A new generation CRISPR technology has been used to restore the retinal and visual functions of mice models suffering from inherited retinal diseas.
The breakthrough study, led by researchers from the University of California, Irvine, was published in Nature Biomedical Engineering, the paper, titled, “Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing”.1 The study lays the foundation for the development of a new therapeutic modality for a wide range of inherited ocular diseases caused by different gene mutations.
“In this proof-of-concept study, we provide evidence of the clinical potential of base editors for the correction of mutations causing inherited retinal diseases and for restoring visual function,” said Krzysztof Palczewski, PhD, the Irving H. Leopold chair and a distinguished professor in the Gavin Herbert Eye Institute, Department of Ophthalmology at the UCI School of Medicine. “Our results demonstrate the most successful rescue of blindness to date using genome editing.”
Inherited retinal diseases (IRDs) are a group of blinding conditions caused by mutations in more than 250 different genes. Previously, there was no avenue available for treating these devastating blinding diseases. However, for the first time, the US Food and Drug Administration and more recently Australia’s Therapeutic Goods Administration have approved the use of a gene therapy – Luxturna (voretigene neparvovec) – for the treatment of patients with IRD caused by pathological biallelic RPE65 mutations, such as Leber’s congenital amaurosis (LCA). Patients must have sufficient viable retinal cells as determined by the treating physician.2
“As an alternative to gene augmentation therapy, we applied a new generation of CRISPR technology, referred to as ‘base editing’ as a treatment for inherited retinal diseases,” said first author Susie Suh, assistant specialist in the UCI School of Medicine Department of Ophthalmology. “We overcame some of the barriers to the CRISPR-Cas9 system, such as unpredictable off-target mutations and low editing efficiency, by utilising cytosine and adenine base editors (CBE and ABE). Use of these editors enabled us to correct point mutations in a precise and predictable manner while minimising unintended mutations that could potentially cause undesirable side effects,” said co-first author Elliot Choi, also an assistant specialist in the UCI Department of Ophthalmology.
Using an LCA mouse model harbouring a clinically relevant pathogenic mutation in the Rpe65 gene, the UCI team successfully demonstrated the therapeutic potential of base editing for the treatment of LCA and, by extension, other inherited blinding diseases. Among other results, the base editing treatment restored retinal and visual function in LCA mice to near-normal levels. Base editing was developed at the Broad Institute of MIT and Harvard in the lab of David Liu, PhD.
“After receiving treatment, the mice in our study could discriminate visual changes in terms of direction, size, contrast and spatial and temporal frequency,” said Palczewski. “These results are extremely encouraging and represent a major advance towards the development of treatments for inherited retinal diseases.”
Gene therapy approaches to treating inherited retinal diseases are of special interest given the accessibility of the eye, its immune-privileged status and the successful clinical trials of RPE65 gene augmentation therapy that led to the first US Food and Drug Administration-approved gene therapy. Now, as demonstrated in this study, base-editing technology can provide an alternative treatment model of gene augmentation therapy to permanently rescue the function of a key vision-related protein disabled by mutations.
This research was supported in part by grants from the National Institutes of Health, National Eye Institute and NEI Audacious Goals Initiative, a Research to Prevent Blindness Stein Innovation Award, Fight for Sight, Eye and Tissue Bank Foundation (Finland), The Finnish Cultural Foundation, Orion Research Foundation, Helen Hay Whitney Foundation, US Department of Veterans Affairs, and a Research to Prevent Blindness unrestricted grant to the Department of Ophthalmology, University of California, Irvine.
- Susie Suh, Elliot H. Choi, Henri Leinonen, Andrzej T. Foik, Gregory A. Newby, Wei-Hsi Yeh, Zhiqian Dong, Philip D. Kiser, David C. Lyon, David R. Liu & Krzysztof Palczewski. Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing. Nature Biomedical Engineering. 19 October 2020