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Roger Reeves


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Roger Reeves

Roger Reeves of Physiology and the McKusick-Nathans Institute of Genetic Medicine on developing treatments for Down syndrome:


How did you become interested in studying Down syndrome?

REEVES: I got into this as brash young post-doc because I thought Down syndrome was the most complex genetic problem that could be solved. And I was half right because I’m still doing it, but I haven’t solved it yet.

We are working on several aspects of what occurs when someone inherits three copies of chromosome 21 instead of two copies, which is what causes Down syndrome. So this means that anywhere from 300 to 500 genes are affected that lead to 80 or 90 possible symptoms of the disease. Any given individual only has a subset of these symptoms, and each symptom of the disease differs in severity between individuals. We would love to know what causes this variability, so we can make the people profoundly affected look more like the people mildly affected.


Do you foresee future treatments developed for Down syndrome?

REEVES: Down syndrome causes the cerebellum –a part of your brain–to be smaller. We use mouse models of Down syndrome that have a lot of parallels to the human disease, including the smaller cerebellum. The smaller cerebellum arises because cells in the cerebellum don’t divide for a short period of time during development. We found out these cells in the mice with Down syndrome don’t see as much of a growth factor as non-Down syndrome mice. We discovered a small molecule that is a potential drug and acts by mimicking the growth factor. When we administer a one-time dose of this drug on the day of birth the cerebellum grows to be completely normal. We have completely fixed the cerebellum in a mouse model. We hope to see this research make its way to the clinic soon.


It seems like this discovery has amazing potential. What other potential treatments are on the horizon?

REEVES: People with Down syndrome have defects in their hippocampus that make it hard for them to determine where they are positioned in their environments. Normally in the brain, there are excitatory and inhibitory neurons, which either can enhance or inhibit the flow of current through the brain. These neurons send signals to the hippocampus of our brain which allows us to develop memory of our environment–kind of like our internal GPS.

When you look in brains of mouse models of Down syndrome there are more inhibitory signals relative to the excitatory. These inhibitory neurons get cues from a receptor that tells them when to fire or not. This receptor just happens to be a target for a lot of different drugs, some under development and some already FDA-approved. If you give the drugs that block the inhibitory neurons to a mouse, you restore balance and the ability of the mouse to find its way through its environment.

If we can restore this response in people with Down syndrome, that may have a long term effect on adaptive behavior, like the ability to live more independently and have more responsibility, and basically to have more potential to do the kinds of things that people without Down syndrome do. We are in the early stages of designing a clinical trial to test two or three of the drugs that block the inhibitory neurons in mice in people with Down syndrome to see if it helps them navigate their environments better.


Does your research have the potential to help the general population?

REEVES: The increased risk for certain diseases in people with Down syndrome allows geneticists a good tool for finding additional genes that we all inherit, which in the wrong combinations could predispose us to disease. One example is congenital heart defect, which is the most common kind of congenital anomaly in all people—one in 100 babies are born with a congenital heart defect. 

Studying Down syndrome is helping us do some good for everybody by learning about genes involved in processes like heart development and cancer. A person with Down syndrome has a 93 percent reduction in the chance that they will get cancer once they are an adult. We found that three copies of a single gene determines how many tumors you will develop in a mouse model of intestinal cancer, that has the same genetic anomaly found in 60 percent of people with colon cancer. Originally researchers believed that this gene caused cancer. If not for the genetic legacy of people with Down syndrome, we would have never figured out that the gene prevents cancer. Now we are looking for drugs that will increase the expression of that gene so the rest of us can also experience protection from cancer.

This is not a population that is taking without giving back by any means. Plus, if you know anyone with Down syndrome, they tend to be pretty interesting individuals in their own right.


On using Down syndrome as a model for other diseases:


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