Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

Abstract

Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

Keywords: AAV2-REP1; choroideremia; gene therapy; retina.

Fig. 1

Optical coherence tomography (left) and fundus photography (right) of (a) early-, (b) mid-, and (c) late-stage choroideremia.

Fig. 2

The interaction between Ras-associated binding (Rab) protein and the Rab escort protein 1 (REP1). Ribosomes (R), located on the endoplasmic reticulum (ER), generate Rab proteins, which subsequently bind to REP1 (1). REP1 presents the Rabs to a catalytic Rab geranylgeranyltransferase (GGTase) subunit for prenylation with usually two prenyl groups (GG) in a geranylgeranyl transfer reaction (2). Following prenylation, Rabs are transported by REP1 to destination organelles such as the Golgi apparatus (GA), where they attach to the lipid membrane (3) (61,63). Figure reproduced with permission from Cold Spring Harbor Laboratory Press (63)

Fig. 3

The surgical procedure for adeno-associated virus–Ras-associated binding (Rab) escort protein 1 vector delivery.