A group of researchers from various departments within the University of Pennsylvania recently reported that the disease course of Leber congenital amaurosis (LCA) in canines and humans share remarkable similarities.
LCA is an inherited retinal degenerative disease that causes blindness.
“When we started characterizing the disease, we found striking similarities between a subset of human patients with LCA and dogs with this mutation,” said Gustavo D. Aguirre, VMD, Ph.D., a co-senior author and professor of medical genetics and ophthalmology at Penn Vet. “We’re very enthused about the potential to narrow down a therapeutic window for this disease and begin testing translational therapies.”
The study, “Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation,” was published in August in the journal Human Molecular Genetics.
“What is striking about the canine disease is that although the dogs lack functional vision in daylight, the cone cells, which are the photoreceptor cells that function in daylight, are still there,” said Dr. Aguirre.
Co-senior author William Beltran, DVM, Ph.D., an associate professor of ophthalmology at Penn Vet, added, “They’re there but they are structurally very compromised. The key question to be answered now is whether therapeutic intervention will not only halt the degenerative process but repair these abnormal cones and restore day vision. We have exciting preliminary gene therapy results that seem to confirm that this is indeed possible.”
Using the canine NPHP5-LCA model, the researchers compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes.
Among their findings: “NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in cell-death and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities.”
Research to deliver via gene therapy a normal copy of the NPHP5 gene in the canine model of disease is already underway, with promising early results, according to Penn Vet.
The study was supported by the National Institutes of Health, Foundation Fighting Blindness, NIH-Merck/Merial Summer Research Fellowship, Hope for Vision, Macula Vision Research Foundation, Alcon Research Institute and Research to Prevent Blindness.