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School of Medicine
HD’s still a black box; the search for a way inside is changing psychiatry.
|Dr. Christopher Ross|
Woody Guthrie had it.
It gives you ceaseless, jerky movements.
That’s what most people know or want to know of Huntington’s disease—even some clinicians. Christopher Ross didn’t have such a tight grasp on HD, either, when he came to Hopkins as an intern two decades ago. But seeing patients in the clinic set up by mentor Marshall Folstein rooted an interest.
Why would a young psychiatrist take on what’s overtly a movement disorder and chip at it for years so that it becomes a defining work? For one thing, HD patients suffer an asylum-full of psychiatric disturbances: apathy, depression, obsessions, psychosis, substance abuse, paranoia. Cognitively, they slip from problems with planning and other executive functions to frank dementia. All—so far—without a cure. For Ross, the lure was the possibility of understanding HD’s biology. Huntington’s is strongly genetic, its symptoms clear. And Ross was ready, having completed an M.D./Ph.D. program in neuroscience, then Hopkins postdoctoral training under hallowed neuroscientist Sol Snyder. When insiders knew the HD gene would soon be found, Ross made his move.
Now the director of Psychiatry’s neurobiology division and head of its Huntington’s Disease Center—possibly the world’s largest HD clinic—Ross has been in the thick of work that’s greatly advanced our understanding. His team developed techniques to detect HD’s novel type of mutation and show that its“severity” matches the disease’s onset age. Using the human HD gene—it codes for the mutant protein huntingtin—he’s created cell cultures and an important mouse model to test therapies. His group identified huntingtin; now they’re defining its abnormalities. They’ve suggested how the protein may disrupt gene expression in affected brain cells. Most interesting are ways they’ve found to slow the disease in the animal models—clues for potential therapy.
Q. The HD gene surfaced in 1993, but there’s still no remedy.
A. We had no idea how difficult it’d be to find how huntingtin kills nerve cells. Still, our progress is real: We know huntingtin’s cleaved into smaller molecules that aggregate inside cells. We know it triggers a host of toxic responses downstream and precisely what they are. We just need the intermediary steps. And we’re checking places to intervene—that first cleavage, for example. If an enzyme causes it, there’s a drug target.
Q. How could drug companies not be interested?
A. They are now! They used to think the market was too small. But that’s changing.
A. Because Huntington’s resembles Parkinson’s and Alzheimer’s diseases in major ways. So if we find an HD treatment, something should be there for the other illnesses. Pharma knows that.
Q. Any possible therapies?
A. Two antidepressants, surprisingly, look interesting. Sertraline (Zoloft) slows brain shrinkage in our model mice. Paroxetine (Paxil) appears to do the same, partly by increasing the growth factor BDNF in the brain. We’re hoping clinical trials could be down the road.
Q. Do we have a strategy for HD?
A. Our plan for now is to delay its onset as long as possible by combining approaches. That means we must catch patients before their symptoms develop—damage begins some 15 years before diagnosis is possible. So we’re actively seeking good predictors in people with the gene, things to tell us when to start treating.
Q. What sets us apart?
A. We use the most advanced molecular and cell biology techniques, along with mouse genetics, to tackle clinical problems. That’s not so common in psychiatry departments.