February 2017




Research highlight

Mounting a defense against macular degeneration

by Maxine Lipner EyeWorld Senior Contributing Writer


Identifying agents to prevent vision loss

Dry macular degeneration causes progressive vision loss in 90% of those with AMD, and has no approved therapies according to Aparna Lakkaraju, PhD, McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Investigators are studying how protective mechanisms in the eye go awry in AMD and are focusing on potential agents that may restore these mechanisms in the retinal pigment epithelium (RPE), one of the primary tissues affected in AMD. In a study published in the Proceedings of the National Academy of Sciences of the United States of America, Dr. Lakkaraju and colleagues honed in on these protective mechanisms and investigated how certain drugs might help preserve RPE health.1

Studying AMD’s beginnings

Dr. Lakkaraju’s lab began to look at what happens at the earliest stages of AMD. “People generally accept that damage to the retinal pigment is one of the key factors that can eventually lead to AMD,” she said. “Some initial insult starts interfering with functions that are required to support the photoreceptors and the choroid.” Since the RPE is post-mitotic and needs to be functional for a lifetime, several protective mechanisms have to be in place, she noted. While no one really knows what the initiating factor for macular degeneration is, polymorphisms in complement pathway proteins have been implicated in susceptibility to AMD. “However, we do not yet know exactly how the complement system functions in the retina and how this can be targeted therapeutically,” Dr. Lakkaraju said, adding that since complement tells the body when to fight infection, a systemic complement inhibitor would not be a possibility anyway. In the recent study they looked at what innate mechanisms are important for the RPE to combat damage mediated by abnormal activation of the complement.
“The complement system is an ancient way to combat pathogens and inflammation,” Dr. Lakkaraju said. “What are the things that keep it in check?” CD59 is a protein that prevents the complement system from getting activated, she explained. “The complement pathway is activated by a sequential recruitment of proteins with names like C3, C4, C5, and so on until C9.” When these proteins come together, they form a hole in the cell membrane, which allows damaging calcium to rush into the cell. When there are enough holes, the cell bursts and dies. “CD59 prevents the last step—it prevents C9 from coming into this huge complex.” In effect, it acts as a gatekeeper because without C9 you cannot form the hole on the membrane, Dr. Lakkaraju explained. Investigators also found another protective mechanism at work: Within seconds, once the hole
is formed, the retinal pigment epithelium moves lysosomes to fuse with the membrane and patch it.
Dr. Lakkaraju’s lab found that in mice with Stargardt macular degeneration, there was little CD59 on the cell surface compared to normal cells. While CD59 normally is recycled within minutes, in the Stargardt disease mouse model, investigators determined that excess cholesterol was causing “traffic jams” on a cellular highway called microtubules, so that the CD59 wasn’t efficiently getting to the surface. “We gave these mice a drug that removes cholesterol, and we restored the CD59 on the cell surface,” Dr. Lakkaraju said, adding they identified drugs already on the market that remove cholesterol or inhibit the enzyme called acid sphingomyelinase (ASMase), both of which prevented RPE damage.

Treatment pathway

One of the two drugs used to clear traffic jams and make the microtubules dynamic again was desipramine, a tricyclic antidepressant that inhibits ASMase, which restored CD59 on the cell surface and prevented fragmentation of the mitochondria. This was given to the mice in their drinking water. The other was a cholesterol-removing drug that investigators injected intraperitoneally. Both of these agents were independently shown to help restore important protections to the RPE, Dr. Lakkaraju explained.
These are, however, just the first drugs to be considered. “Desipramine is a drug that was used 50 years ago, and it has significant side effects,” Dr. Lakkaraju said, adding that there are a bunch of other ASMase inhibitors that are already FDA approved, such as a drug to treat osteoporosis and a couple of SSRI antidepressants, that are also possibilities.
In addition to finding the most effective drug with the least side effects, it is important to consider the mode of administration. Currently, drugs are only available to treat wet AMD in the form of injections, Dr. Lakkaraju pointed out. “I would want to give this formulation in a noninvasive manner,” she stressed, adding that the idea is to develop an oral formulation or a patch to stop the disease at its earliest stages. Investigators are now looking to partner with a pharmaceutical company or biotech firm to take this to the next level.
Dr. Lakkaraju hopes to have a small clinical trial launched within about 3 years. She emphasized that the current proof-of-concept work was done in a very preliminary mouse model that is not yet ready for humans.


1. Tan LX, et al. Protective responses to sublytic complement in the retinal pigment epithelium. Proc Natl Acad Sci USA. 2016;113:8789–94.

Editors’ note: Dr. Lakkaraju has no financial interests related to her comments.

Contact information

Lakkaraju: lakkaraju@wisc.edu

Mounting a defense against macular degeneration Mounting a defense against macular degeneration
Ophthalmology News - EyeWorld Magazine
283 110
283 110
True, 2