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.

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

“…Although no effective treatment currently exists for most forms of IRDs, this field has been undergoing dramatic changes over the last decade, mainly due to the development of novel therapeutic modalities that are either gene‐based (gene therapy and targeted pharmacological agents) or non‐gene‐based (regenerative medicine and retinal implants; Kannabiran & Mariappan, ). The recent success of gene therapy for RPE65 deficiency (voretigene neparvovec‐rzyl, i.e., Luxturna) has led to a large number of ongoing gene therapy clinical trials targeting additional IRD‐related genes (Miraldi Utz, Coussa, Antaki, & Traboulsi, ; Ong, Pennesi, Birch, Lam, & Tsang, ). Moreover, due to the marked genetic and etiologic heterogeneity of IRDs, both gene‐based and non‐gene‐based therapies have to be tested on sets of patients with a known genetic diagnosis to prove their efficiency.…”

Fundoscopy-directed genetic testing to re-evaluate negative whole exome sequencing results

“…Successful identification of genetic changes in patients with clinical presentations of IRDs has driven the application of precision medicine for disease management and treatment. Therapeutic options such as adeno-associated virus vector-based gene therapy hold a great promise to reverse visual impairment in patients with IRDs [8,9].…”

A Magnetically Navigated Microcannula for Subretinal Injections

“…where p d is the 3D distal position of the cannula from (6). Assume that L, the insertion length of the cannula, which is itself controlled by a human operator, is known.…”

“…Gene therapy using the adeno-associated virus (AAV) for mutations of the RPE65 gene that is associated with certain forms of inherited LCA, was successfully demonstrated in several clinical trials, resulting in the first-ever FDA-approved gene therapy. Treatments for other retinal disorders including choroideremia [6], and wet-AMD [7], are currently in clinical trials. Additionally, stem cell grafts of retina pigment epithelial (RPE) cells are being studied for treating AMD [8].…”