| In the 10 years that have passed since the discovery of the gene that causes Huntington’s disease—the degenerative neurological disorder characterized by cognitive, motor, and behavioral impairments—Columbia has remained in the vanguard. |
Columbia has been talking and thinking about Huntington’s since the very beginning, when George Huntington, an 1871 P&S graduate, published his groundbreaking paper on the subject a year later. Today, researchers continue to seek a cure and effective treatments for this fatal hereditary disease.
Research done in Venezuela by Dr. Nancy Wexler, the Higgins Professor of Neuropsychology in the departments of neurology and psychiatry, and an international team of top researchers including neurologists, geneticists, and neuropsychologists was instrumental in isolating the HD gene in 1993. Dr. Wexler, who has been at Columbia since 1984, has familial connections to the school and to HD. Her father, Dr. Milton Wexler, received his Ph.D. in clinical psychology from Columbia in 1948. Her mother, Leonore Sabin Wexler, received her master’s degree in biology from Columbia in 1936. Leonore Wexler, whose father and three brothers had Huntington’s disease, died of the disease in 1978. With his two daughters at risk for HD (Nancy Wexler’s sister, Alice Wexler, is an author and historian), Dr. Milton Wexler founded the Hereditary Disease Foundation in 1968, now the essential catalyst for stimulating and funding HD research internationally.
Dr. Nancy Wexler is president of the foundation, which will be moving into Columbia’s Audubon Research Park this winter. The foundation is a major funding source for HD research, offering research grants and postdoctoral fellowships, as well as sponsoring the Cure Huntington’s Disease Initiative. “This program focuses on the high impact of developing new therapeutics,” Dr. Wexler explains. Applications are accepted at any time instead of being solicited on a firm deadline cycle. “Whenever you have an idea, write to us, tell us what you’re thinking about,” she says. “It’s a fast-track, catalytic program to develop new treatments.”
Such a program would not have been possible before the gene was discovered. In 1979, Dr. Nancy Wexler took her original steps in the journey to discovery, when she first studied the world’s largest known HD family. She learned from Dr. Americo Negrette, a Venezuelan physician and biochemist who had discovered and described an extended family with HD, living along the shores of Lake Maracaibo, Venezuela, in which numerous people are afflicted with the disease. The proximity of the families made it unlikely that variations in symptoms would be caused by environmental differences. And it seemed likely that the disease would be traced to a single shared ancestor.
Dr. Wexler said it was meaningful for the Lake Maracaibo HD families to find out that she was also at risk for the disease. During her earliest days in Venezuela she showed patients her skin biopsy scar. The people were impressed by her sincerity, which helped to enlist their cooperation.
Since then, she and her team have spent six to eight weeks in the area annually, collecting blood samples and building a pedigree of more than 18,000 people. The disease was traced back to an ancestor who lived in the early 19th century. Each year, the researchers perform neurological and neuropsychological evaluations on approximately 1,000 individuals.
Especially in the project’s early days, the group worked under less than state-of-the-art conditions in the poverty-stricken villages. Even now they are only able to draw blood for testing when one of the researchers is returning to the United States and can act as a courier, delivering samples to labs within 48 hours. Most members of Dr. Wexler’s original research team stayed with the Venezuela project for more than two decades.
Just three years into the Venezuela project and thanks to genetic and clinical data from the families, a marker for the HD gene was discovered at the tip of human chromosome 4. It took a decade of arduous, collaborative work to isolate the HD gene itself. The Hereditary Disease Foundation organized and supported the Huntington’s Disease Collaborative Research Group of more than 150 investigators from around the world, who published the seminal paper, “A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes,” in Cell on March 26, 1993.
Information collected from the Venezuelan families continues to be a treasure trove for researchers. “We have incredible amounts to learn from it,” Dr. Wexler says. “There is a strong correlation between the number of repeats—polyglutamines—in the gene and the age of onset of Huntington’s,” for example. The age of onset is typically between 35 and 50. Someone with more than 60 repeats, however, will show symptoms before age 20—even as young as 2 years of age—while a person with fewer repeats may have onset delayed until he or she is age 60 or older.
The Hereditary Disease Foundation has developed a wide range of model systems containing the HD gene, including cells, yeast, C. elegans, drosophila, and many different mouse models. The Columbia lab of Dr. Argiris Efstratiadis, the Higgins Professor of Genetics and Development, and Dr. Scott Zeitlin, former assistant professor of clinical pathology, created the first knock- out mouse model for Huntington’s disease and proved, since the mouse died in utero, that a normal protein, huntingtin, is essential for life. A mutation that expands the length of a glutamine repeat in the protein, however, causes Huntington’s.
A decade after the gene’s discovery, Dr. Wexler is hopeful and optimistic about progress in HD research. “There’s been a plethora of models, and having the gene in hand has allowed us to look at all of these model systems—mice models, yeast models, cell models, drosophila models. Any promising compound, we can try through a wide range of preclinical testing. The best drugs we can test in mice. The most effective of these, we can try in people.”
A new brain bank at Columbia should also be a research catalyst. Dr. Jean-Paul Vonsattel, professor of pathology, joined Columbia in 2001 to create and direct Columbia’s brain bank, where brain donations are used to study a range of neurodegenerative diseases, including Huntington’s disease.
Dr. Wexler cites work done at Columbia by Dr. Ai Yamamoto in the laboratory of Dr. René Hen, supported by the Hereditary Disease Foundation, as “the most exciting piece of research in ages, practically since finding the gene.” (See “Graduate School Life,” page 29, for more about the research.)
“Ai Yamamoto genetically engineered a mouse so she could turn the Huntington’s gene on and off, like putting it on a light switch,” Dr. Wexler says. “When she turned the gene off, the brain cured itself, movements got better, cognition got better, memory got better.” Dr. Wexler believes the research results gave scientists a new way of looking at the disease and possible treatments. Once the HD-causing gene was turned off, the mice in Dr. Yamamoto’s research “got back to a kind of normality that even surprised the most optimistic person! And that was done here at Columbia!”
Columbia’s Huntington’s Disease Society of America Center for Excellence at the New York State Psychiatric Institute also is busy with HD research, as well as assisting HD patients and people at risk. “We’re at the forefront both of clinical trials and of trying to determine how to make people’s lives a little bit better,” says Dr. Karen Marder, who has been the center’s director since 1991. She is the Sally Kerlin Professor of Neurology (in the Sergievsky Center, the Taub Institute, and Psychiatry), a former member of the Huntington’s Study Group’s executive committee, and head of the Huntington’s Study Group’s Clinical Correlates Working Group.
The center is modeled after New York State Psychiatric Institute’s Memory Disorder Center. Its staff is a multidisciplinary team of neurologists, psychiatrists, physical therapists, an occupational therapist, a speech therapist, a nurse practitioner, a social worker, a genetic counselor, and others. “A person might spend two or three hours at one of our clinics, held three times a month, and see all of those different disciplines and get an evaluation from all of those professionals at any one time,” Dr. Marder says. “We try to offer the best clinical care available and also offer people an opportunity to participate in clinical research. Our professional services are offered free of charge. We’re unique. There’s nothing like it anywhere in the country.”
The center participated in CARE-HD, the largest and longest HD clinical trial, involving 340 patients participating for 31 months, and is now completing a trial to see if creatine improves motor function.
Dr. Marder finds two current observational studies particularly exciting. One follows people who are at risk for HD, don’t know their genetic status, and don’t plan to have genetic testing. These healthy participants will be evaluated over five years. Researchers hope the study will pinpoint the very earliest signs of HD; the information may eventually be used to design a presymptomatic trial. The second study will document the earliest signs of the disease in people known to have the HD gene. Dr. Marder says, “These studies are being done because we think we’re going to be at a point where we will have agents to offer people at risk that will prevent symptoms.”
Dr. Marder’s involvement with HD research goes back to 1987. She describes herself as being hooked on the disease. “As a neurologist, it’s an unusual opportunity to be more like a family practitioner,” she explains. “As a specialist, you usually don’t get to take care of whole families, and I do. I might know somebody, know the kids, know the grandchildren. Families are so invested, everyone has a lot at stake.”
Dr. Marder has been to Venezuela with Dr. Wexler as part of the Venezuela project. “The Venezuela project is a good cross-pollination for training neurologists how to recognize Huntington’s disease, seeing people at all stages of the disease, living with the disease. It gave me a tremendous appreciation for what it is to live with Huntington’s. A lot of neurologists have volunteered over the years. It’s made us much better neurologists and better able to take care of people with Huntington’s.”
Once the gene was discovered, genetic testing for HD became possible. Less than 3 percent of people at risk for HD—who are over age 18 and eligible for testing—have been tested. “It’s a big issue,” Dr. Marder says. “We have a genetic testing program here, and we spend a huge amount of time—instead of just sending out a lab test—discussing what they might do or not do if they had that knowledge,” Dr. Wexler and Dr. Marder agree. “Once an individual knows this information, you can’t take it away.”
