Gene therapy to prevent eyes from becoming blind from some genetic diseases with evolved virus that penetrates the retina

Over the last six years, several teams of scientists have successfully treated people with a rare inherited eye disease by injecting a virus with a normal gene directly into the retina of an eye with a defective gene. Despite the invasive process, the virus with the normal gene was not capable of reaching all the retinal cells that need fixing.

Inherited retinal degenerative diseases are a clinically promising focus of adeno-associated virus (AAV)–mediated gene therapy. These diseases arise from pathogenic mutations in mRNA transcripts expressed in the eye’s photoreceptor cells or retinal pigment epithelium (RPE), leading to cell death and structural deterioration. Because current gene delivery methods require an injurious subretinal injection to reach the photoreceptors or RPE and transduce just a fraction of the retina, they are suitable only for the treatment of rare degenerative diseases in which retinal structures remain intact. To address the need for broadly applicable gene delivery approaches, we implemented in vivo–directed evolution to engineer AAV variants that deliver the gene cargo to the outer retina after injection into the eye’s easily accessible vitreous humor. This approach has general implications for situations in which dense tissue penetration poses a barrier for gene delivery. A resulting AAV variant mediated widespread delivery to the outer retina and rescued the disease phenotypes of X-linked retinoschisis and Leber’s congenital amaurosis in corresponding mouse models. Furthermore, it enabled transduction of primate photoreceptors from the vitreous, expanding its therapeutic promise.

They generated 100 million variants of adeno-associated virus – each carrying slightly different proteins on its coat – from which he and his colleagues selected five that were effective in penetrating the retina.

They then used the best of these, labeled 7m8, to transport genes to cure two types of hereditary blindness for which there are mouse models: X-linked retinoschisis, which strikes only boys and makes their retinas look like Swiss cheese; and Leber’s congenital amaurosis. In each case, when injected into the vitreous humor, the engineered virus delivered the corrective gene to all areas of the retina and restored retinal cells nearly to normal.

“Building upon 14 years of research, we have now created a virus that you just inject into the liquid vitreous humor inside the eye and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically non-invasive and safe. It’s a 15-minute procedure, and you can likely go home that day.”

The engineered adeno-associated virus works far better than current therapies in rodent models of two human degenerative eye diseases, and can penetrate photoreceptor cells in the eyes of monkeys.

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