March 2017

 

RETINA

 

Research highlight
Researchers identify possible unifying pathway behind many retinal diseases


by Liz Hillman EyeWorld Staff Writer

     








Fundus images (left) mice lacking Nampt with severe retinal degeneration at 6 weeks compared to normal mice. Retinal sections (right) show a reduced outer nuclear layer thickness and secondary retinal degeneration in mice lacking Nampt at 6 weeks compared to normal mice.
Source (all): Cell Reports via CC BY 4.0

Finding could someday lead to treatment to prevent vision loss

Age-related macular degeneration. Retinitis pigmentosa. Leber congenital amaurosis.
What do these diseases have in common? Photoreceptor death leading toward vision loss and blindness—and the list of other retinal diseases with a similar endpoint could go on. What leads to damage and dysfunction of these cells differs depending on the disease, but one study suggests a unifying, underlying pathway that could connect them all.
Recent research published in Cell Reports showed how disruption of a metabolic pathway led to damage of rods and cones and photoreceptor death.1 What’s more, scientists were able to “rescue” these cells, suggesting a possible therapy for patients with many different types of retinal disorders in the future.
Jonathan Lin, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, and MD/PhD candidate in the neuroscience graduate program, led research that disrupted the biosynthesis of the essential coenzyme nicotinamide adenine dinucleotide (NAD+) in a mouse model. According to the study, previous research has described the different processes that involve NAD+, including metabolism, aging, and neurodegeneration. The role of NAD+ in retinal degeneration, however, was “relatively unexplored.”
“It seems clear that the retina photoreceptors have enormous energy requirements. We thought metabolism might be a key unifying factor that’s identified in different diseases,” Mr. Lin, first author of the study, said. “Along those lines, there are also recent reports that Leber congenital amaurosis, which is a blinding disease in children, can be caused by mutations of this protein called NMNAT1. This is a key protein in the NAD+ pathway. Since there have been a lot of reports of the importance of NAD+ in other neurodegenerative diseases… we wanted to understand whether this NAD+ pathway is also important in retinal degeneration.”
The researchers created conditional knockout mice that didn’t have nicotinamide phosphoribosyltransferase (Nampt)—a catalyst in the most common NAD+ production pathway in mammals. In other words, they created mice that did not produce normal levels of NAD+ by deleting the gene for this in rod cells. The researchers observed reduced Nampt gene expression and a 25% reduction in retinal NAD+ at 3 weeks. In rods specifically, a 45% reduction in NAD+ levels was observed compared to normal mice.
By 6 weeks, “massive atrophy of the neurosensory retina, vascular attenuation with pigment mottling, and atrophy of the underlying retinal pigment epithelium (RPE) cells” was observed in the experimental mice group. A disruption in visual function was also observed. There were similar results in mice with the Nampt deletion in cone cells.
“To us, it was remarkable how dramatic the degeneration was. By 6 weeks, there is almost a complete absence of that photoreceptor layer,” Mr. Lin said. “It was remarkable that you could delete a single enzyme in this one pathway and actually cause complete degeneration and impair retinal function.”
The measurable reduction in NAD+ at 3 weeks, followed by functional deficits by 6 weeks, is significant.
“At that point, there is still a relatively intact photoreceptor layer and some measurable retinal function. It does seem that NAD+ deficiency is preceding the degeneration,” Mr. Lin said. “Further we’ve looked at a few different mouse disease models, including a chemically induced diabetic retinopathy model … and a light-induced degeneration model, and we also looked at aging as a process. In all of these cases, we actually observed retinal NAD+ deficiency that occurred prior to noticeable functional changes. This is something that’s preceding the retinal degeneration and function and could indeed be a viable therapeutic target.”
The idea is that NAD+ levels could someday be used as a diagnostic tool or alert to the need for therapy before visual function is impaired. This, however, is still a long way off, said Rajendra Apte, MD, PhD, Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, Washington University School of Medicine, in whose lab the studies were conducted.
“Right now you can potentially do systemic testing to see what the NAD+ levels are in the rest of the body and indirectly conclude about [NAD+ levels in the retina,]” Dr. Apte said. “But it’s a little complicated to do—it’s more of a research tool—but you can see down the road how that could provide more insight into maybe people who are more susceptible than others.”
As for rescuing at-risk cells before they’re actually damaged or lose function, the study demonstrated that administration of nicotinamide mononucleotide (NMN)—an NAD+ precursor—in mice lacking the gene to drive the NAD+ pathway prevented vision loss.
“NMN is the downstream product of the enzyme we knocked out,” Mr. Lin explained. “It makes sense that if you’re knocking out this pathway, that in order for you to rescue it, you have to bypass it. That’s what NMN can do.”
Dr. Apte said that clinical trials using different NAD+ metabolites, such as nicotinamide riboside, are already taking place to establish safety and efficacy of the compounds increase NAD+ 2. A phase 1 clinical trial using NMN on healthy people began in 2016 at Keio University School of Medicine, Tokyo, Japan, and U.S. trials will begin in spring 2017.
“We’re making good progress in trying to see if there are any effects modifying this pathway,” Dr. Apte said. “In the best case scenario, if something like this becomes a drug, then we will have treatment options that will compliment what we have now for things like macular degeneration [and also] maybe therapies for which there are very few options available, like some of the retinal degeneration diseases.”

References

1. Lin, J, et al. NAMPT-mediated NAD+ biosynthesis is essential for vision in mice. Cell Reports. 2016;17:69–85.
2. Trammell, S, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7. E-pub.

Editors’ note: Dr. Apte and Mr. Lin do not have financial interests related to their comments.

Contact information

Apte: apte@wustl.edu
Lin: jblin@wustl.edu

Researchers identify possible unifying pathway behind many retinal diseases Researchers identify possible unifying pathway behind many retinal diseases
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