BrightFocus friend and past Macular Degeneration Research grantee, Donald Zack, MD, PhD, of the Wilmer Eye Institute at Johns Hopkins, has been in the news quite a bit lately.
"If you talk to patients and they rate what they're most scared of, obviously it's cancer and dying, but vision always comes out as one of the things that people are afraid of losing and really value," Zack told the Sun reporter. The hope is that someday it might be possible to restore sight by transplanting bioengineered cells, like the ones Zack and Sluch are working on, into the eye.
Currently there’s no way to restore sight that is damaged or lost due to glaucoma and other vision diseases. Our nerve cells that are responsible for both sensing light (photoreceptors) and transmitting those signals to the brain (rRGCs) do not naturally regenerate.
However, despite the early success by Zack and others to replicate RGCs, there remains much work to be done. A lot of it has to do with “rewiring” the connections between the eye and the brain—a process that in normal-sighted individuals, starts at birth and builds from there. Because these neural connections are so varied, complex, and important, even when cell transplants became possible in humans, the vision restored would likely be minimal and not highly focused.
So the work continues. Zack is a professor of ophthalmology and co-director of the Johns Hopkins Center for Stem Cells and Ocular Regenerative Medicine. In the past he has received four BrightFocus grants to study RGCs.
In August 2014, we reported another success story from his lab involving CRISPR, the state-of-the-art tool for gene editing that uses microscopic “scissors” to edit the spelling of DNA. In that earlier discovery, which was funded in part by BrightFocus, Zack, Vinod Ranganathan, PhD, and others from their lab found a way to modify CRISPR to improve its speed and efficiency for building cellular models (Ranganthan et al, Nature Communications, 2014).
CRISPR techniques that Zack and Ranganathan perfected with the help of a BrightFocus grant were used in these latest experiments to grow RGS—and are being employed widely throughout research into a multitude of diseases and cures.
Exciting Genetic Discoveries for Macular Degeneration
Zack also took part in a large-scale international genome-wide association study (GWAS) just published online in Nature Genetics on December 21, and is one of dozens of coauthors (Fritsche et al, 2015).
This was a wide-reaching effort to study the genetic contributors to AMD in some 43,000 subjects whose genetic material was entered into registries at 26 centers worldwide. That cooperative effort was led by the International AMD Genomics Consortium and funded in part by the National Institutes of Health (NIH). Its achievements were described in a December 21 NIH news release.
AMD is a progressive disease that causes the death of the retinal photoreceptors, as opposed to the RGCs, which are affected by glaucoma. It is caused by a combination of genetic, environmental and lifestyle risk factors. Of all of these, age poses the greatest risk, and the genetic contributors to AMD have been especially difficult to pinpoint.
Up to this point, researchers had identified 21 regions of the genome—called loci—that influence the risk of AMD. This new research brings the number of loci that may be involved up to 34 loci. So now, altogether, researchers have discovered a total of 52 genetic variants that are associated with AMD and are located among 34 loci, 16 of which had not been previously associated with AMD.
The most common genetic variants have only an indirect association with AMD and may be susceptible to preventive efforts, like nutrition. Rare variants, by contrast, are more likely to alter protein expression or function and have a direct or causal association with a disease (but these were found in less than 1 percent of the study population).
“If you think of these loci as points on our Google map in our search for the crime syndicate members, or the genetic causes of AMD, in some cases they are as big as a Zip Code, but in other cases they pinpoint an area as narrowly defined as a few houses within a neighborhood subdivision,” explained Anand Swaroop, Ph.D., chief of NEI’s Neurobiology-Neurodegeneration and Repair Laboratory, in the NIH news release.
Either way, these newly identified gene loci will provide additional clues to an army of researchers who are looking for therapies that will turn off genetic signaling that leads to AMD progression, and turn on signals that activate the body’s natural defenses against AMD. Numerous BrightFocus grantees currently are pursuing these goals in their laboratory research.
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