Research into the Genetics of Macular Degeneration

In the broad search for a cure for Age-related Macular Degeneration, researchers around the world are approaching the human body, the human eye, and the cells of the macula from every angle. It is common practice, for example, to recommend nutritional pigment to replace lost pigment in the macula. Also common: injecting a chemical into the eye every month to stop abnormal blood vessels in wet AMD from developing behind the macula. In labs, scientists are exploring the possibility of growing new photoreceptor cells — new rods and cones — from stem cells. And now some scientists believe they will soon be able to insert new code into the body’s own genome — the instruction manual “written” on the chromosomes in every cell — to direct the body to build or rebuild healthy eyes long into maturity. The American Macular Degeneration Foundation in late 2013 granted $150,000, to be distributed over two years, to the laboratory of Dr. Neena Haider at Schepens Eye Research Institute at Massachusetts Eye and Ear Infirmary, for her work in this field. Haider believes that genetics research could result in a treatment and prognostics (predictors) for AMD. She is convincing on this subject because she has already proven her point with a population of laboratory mice.

Haider, Associate Scientist at Schepens and Associate Professor of Ophthalmology at Harvard Medical School, is essentially a code breaker by trade. She was part of a team at the University of Iowa, which contributed to the completed map of the human genome in 2003. “Map” is a commonly used metaphor for the known chemistry of the over 20,000 genes on 23 pairs of human chromosomes — the X-shaped genetic material in our cells — but a better metaphor would be “code.” Each segment of code is a gene. Each gene, or set of genes, has instructions that direct the body to do something: to become male or female, to have red hair or blonde, to produce healthy liver enzymes, to process gluten (or not), to be allergic to pollen (or not), and on and on. The map, the code, which was developed in the early 2000s, described in scientific terms those 20,000 gene sequences. Now, laboratories like Haider’s are figuring out what the mystery gene sequences do. As a graduate student Haider discovered and studied a gene known as NR2E3. A particular mutation — a rare form — of that gene resulted in the loss of rods and cones in the retina, and a corresponding loss of vision.

After her PHD work on NR2E3, Haider continued to focus her full attention on retinal diseases and has identified genes which can be chemically snipped from the chromosomes of a mouse cell and replaced with genes from a mouse with healthy eyes. A one-time treatment of certain healthy genes has left laboratory mice with retinal disease “rescued” for up to a year so far –rescued, meaning they never get retinal disease. In other words, they are cured. And these are the same kinds of cells that are dying in human AMD. Currently there are few models for AMD and they don’t always mimic the disase. Dr. Haider is developing unique AMD models and will be testing these master genes to determine if they can rescue retinal disease in AMD.

This is particularly interesting because mice and humans have more than 80 percent of the same coding. Haider, like other scientists, does not yet know what specific processes these genes are turning on or turning off. It’s probably far more than one simple answer. Theories include that the genes direct cells to process Vitamin D a certain way. And the genes might have something to do with the activation (or deactivation) of the body’s immune system and the inflammatory system. The genes almost certainly have jurisdiction in the circulatory system, in the building of blood vessels. And certainly some genes regulate the body’s response to risk factors — smoking, for example. For now the one thing that’s fairly sure is that healthy versions of the genes of mice — which have sci-fi movie names like ROBO1, NR1D1, and RORA — are reversing AMD like a complex system of “dimmer switches” turning on or off, and those switches are infinitely small volumes of cellular hormones.

Why not just put the healthy version of the human gene into a person now, and get this process started? Who really cares why the gene works? Tempting. But turning the dimmer switches up or down is not an isolated process. These same genes –ROBO1 and the others — turn cells up in other parts of the body, including the liver, kidneys, and brain. (Interestingly, the gene NR1D1 is related to circadian rhythms in the body. Circadian rhythms are the body’s biological cycles which coincide with the cycle of a day.) The last thing Haider wants to do is insert a gene that restores eyesight but causes healthy cells in other parts of the human body to go into dangerous overgrowth while it restores sight. Two thousand of the genes in the human genome — that instruction manual — are estimated to be related to the retina in some way.

Haider’s lab is in the process, now, of getting all 2000 retinal puzzle pieces on the table, and defining which 2000 genes are important for AMD. After that she will try to piece together major parts of the retinal puzzle — that is, figure out what the major genes are doing, enough so that she and other scientists feel it is safe to try gene treatment on humans. She is hoping that the work will take less time than other research has because gene technology and lab techniques are improving rapidly. Five years? Eight? She is hoping for results sooner than a decade.