Retinal Organoids for the Study of Rare LCA

Article: Researchers use patients’ cells to test gene therapy for rare eye disease
Source: National Eye Institute
Published: January 28, 2021

Human retinal organoid

Researchers at the National Eye Institute recently investigated gene augmentation in a rare autosomal dominant form of Leber congential amaurosis (LCA) through retinal organoid models made from patient cells. Leber congenital amaurosis is a rare inherited retinal disease caused by a number of different faulty genes, resulting in improper function of the opsin proteins in the eye's photoreceptors. Opsins are necessary for the detection of light. Leber congenital amaurosis gained public attention in 2017 when the FDA approved Luxturna (voretigene neparvovec) for the treatment of one form of LCA due to a mutation in the gene RPE65. As a gene therapy, Luxturna very specifically treats one particular form of LCA and is ineffective for other forms caused by other faulty genes, such as the form addressed in the present study. Of particular note is the fact that the form of LCA under study at the NEI, caused by mutations in the CRX gene, is autosomal dominant. Autosomal dominant diseases present additional challenge to gene therapy in the sense that the mutated protein often interferes with the proper functioning of the normal protein, so increasing the normal protein could exacerbate the disease in unpredictable ways. To explore the effect of gene augmentation, the NEI scientists created retinal organoid models from two patients with CRX-related LCA as well as from their unaffected family members. The details of the engineering steps can be found in the NEI article. But the result of this proof-of-concept study is that gene augmentation restored some CRX protein expression (opsins) in the retinal organoids from the two affected patients. Autosomal dominant LCA is an extremely rare eye disease, but it provides the opportunity for development of gene therapy techniques for a variety of inherited diseases.

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Kruczek K, Qu Z, Gentry J, et al. "Gene Therapy of Dominant CRX-Leber Congenital Amaurosis using Patient Stem Cell-Derived Retinal Organoids." Stem Cell Reports.  16(2):252-263. 28 January 2021. https://doi.org/10.1016/j.stemcr.2020.12.018