UF Ophthalmology Research Roundup: Major Contributions to Sight-Saving Therapies
Disease Mechanisms of Mutations in Cone Photoreceptors
Understanding genetic mutations in the cone photoreceptors that are responsible for visual acuity and color vision has long posed a challenge. Until recently, the studies on diseases that arise due to cone opsin mutations were done in cells outside of living organisms. That meant the mutations’ full effects on cone structure were not well understood in their normal environment.
Then, in 2021, UF Health researchers achieved a breakthrough: In the first animal study of its kind, they shed new light on the molecular mechanisms of five genetic mutations associated with cone dysfunction.
To establish their findings, Wen-Tao Deng, PhD, and her colleagues focused on mutations affecting L and M cones within the retina. Those mutations can lead to a variety of serious cone defects, including high myopia, blue cone monochromacy and X-linked cone dysfunction.
The researchers characterized five cone opsin mutations by using adeno-associated virus vectors in mice that lacked normal M cone function. Inducing the mutations gave researchers the chance to identify the mutations’ disease-causing effect on cone structure, function and viability. They concluded that while each of the mutations has a distinct consequence for cone opsin structure and function, they also appear to present dominant phenotypes.
Using adeno-associated virus vector technology gave researchers a powerful tool that allowed them to study the disease mechanisms of cone opsin mutations in animals. The results are essential to determining future treatment strategies and the most useful preclinical models for further study, the researchers noted.
The findings appeared in September 2021 in The FASEB Journal, which is published by the Federation of American Societies for Experimental Biology.
The Challenges of Usher Syndrome
Usher syndrome is the leading genetic cause of combined deafness and blindness. It causes the progressive dysfunction and degeneration of light-sensing photoreceptor neurons in the retina and the auditory hair cells in the cochlea. Loss of vision manifests as retinitis pigmentosa, with night blindness and constricted visual fields. Rod degeneration is followed by cone death, which causes severe visual impairment by the fourth decade of life.
In a paper outlining the current challenges and developments related to Usher syndrome, University of Florida Health ophthalmology researcher Astra Dinculescu, PhD, and two colleagues highlighted several hurdles that should be overcome to optimize development of gene therapy for specific inherited diseases. These challenges generally include understanding the molecular pathology of the specific disease and developing gene therapy vectors that safely reach the target cells to effectively correct biochemical defects without causing collateral damage. The paper was co-authored by David A. Saperstein, MD, a retinal surgeon in Atlanta and Seattle; and Brian A. Link, PhD, a professor at the Medical College of Wisconsin. It was published in the fall 2021 edition of International Ophthalmology Clinics.
In developing a gene therapy treatment for Leber congenital amaurosis type 2 — which included major contributions by UF professor and eminent scholar William A. Hauswirth, PhD — scientists had a detailed understanding of a key gene’s role in vision (RPE65 enzyme), and available animal models. That allowed many researchers to treat the animals in proof of concept studies and ultimately led to the approval of Luxturna for use in humans in 2017.
Developing treatments for vision loss in Usher syndrome presents significantly larger challenges, the researchers noted. A lack of solid understanding of the normal function of associated proteins and how their omission affects the retina limit the ability to develop therapies for Usher syndrome. Major barriers that prevent the development of treatments for vision loss in this disorder are the lack of animal models that closely mimic the human ocular disease and the fact that USH proteins are expressed at very low levels in the retina, leading to conflicting reports regarding their cellular/subcellular localization patterns.
One striking example, the researchers noted, is the expression of clarin-1, or CLRN1, the gene associated with Usher syndrome type 3, or USH3. In another recent paper, Dinculescu and her collaborators showed that in contrast to other USH genes, CLRN1 transcripts in human and mouse adult retinas are specifically enriched in Müller glia and not photoreceptors. These results challenge a “neuron-centric” view in USH3 retinal pathology and shift the focus toward Müller glia-photoreceptor interconnectivity.
One crucial tool to be developed is a suitable large-animal model that has a robust visual dysfunction and retinal degeneration phenotype. Novel animal models will give researchers a better understanding of the molecular basis of disease and enable translational laboratories to develop effective therapies, the researchers concluded.