Gene Therapy for Retinal Diseases Is Within Sight

Charles C. Wykoff, MD, PhD


May 07, 2014

In This Article

Retinal Gene Therapy to Replace a Defective Gene Product: Early Results of Human Clinical Trials

Leber Congenital Amaurosis Type 2 (Caused by RPE65 Mutations)

Leber congenital amaurosis (LCA) is a severe, blinding, typically autosomal recessive retinopathy resulting from mutation in one of more than a dozen causative genes.[13] Affected people are usually diagnosed within the first few months of life, typically being born with very poor visual function and experiencing progressive visual decline that often leads to total blindness. Mutations in the RPE65 gene disrupt the visual-retinoid cycle and impair production of the visual pigments rhodopsin and cone opsin with concomitant toxic accumulation of all-trans-retinyl esters, promoting photoreceptor death and leading to LCA type 2 (LCA2).

Despite its rarity, affecting < 1 in 1 million live births, LCA2 is an ideal pathology for the application of retinal gene therapy because, although photoreceptors degenerate, RPE cells are relatively well preserved; therefore, restoration of RPE65 function in RPE cells was hypothesized to lead to photoreceptor reactivation and restoration of sight.[11]

On the basis of this reasoning, a tremendous amount of research has focused on the development of a gene-based therapy for LCA2, and it has been exceptionally successful in a multitude of animal models. In canine, porcine, and rodent LCA2 models, rAAV vectors have been used to deliver functional retinoid isomerohydrolase, restoring retinal function with dramatic visual improvement.[14]

Building on this success, phase 1 human clinical trials have been performed. For example, 3-year data were reported from a dose-escalation, phase 1 study of 15 patients aged 11-30 years who were treated with subretinal injection of a rAAV vector expressing RPE65. It revealed no systemic toxicity, good ocular tolerance, and improvement in visual function in all patients -- dramatically in some.[15] A 24-patient phase 3 trial is currently recruiting patients in Iowa and Pennsylvania.[16]


Choroideremia is an X-linked recessive retinal degenerative disease affecting about 1 in 50,000 people with loss of night vision beginning in the first decade of life, followed by gradual peripheral visual loss with progression to blindness by the fifth decade in most patients. Retinal degeneration is caused by prenylation deficiency due to absence of Rab escort protein-1 (REP-1) encoded by the CHM gene.

Partial results of a phase 1 study involving 6 men aged 35-63 years who were treated with subretinal injections of a rAAV vector expressing REP-1 were recently published.[17,18] Mean visual acuity improved by 3.8 letters among all patients, with 2 patients experiencing substantial improvements in visual acuity of 21 and 11 letters (over 4 and 2 lines of visual acuity, respectively).

Retinal Gene Therapy to Supply a Therapeutic Gene

Neovascular Retinal Diseases

In addition to replacing dysfunctional gene products caused by mutations in a person's germline, gene therapy can serve as a platform for drug delivery. For example, any retinal disease that could benefit from local production of a specific RNA or protein is a potential candidate for gene therapy.

Currently, therapies applied for neovascular AMD involve pharmacologic agents that block vascular endothelial growth factor (VEGF). These medications achieve VEGF suppression remarkably well, but the relatively short half-lives of these biological proteins, on the order of hours to days, often necessitate monthly administration for maximal clinical effect and visual benefit, especially in recalcitrant cases.[19,20] Repeated treatments incur additional patient risks and inconvenience.

The need for longer-acting therapeutics may be fulfilled with gene therapy. For example, an adenoviral vector expressing pigment epithelium-derived factor that inhibits angiogenesis was used with success in a phase 1 trial.[21] Currently, a phase 1 trial is under way to evaluate an intravitreally administered rAAV vector expressing a soluble portion of a VEGF receptor intended to block VEGF (sFlt01).[22]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: