Leber congenital amaurosis is a degenerative disease of the retina characterized by onset during childhood and severe loss of vision. Recently, patients with Leber congenital amaurosis type 9 were found to carry mutations in the enzyme NMNAT1 that plays a critical role in the synthesis of the vital molecule nicotinamide adenine dinucleotide (NAD+). It is clear that deficiency of NAD+ in the retina is an early feature of retinal degenerative disorders, but what cell types and biological pathways are affected in Leber congenital amaurosis remains unclear.
Sasaki and colleagues from the Washington University School of Medicine, St. Louis, demonstrated that NMNAT1 depletion causes the selective loss of photoreceptors, special cells in the eye’s retina that are responsible for converting light into signals that are sent to the brain. In their article published in the journal eLife, they show that loss of NMNAT1 activates the NAD+-consuming enzyme SARM1, the central executioner of nerve fiber degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1. “Our identification of SARM1 as the executioner of photoreceptor death in this model of Leber congenital amaurosis type 9 opens up new therapeutic possibilities,” said the investigators in their study.
NMNAT1 plays important roles in diverse retinal functions. Loss of NMNAT1 in the developing mouse retina causes severe retinal dystrophy and loss of retinal function. NMNAT1 promotes the survival of mouse retinal progenitor cells. Strangely, even though NMNAT1 is found in basically every cell of the human body, Leber congenital amaurosis patients do not manifest medical complications other than retinal degeneration. But exactly what NAD+ and NMNAT1 are doing in the retina are largely unknown.
In this study, Sasaki and colleagues looked into which cell types cause retinal degeneration in Leber congenital amaurosis type 9. They showed that photoreceptors degenerate rapidly after the loss of NMNAT1 and that depletion of NMNAT1 in rod or cone cells is necessary and sufficient for the retinal degeneration and a concomitant reduction in retinal function. Also, cell-type specific deletion of NMNAT1 in the photoreceptors of young mice is sufficient to induce retinal degeneration. Hence, NMNAT1 is required for the survival and function of both developing and mature photoreceptors.
Sasaki and colleagues then showed that viral-mediated gene replacement in photoreceptors is capable of improving retinal function. They used a naturally occurring, innocuous virus used in gene therapy to restore structure and function to diseased cells called adeno-associated virus (AAV) to restore NMNAT1 in the retina. The investigators showed that rescuing NMNAT1 in photoreceptors can partially rescue retinal degeneration and improve retinal function in this model of Leber congenital amaurosis type 9.
Recently, the U.S. FDA approved a version of AAV as a therapeutic reagent for Leber congenital amaurosis type 2 and other retinal dystrophies with known mutations. “Theoretically, LCA9 caused by the loss of NMNAT1 function is a reasonable target for AAV-mediated gene therapy,” said the investigators in their article. “Future studies will assess the efficacy of gene replacement after deletion of NMNAT1 to more closely mimic the human condition.”
Finally, the investigators wanted to better understand how NMNAT1 was controlling photoreceptors survival. They showed how loss of NMNAT1 leads to photoreceptor degeneration. Loss of NMNAT1 activates SARM1, a gene that triggers the degeneration of axons in neurons. Moreover, photoreceptor degeneration is mediated by SARM1 in the absence of NMNAT1.
“This surprising result extends our understanding of both the mechanisms causing retinal degeneration and the potential role of SARM1 in human disease,” said the investigators. “Since the SARM1 pathway is likely druggable, these findings provide a framework for developing new therapeutic strategies for treating patients with LCA9 and potentially other retinal disorders.