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NIH researchers develop gene therapy for rare ciliopathy

Gene augmentation rescues cilia defects in photosensitive cells derived from patients with blinding disease.

National Eye Institute (NEI) researchers have developed a gene therapy that rescues eyelash defects in retinal cells affected by a type of Leber congenital amaurosis (ACL), a disease that causes blindness in early childhood . Using patient-derived retina organoids (also known as retinas in a dish), researchers found that a type of ACL caused by mutations in the NPHP5 (also called IQCB1) causes severe abnormalities in the primary cilium, a structure found in almost every cell in the body. The results not only shed light on the function of the NPHP5 protein in the primary cilium, but also led to a potential treatment for this blinding condition. NEI is part of the National Institutes of Health.

“It’s so sad to see little children go blind from the onset of stroke. NPHP5 deficiency causes early blindness in its mildest form, and in the most severe forms many patients also experience kidney disease associated with retinal degeneration,” said study lead researcher Anand Swaroop, Ph.D., principal investigator at the NEI Neurobiology Neurodegeneration and Repair Laboratory. “We have designed a gene therapy approach that could help prevent blindness in children with this disease and which, with further research, may even help treat other effects of the disease.”

ACL is a rare genetic disease that causes degeneration of the light-sensitive retina at the back of the eye. Defects in at least 25 different genes can cause ACL. Although there is gene therapy treatment available for one form of stroke, all other forms of the disease have no treatment. The type of stroke caused by mutations in NPHP5 is relatively rare. It causes blindness in all cases, and in many cases it can also lead to kidney failure, a condition called Senior-Løken syndrome.

Three postdoctoral fellows, Kamil Kruczek, Ph.D., Zepeng Qu, Ph.D., and Emily Welby, Ph.D., along with other members of the research team collected stem cell samples from two affected patients NPHP5 deficiency at the NIH Clinical Center. These stem cell samples were used to generate retinal organoids, clusters of cultured tissue that possess many structural and functional characteristics of the actual native retina. Patient-derived retinal organoids are particularly valuable because they closely mimic the genotype and presentation of retinal disease in real patients and provide a “human” tissue environment for testing therapeutic interventions, including gene therapies. As in the patients, these retinal organoids showed defects in the photoreceptors, including loss of the part of the photoreceptor called the “outer segments.”

In a healthy retina, the outer segments of photoreceptors contain light-sensitive molecules called opsins. When the outer segment is exposed to light, the photoreceptor initiates a nerve signal that travels to the brain and regulates vision. The outer segment of the photoreceptor is a special type of primary cilia, an ancient structure present in almost all animal cells.

In a healthy eye, the NPHP5 protein is thought to reside in a gate-like structure at the base of the primary cilium which helps filter out proteins that enter the cilium. Previous studies in mice have shown that NPHP5 is involved in the cilium, but researchers do not yet know the exact role of NPHP5 in the photoreceptor cilium, nor is it clear exactly how mutations affect the function of the protein. .

In the current study, the researchers found reduced levels of NPHP5 protein in patient-derived retinal organoid cells, as well as reduced levels of another protein called CEP-290, which interacts with NPHP5 and forms the gate of the primary cilium. . (mutation in CEP-290 are the most common cause of ACL.) Furthermore, the outer segments of the photoreceptors in the retinal organoids were completely absent, and the opsin protein that should have been located in the outer segments was instead found elsewhere in the cell body of the photoreceptors.

When researchers introduced an adeno-associated virus (AAV) vector containing a functional version of NPHP5 as a vehicle for gene therapy, retinal organoids showed significant restoration of the protein opsin concentrated in the right place in the outer segments. The results also suggest that functional NPHP5 may have stabilized the gate of the primary cilium.

The study was funded by the NEI intramural program. Patient samples were collected at the NIH Clinical Center.

NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…stimulating innovation, fostering collaboration, expanding the vision workforce and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to expand opportunities for people with visual impairments. For more information, visit

About the NIH Clinical Center: The NIH Clinical Center is the world’s largest hospital devoted entirely to clinical research. It is a national resource for rapidly translating scientific observations and laboratory discoveries into new approaches to diagnose, treat and prevent disease. More than 1,600 clinical research studies are conducted at the NIH Clinical Center, including those focused on cancer, infectious diseases, blood disorders, heart disease, lung disease, alcoholism and drug addiction. For more information about the clinical center, visit:

About the National Institutes of Health (NIH): The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit

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Kruczek K, QuZ, Welby E, et al. “In Vitro Modeling and Rescue of Ciliopathy Associated with IQCB1/NPHP5 Mutations Using Patient-Derived Cells.” Stem Cell Reports. September 8, 2022.

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