy for delivering the CHM cDNA encoding REP1, Robert MacLaren and colleagues initiated a first-in-man gene therapy trial that recruited six male patients with choroideremia and good central visual acuity of 6/6 or better.…”

Gene Therapy for Retinal Disease: What Lies Ahead

“…Although REP1 is expressed ubiquitously, the primary cell type that drives the disease phenotype is the RPE. This is evidenced by a very similar phenotype in patients with dominant RP6E5 mutations, because the expression of the RPE65 gene is restricted to the RPE [18]. One difficulty in getting choroideremia gene therapy into a clinical trial was the lack of an ideal animal model.…”