Retinoids Explored as Treatment for Usher Syndrome

Article: Retinoid Therapy May Improve Vision in People with Rare Genetic Disorder
Source: University of Maryland Medicine
Published: November 9, 2021
Article: Retinoid Therapy Improves Vision in Mice with Usher Syndrome 
Source: Genetic Engineering & Biotechnology News
Published: November 10, 2021 

The light-dark cycle proteins (purple and green) are spread
throughout the two photoreceptor compartments in eye tissue
from an Usher syndrome mouse model (right) compared to
being separated in healthy mouse eye tissue (left)

Usher syndrome type 1F (USH1F) is characterized by deafness, progressive retinal degeneration, and vestibular areflexia. Its prevalance is highest among Ashkenazi Jews, with carrier genes accounting for roughly 60% of their Usher syndrome type 1 cases. Thus far, there is no treatment for the disease. In the 2000s, a few scientists began collecting data about the natural history of USH1F disease progression, enrolling 13 participants with USH1F to follow the natural progression of their accompanying blindness over 20 or more years. This longitudinal phenotyping revealed progressive retinal degeneration leading to severe vision loss with macular atrophy by the sixth decade, with half of the individuals being legally blind by their mid-50s. Simultaneously, other scientists were working on a mouse model of an Usher syndrome variant found in 13 of the patients in the natural history project. The most recent work combined the research findings that had been independently collected in the human subjects and the mouse models. The collaboration led to new discoveries, such as identifying the function of a previously identified gene, PCDH15, that leads to a shortened version of the protein protocadherin-15 (mutation Pcdh15^R250X). They found that protocadherin-15 helps light-dark cycle proteins move back and forth between the different compartments of the eye's photoreceptors, and is required in recycling of retinoids by the retinal pigmented epithelium (RPE). Reduced levels of retinoid cycle proteins (RPE65 and CRALBP) were found in mice with USH1F mutation. Next, the researchers explored whether supplementing retinoids would improve vision in these mice. They report that "[e]xogenous 9-cis retinal improved ERG amplitudes in Pcdh15^R250X mice." One of the researchers remarks, "There are currently FDA-approved relatives of these retinoid drugs that are available and have passed clinical trials for safety, along with others that are in Phase II clinical trials to treat other types of vision loss disorders." They hope to test these drugs in clinical trials. Although the drugs will not recover lost vision, they might help Usher syndrome patients with function of the retinal tissue that they still have.

My rating of this study: ⭐⭐⭐

Sethna S, Zein WM, Riaz S, et al. “Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome.” eLife.  10:e67361. 29 October 2021. https://doi.org/10.7554/eLife.67361