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Researchers develop a new non-invasive route to deliver gene therapy to the retina

Researchers at the Johns Hopkins University have tested an alternative route to deliver gene therapy vectors to the retina that could potentially help patients with age-related macular degeneration (AMD) and inherited retinal disorders (IRDs). The new route of administration, called suprachoroidal injection, has been investigated initially in preclinical experiments in animals and uses a microneedle to inject gene-carrying therapeutic viruses into the suprachoroidal space between the white of the eye (the sclera) and the eye’s vascular layer (the choroid).

Currently, the surgeon has two ways of delivering gene therapy to the eye. By injecting it into the vitreous (intravitreal injection) or by administering the therapy under the retina in the space between the retinal pigment epithelium (RPE) and the photoreceptors (subretinal injection). The former is being used for therapies under study for Leber hereditary optic neuropathy or RNA therapies that employ antisense oligonucleotides for the treatment of Leber congenital amaurosis due to the p.Cys998X mutation in the CEP290 gene or Usher syndrome type 2 caused by USH2A exon 13 mutations. The method is relatively safe but it can have complications such as endophthalmitis, and shows limited transduction efficiency confined to inner retinal cells.

On the other hand, subretinal injection is the preferred route of administration for gene addition therapies that target photoreceptor cells or RPE cells, as is the case of the already approved treatment with Luxturna. Delivery of gene therapy below the retina via subretinal injection allows strong expression of the wild-type gene in the RPE and photoreceptors but it also has disadvantages. It is administered following a type of surgery (vitrectomy) that carries a high risk of inducing cataracts and a low risk of retinal detachment. Delivery of the gene is also limited to an area near the injection site and although the fovea is a high priority region this type of intervention may cause permanent damage to this area as it involves detaching the retina from the RPE.

That is why the new administration route under study might be a safer alternative. Delivery of gene therapy in the suprachoroidal space would not require surgery and could be performed in an outpatient setting, like intravitreal injections, avoiding the risks associated with surgical procedures. In rats, nonhuman primates, and pigs, investigators have shown expression of the transgene through a larger area of RPE, choroid and retina, compared with subretinal injection.

To test the efficacy of this alternative route, researchers used animal models of neovascular age-related macular degeneration. Current treatment of wet AMD involves injection of vascular endothelial growth factor (VEGF)-neutralizing proteins into the vitreous but injections need to be repeated every four to six weeks due to their limited life span.

There are several efforts investigating gene therapies to turn retinal cells into little factories that continuously produce anti-VEGF proteins, therefore avoiding repeated injections. Investigators studied rats with macular degeneration that were treated with the anti-VEGF gene therapy vector delivered into the suprachoroidal space and compared them with rats treated by subretinal injection, and found that the new route works as well as the conventional technique.

It is not known if suprachoroidal injections may be suitable for people that had preexisting immunity to virus similar to the one used in this approach, but for a substantial number of patients it may represent a noninvasive route for gene therapy that can be performed in an outpatient setting.

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