Gene therapy entails the use of virus vectors to transfer therapeutic genes into target cells. These vectors are delivered at high concentration in solution, which are injected in close proximity to the target tissue. Currently, treatment aims primarily to correct the pathological origin of diseases with a genetic basis, and many such retinal disorders are undergoing clinical trials.
Adeno-associated virus (AAV) 2-RPE65 (LUXTURNA→) is used to treat Leber’s congenital amaurosis associated with RPE65 gene defects (LCA-RPE65); it became the first gene therapy product to obtain market approval in the U.S. and Europe. RPE65 protein is active in the retinal pigment epithelium (RPE) and is involved in the visual cycle. Replacement of RPE65 using an adeno-associated virus was shown to be safe and to improve vision in patients suffering from these conditions.
Choroideremia is an X-linked inherited retinal disease caused by mutations in the CHM gene. Current gene therapy clinical trials are assessing the safety and efficacy of subretinal AAV2-REP1, which aims to prevent disease progression by restoring the intracellular trafficking and prenylation activity functions of the Rab escort protein 1 (REP1).
X-linked retinitis pigmentosa (RP) is commonly caused by mutations in the gene encoding for the RP GTPase regulator protein (RPGR), resulting in progressive degeneration of rod and cone photoreceptors. Recent advances in AAV-mediated delivery of a functional RPGR gene have led to Investigational New Drug approvals for three AAV-based gene replacement therapies which are currently in early stages of clinical trials and are at present the most promising therapeutic approach.
Apart from monogenic diseases, common acquired diseases of the retina such as age-related macular degeneration (AMD), have become targets for gene therapy. In these types of diseases, the gene therapy is not aimed at correcting the genetic mutation responsible for the disease, but to target genes known to be involved downstream pathological pathways such as those driving neovascularisation. Gene therapy approaches for these conditions are less developed than those for inherited retinal disorders. Nevertheless, several companies are currently in phase 1 or preclinical stages of evaluating gene therapy product candidates for both wet and dry AMD. Other disease processes such as inflammation and scarring are also being targeted for possible future gene therapy.
This objective is met through:
Modified viral vectors are currently the best approach to deliver or modulate genes in target cells of various ocular tissues with very high efficiency. They can be designed to selectively infect or express in specific target cells.
The main vectors suitable for retinal cells are derived from:
In retinal gene therapy, virus solutions containing up to 2.0 x 1010 copies in 100μl can be injected into the required intraocular compartment. Currently, these solutions are injected into either the subretinal or intravitreal spaces. The protected immunogenicity of the eye makes gene therapy more tolerable, though immunosuppression is needed and the risk of harmful inflammatory response still exists though likely less than that which a systemic administration of the viral vector might cause. The localized approach also minimizes the required dose of vector and limits leakage into the systemic circulation, thus reducing the risk of damaging immune responses.
General Surgical Approach:
Setup – Vitrectomy Pack, 41-gauge needle/MEDONE injector system, VFC canula, intraoperative OCT (preferred but not essential).
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