Restoration of retinal and visual function following gene therapy
New generation CRISPR technology lays foundation for therapeutics to
treat a wide range of inherited ocular diseases

Date:
October 19, 2020
Source:
University of California - Irvine
Summary:
A breakthrough study results in the restoration of retinal and
visual functions of mice models suffering from inherited retinal
disease.



FULL STORY ==========================================================================
A breakthrough study, led by researchers from the University of
California, Irvine, results in the restoration of retinal and visual
functions of mice models suffering from inherited retinal disease.


========================================================================== Published today in Nature Biomedical Engineering, the paper, titled, "Restoration of visual function in adult mice with an inherited retinal
disease via adenine base editing," illustrates the use of a new generation CRISPR technology and 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. Recently, the FDA approved the first gene augmentation
therapy for Leber congenital amaurosis (LCA), a common form of IRD which originates during childhood.

"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 utilizing 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 minimizing 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 harboring 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.

"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, the Research to Prevent Blindness Stein Innovation Award,
Fight for Sight, the Eye and Tissue Bank Foundation (Finland), The
Finnish Cultural Foundation, the Orion Research Foundation, the 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.


========================================================================== Story Source: Materials provided by
University_of_California_-_Irvine. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. 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, 2020; DOI:
10.1038/s41551-020-00632-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201019155922.htm

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