Leber congenital amaurosis type 10 (LCA10) and Usher syndrome are both genetic diseases that lead to blindness. LCA10 is a retinal disease that leads to severe visual impairment or blindness in early childhood. Usher syndrome is the leading cause of both blindness and deafness, with type 2A (USH2A) being the most common type. This type leads to deafness from birth, and later there is the development of retinitis pigmentosa, eventually leading to blindness.
Since there are no treatments for these diseases, they are the subject of numerous research studies. Recent breakthroughs in medical research show that there is a path leading to potential treatments.
An Old Drug for LCA10
A group of researchers at the National Eye Institute, part of the National Institutes of Health, identified five possible drugs that can be utilized to treat LCA10, one of which is Reserpine, a hypertension drug that was approved by the Food & Drug Administration (FDA) in the 1950s.
Using mouse models of LCA10 and two types of lab-created tissues from stem cells, scientists looked for compounds that promoted the survival of photoreceptors, the cells that die in LCA, that lead to blindness. They discovered a breakdown in the process of eliminating old or abnormal proteins in the retina cells.
This led to a dysfunction in the primary cilia, the cell organelle that comes out of the cell’s surface. When the cilium works correctly, it senses the external environment and controls the signaling pathway in many types of tissue. Genetic mutations that lead to cilium dysfunction are associated with many diseases, ranging from kidney malformations to congenital retinal degeneration.
In the case of LCA10, a mutation in gene CEP290 caused the dysfunction of the primary cilium in the retinal cells. Reserpine partially restored the ability of cells to break down the troublesome proteins. This in turn improved primary cilium assembly. Reserpine could be used as a relatively inexpensive way to deal with retinal ciliopathies caused by over 160 diseases. In comparison, gene therapy involves the development of an individual gene-based therapeutic that is both labor-intensive and very expensive.
A New Window into Usher Syndrome Blindness
While a model for the hearing loss aspects of Usher Syndrome has been developed, there wasn’t a model for the blindness aspects—that is until recently. Researchers in the lab of Muna Naash, the John S. Dunn Endowed Professor of Biomedical Engineering at the University of Houston developed a model that expresses the c.2299delG gene, which is the most common mutation in USH2A.
This model showed the intricacies of retinal degeneration and displayed a protein that was not located in its usual place, namely the photoreceptor’s inner segment. The degeneration is associated with reduced retinal function, abnormalities in connecting cilium and a mislocated usherin interacting partners, including the very long G-protein receptor 1 (VLGR1) and whirlin (WHRN).
Examining the retina in this model revealed structural anomalies in the photoreceptors, which lead to the death of these cells and, subsequently, vision loss. Since this model mirrors the disease, it will allow scientists to study the disease in greater detail and explore treatment options.
Repurposing an old drug and developing a disease model will lead to improved treatments and hold the promise of brighter days for those dealing with LCA10. and Usher syndrome. These discoveries open the door to treatments and better outcomes.