Potential Gene Therapy for Leber Congenital Amaurosis Identified in NIH Study


The disease models used also helped to establish the function of NPHP5 in cilia morphogenesis.

Retinal organoid disease models derived from patients with Leber congenital amaurosis (LCA) caused by a mutation in the NPHP5 gene (NPHP5-LCA) had cilia defects rescued by an adeno-associated virus (AAV)-mediated NPHP5 gene augmentation therapy, indicating a potential treatment for NPHP5-LCA, according to preclinical research carried out by National Institutes of Health (NIH) investigators that was published in Stem Cell Reports.1

“It’s so sad to see little kids going blind from early onset LCA. 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, PhD, senior investigator, National Eye Institute (NEI) Neurobiology Neurodegeneration and Repair Laboratory, said in a statement regarding the findings.2 “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.”

Skin biopsies for the disease models, which were reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated, were obtained from 4 patients with NPHP5-LCA and 3 healthy familial control individuals from 3 families.1 Among these individuals, 6 different mutant alleles were represented. The disease models derived from these patients helped to establish the function of NPHP5 in cilia morphogenesis. 

“To our knowledge, this is the first report showing reduced levels of CEP290 protein in NPHP5-LCA patient-derived fibroblasts as well as in RPE and retinal organoids derived from patient iPSCs,” first author Kamil Kruczek and colleagues noted.1 “We can therefore hypothesize that LCA caused by NPHP5 mutations is the result of reduced CEP290 protein in sensory tissues and that NPHP5 is needed to stabilize the ciliary gate complex.”

After delivery of functional copies of NPHP5, the disease models showed a significant increase of opsin protein in the outer segments of the photoreceptor, where it would be typically found in the healthy phenotype, and CEP290 protein became detectable.1,2 Additionally, the primary cilium gate may have been stabilized by the restoration of functional NPHP5.2

The investigators pointed out that their findings complemented previous research in animal models, which demonstrated vision improvements in NPHP5−/− mice and a spontaneous dog model carrying an NPHP5 mutation after complete copies of NPHP5 were delivered with an AAV vector. The investigators ultimately concluded that the reduced CEP290 protein levels and abnormal cilia morphology seen in their own model provide additional insight into the mechanistic underpinnings of the NPHP5-LCA phenotype and expressed optimism that the model system could be useful in developing potential treatments for NPHP5-LCA and other ciliopathies.

“Gene therapy using AAV vectors has emerged as an effective treatment approach for many inherited retinopathies...,” Kruczek and colleagues noted.“ In this study, we were able to partially rescue outer segment development in NPHP5-LCA retinal organoids with improvements in both L/M cones as well as rod cells by AAV-mediated NPHP5 gene augmentation. Treatment effect in L/M cones is particularly important given that useful high-acuity color vision in humans relies on cones and that cone cell bodies are present in the fovea of NPHP5-LCA patients at all ages studied. The animal models provided essential in vivo proof of concept, whereas our work complements these studies with a human-specific system and evaluated the rescue of photoreceptor phenotype in patient-derived tissue in vitro.”

1. Kruczek K, Qu Z, Welby E, et al. In vitro modeling and rescue of ciliopathy associated with IQCB1/NPHP5 mutations using patient-derived cells. Stem Cell Reports. Published online September 8,2022. doi: 10.1016/j.stemcr.2022.08.006
2. NIH researchers develop gene therapy for rare ciliopathy. News release. National Institutes of Health. September 8, 2022. https://www.nih.gov/news-events/news-releases/nih-researchers-develop-gene-therapy-rare-ciliopathy 
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