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Best’s disease gene therapy on horizon following successfully gene therapy rescue in canine models of human disease

Researchers, based at the School of Veterinary Medicine, University of Pennsylvania, and at the Scheie Eye Institute, also at Philadelphia’s University of Pennsylvania, have successfully treated animal models of the rare RPE disorder, Best’s disease, with a novel gene therapy. The macular degenerative disorder, caused by mutations in the Best1 gene, is generally detected in childhood and follows an autosomal dominantly inherited pattern with high variable clinical expression and penetrance. While many individuals with Best1 gene defects can have completely normal vision and normal fundus examination findings, others may show a characteristic large yellow yolk-like lesion in the central macula, potentially leading to retinal degeneration. An accumulation of lipofuscin-like material in the RPE has been reported in such patients where the original vitelliform may be replaced by non-specific scarring and atrophy leading to decreased visual acuity. Should pending work progress successfully, the initial gene therapy rescue reported in canine models may be translated to human studies in approximately 2 years.


According to the US research group, Best1 mutations lead to a detachment of the retina followed by a degeneration of photoreceptor (PR) cells. The detachment is understood to arise from a primary channelopathy in the supporting retinal pigment epithelium (RPE) cells of the retina. A canine model of the disease demonstrates a series of symptoms and pathology similar to that seen in humans and was therefore suitable for both disease modeling and gene therapy rescue experiments. Researchers successfully cloned a functioning copy of the Best1 gene which was then incorporated into viral vectors (AAV2/2), prior to sub-retinal injection into the eyes of affected animals. The delivery of functional Best 1 gene transcripts resulted in the reversal of clinically detectable sub-retinal lesions and the reversal of diffuse micro-detachments. Furthermore, immune-histochemical tests of treated animals indicated that there had been a correction of the structural alterations at the RPE–PR interface in areas of the retina with BEST1 transgene expression.


Commenting on the achievement, published in the journal Proceedings of the National Academy of Sciences (PNAS), the researchers stated that, “[o]ur results showed that AAV-mediated BEST1 gene augmentation is safe, reverses the clinically obvious lesions, ameliorates the diffuse microdetachments, and results in normalization of hyperthick ONL. Furthermore, we demonstrated gene therapy success in three distinct BEST1 genotypes with both focal and multifocal presentations, and confirmed long term durability of the treatment effect. At the molecular level, we confirmed that both the canine as well as the human BEST1 transgene can correct the apposition of the RPE–PR complex and restore the cytoarchitecture of this critical interface. Our study suggests that early as well as more advanced stages of autosomal recessive disease are sensible to approach with this therapy.”