Researchers Develop Potential Gene Therapy to Treat Blindness

Researchers at the National Eye Institute have designed a gene therapy approach that could help prevent blindness in children with Leber congenital amaurosis, a rare form of blindness.

A discovery by the National Eye Institute (NEI), part of the National Institutes of Health, could lead to a second gene therapy for a rare form of blindness. The researchers discovered that a type of Leber congenital amaurosis (LCA) is caused by mutations in the NPHP5 (also called IQCB1) gene and leads to severe defects in the primary cilium, a structure found in nearly all cells of the body. Primary cilia play a role in cell cycle regulation. In the eye, cilia play important roles in maintaining normal eye function.

Leber congenital amaurosis is an eye disorder that affects the tissue at the back of the eye that detects light and color. It is also associated with sensitivity to light, involuntary movements of the eye, and extreme farsightedness. Leber congenital amaurosis affects 2 to 3 per 100,000 newborns and is one of the most common causes of blindness in children.

There are at least 13 types of Leber congenital amaurosis, according to the National Library of Medicine. The types are distinguished by their genetic cause, patterns of vision loss, and related eye abnormalities. One gene therapy has already been approved to treat a degenerative eye disease. It is available for blindness associated with a mutation of RPE65, which provides the instructions for making a protein important for normal vision. In 2017, the FDA approved Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl), the first one-time gene therapy for patients with RPE65 mutation-associated retinal dystrophy and viable retinal cells.

The type of Leber congenital amaurosis caused by mutations in NPHP5 is relatively rare. In a healthy eye, NPHP5 protein is believed to help filter proteins that enter the cilium. Previous studies in mice have shown that NPHP5 is involved in the cilium, but researchers didn’t know the exact role of NPHP5.

“NPHP5 deficiency causes early blindness in its milder form, and in more severe forms, many patients also exhibit kidney disease along with retinal degeneration,” the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator at the NEI Neurobiology Neurodegeneration and Repair Laboratory, said in a press release. “We’ve designed a gene therapy approach that could help prevent blindness in children with this disease and one that, with additional research, could perhaps even help treat other effects of the disease.”

Three post-doctoral fellows, Kamil Kruczek, Ph.D., Zepeng Qu, Ph.D., and Emily Welby, Ph.D., at the National Eye Institute collected stem cell samples from two patients with NPHP5 deficiency at the NIH Clinical Center. These stem cell samples were used to generate retinal organoids, cultured tissue clusters that possess many of the structural and functional features of actual, native retina.

The found reduced levels of NPHP5 protein within the patient-derived retinal organoid cells, as well as reduced levels of another protein called CEP-290, which interacts with NPHP5 and forms the primary cilium gate. They also found that photoreceptor outer segments in the retinal organoids were missing and the opsin protein — a light sensitive protein — that should have been localized to the outer segments was instead found elsewhere in the photoreceptor cell body.

Researchers introduced an adeno-associated viral (AAV) vector —a virus that is used mechanism to deliver the gene — containing a functional version of NPHP5. The retinal organoids showed a restoration of opsin protein concentrated in the proper location in outer segments. The findings also suggest that functional NPHP5 may have stabilized the primary cilium gate.

The study was funded by the NEI Intramural program.