An Interview with Dr. Nancy Wexler: Discovering the Huntington Disease Gene By: Kristin Darwin One Morning in 1968, Dr

InsightsTM HD periodical A Huntington disease research Issue No 3 -- Fall 2012 Research Round-Up Antisense Meet Isis HD Research in Chile Dr. Lise Munsie Oligoneucleotides Pharmaceuticals Dr. Claudio Hetz and overviews recent Dr. Emily Mitchell Senior Vice President Dr. Rene Vidal discuss developments in HD Sontag overviews the Dr. C. Frank Bennett interventions that may research. CHDI Highlights promises and discusses the company’s alleviate secretory Page 3 Notes on this year’s challenges of using drug development pathway stress in HD. presentations at the Status Report: ASOs for gene efforts using ASOs. Page 11 CHDI HD Clinical Trials silencing. Page 8 Therapeutics At a glance Page 6 Conference in Palm information on Springs, California. current clinical trials Page 4 in HD. Page 5 An Interview with Dr. Nancy Wexler: Discovering the Huntington Disease Gene By: Kristin Darwin One morning in 1968, Dr. Nancy Wexler’s mother, Leonore Wexler, had jury duty in downtown Los Angeles. As Leonore crossed the street on the way to the courthouse, a policeman yelled to her, “How can you be drunk so early in the morning?” Leonore realized that she had been staggering – an obvious sign that something was wrong. Soon after, Leonore was diagnosed with Huntington disease (HD). Nancy Wexler, who was pursuing a PhD in clinical psychology at the time of her mother’s diagnosis, devoted her life to the study of HD. In 1979, Wexler and her colleagues began a research project in Venezuela to search for the HD gene. They surmised that finding the gene was the most direct route to the development of treatments, even cures! They developed a pedigree of over 18,000 individuals and collected more than 4,000 blood samples from the largest extended family with HD ever to have been discovered. Their data led to the identification of the gene responsible for HD. Today, Wexler continues her involvement with HD as the Higgins Professor Nancy Wexler, PhD of Neurophysiology at Columbia University, and as President of the Dr.Wexler is the Higgins Professor of Hereditary Disease Foundation. At the November 2011 Huntington Study Neuropsychology in the Dept.s of Neurology Group meeting, Wexler told HD Insights about the series of events that led and Psychiatry of the College of Physicians and to the discovery of the gene responsible for HD. Surgeons at Columbia University, as well as the (continued on Page 2...) President of the Hereditary Disease Foundation. HD Insights, Vol. 3 Copyright © Huntington Study Group 2012. All rights reserved. 1 HD INSIGHTS Nancy Wexler, cont... “They’re not drunk. Wexler says that her father, Dr. Milton what the abnormal protein was doing.” Wexler, was an invaluable contributor They’re sick.” Wexler and her colleagues began to the discovery of the HD gene. She compiling pedigrees and collecting and her father, who was a clinical They estimated a realistic timeframe for blood samples from HD families. She psychologist and an expert group HD gene discovery was 50 to 100 years. and colleague Dr. Tom Chase eventually therapist, began HD workshops the found many children with juvenile HD same year her mother was diagnosed. In fact, the large HD family Wexler and in a small stilt village in Lake Maracaibo. These workshops were the foundation her colleagues sought had already been One two-year-old child had a “giant for the Hereditary Disease Foundation discovered by Venezuelan physician Dr. expansion of 109 CAGs – a very that is still active in HD research today. Americo Negrette, who in 1955 practiced dramatic expansion.” Wexler began to Wexler recalls, “We had a workshop for in the small Venezuelan town of San collect blood samples from “all these two days and came up with a research Luis, near Lake Maracaibo. According to layers and layers and layers of families, agenda. My dad took what he learned Wexler, “As he walked around the from great-grandchildren all the way from group therapy, and from creativity, streets, he thought, ‘These people are up.” Homozygous families and the and off-the-wall thinking, and put it into drunk all the time! The nursing mothers children with juvenile HD were both these workshops. And in the 1970s, [the are drunk, the fathers are drunk, essential to finding the HD marker and study of] DNA was kind of just being everybody is drunk. What's the matter the gene. born. So we said, ‘Does that have an with them?’ Finally, a woman pulled Wexler gave the blood samples she had answer for us?’” him aside, and said, ‘You're such an collected to Dr. James Gusella, Dr. David arrogant doctor! Have you even looked Housman and Dr. Michael Conneally for Wexler collaborated with Dr. David at these patients? Have you smelled benchwork analysis. In 1983, Gusella Housman to organize a workshop at the their breath? Nobody's drinking. They're and Conneally determined that the gene National Institutes of Health to discuss not drunk. They’re sick.’” responsible for HD is located at the tip of the feasibility of finding DNA markers Negrette realized that the woman was chromosome four.1 Wexler was working for the HD gene. “There were very correct. He began to write up cases and prestigious scientists at the workshop,” at the National Institute of Neurological make pedigrees of individuals from San Disorders and Stroke (NINDS) when Wexler says. It was the early 1970s. A big Luis and its neighboring villages around question was, “How are you going to go they made their breakthrough. “It was Lake Maracaibo. He concluded that the incredible,” she says. “I just started from here to the moon if you don't even people had HD. Negrette and colleagues know where the moon is, and you have screaming at the top of my lungs: ‘We made a video of the affected people in found the gene!’ I called my dad. I said, to build your own spacecraft?” the villages and presented it at the 1972 Additionally, genetic studies were ‘Dad, we did it’ and he started crying. I World Federation of Neurology Research called my sister. It was just euphoric.” difficult – all restriction fragment length Group on Huntington’s Disease. Nancy polymorphisms were hand-crafted. and her father Milton Wexler were both Wexler also understood the larger Polymerase chain reaction had not yet in the audience. implications of the discovery of the HD been invented. Wexler continues: “At the gene. “It meant that our strategy would workshop, there were lots of arguments Negrette’s video presentation and data work not only for HD, but for about how many markers you needed to were central to Nancy Wexler’s everything worldwide. At that point, we evenly cover the genome. We had to determination that she should travel to realized we had the human genome in hand craft each marker and find enough Venezuela to study HD. With the our hand. We said, ‘Yes, you can do this, to evenly cover the human genome. And support and guidance of Negrette, in you can find new genes.’ We found the everybody talked about families. The July 1979, Wexler and colleagues began a marker. That just revolutionized criterion for a family critical for gene search in Venezuela for a person who everything.” mapping was a very large family in was an HD homozygote. Her search for which you had both grandparents, both a homozygote was inspired by Today, nearly two decades after the parents, and 10 or 14 kids.” At the time revelations in familial discovery of the HD gene, a successful of this workshop, such an HD family hypercholesterolemia. Wexler explains, disease-modifying treatment for HD has was believed not to exist. Some in “The godsend was that Dr. Michael yet to be developed despite efforts from attendance at the workshop even told Brown and Dr. Joseph Goldstein had researchers worldwide. However, Wexler it was unethical to publicly found the gene causing familial Wexler remains hopeful. When HD announce that a search had begun for hypercholesterolemia by studying Insights asked what she thought would the HD gene. homozygotes for the gene. Without the be the next euphoric moment in HD, normal protein, it was more obvious Wexler replied, “When we cure it!” 1. Gusella JF, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983 306:234-238. 2 Copyright © Huntington Study Group 2012. All rights reserved. HD Insights, Vol. 3 HDHD INSIGHTSINSIGHTSTM Research Round-Up By: Lise Munsie, PhD In the beginning... In the lab... In the clinic... In the past year, researchers have published There is a vast breadth of recently Important studies reviewing and on the use of stem cells to model Huntington published basic research in HD. analyzing previously obtained clinical disease (HD) and on investigations of stem data give new insights into disease cell use as a treatment for HD. Dong and colleagues5 recently identified mechanisms and assess current Sadan and additional post-translational modifications treatments for HD. colleagues1 induced in huntingtin. They coupled tandem 8 mesenchymal stem affinity purification and 2D nano-LC mass Ji and colleagues conducted a cells into spectrometry and found novel population-based study assessing the neurotrophic factor– phosphorylation sites at serines 431 and incidence of cancer in Swedish patients secreting (NTF) cells, 432. Phosphorylation at these sites was with HD and other neurological diseases. then transplanted the NTF cells into rats that specific to polyglutamine-expanded The standardized incidence of cancer was had striatal lesions induced by quinolinic huntingtin when N-terminal fragments significantly lower in patients with acid (QA). The NTF cells, whether derived were overexpressed in 293 cells. polyglutamine disease. The largest from an HD patient or a control, survived difference (0.47) was associated with HD Milnerwood and colleagues6 developed a transplantation and maintained an NTF- gene carriers.

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