Meet the Founder
NAME: Ira Shoulson, MD
POSITION: Professor of Neurology, Pharmacology and Human Science; Director, Program for Regulatory Science and Medicine (PRSM); Principal Investigator, FDA-Georgetown Center of Excellence in Regulatory Science and Innovation (CERSI), Georgetown University, Washington, DC
EDUCATION: MD, Internal Medicine residency (1971–73), Neurology residency (1975–77), Chief Resident in Medicine and Neurology (1977–78), University of Rochester School of Medicine and Dentistry; Experimental Therapeutics Fellowship (1973–75), National Institutes of Health, Bethesda, MD
HOBBIES: Traveling, exercising, and spending time with his young grandson
Dr. Ira Shoulson has been a driving force in HD research and discovery since the late 1970s. He founded the Parkinson Study Group (PSG) in 1985 and the Huntington Study Group (HSG) in 1994, both groundbreaking research networks for clinical trials in Parkinson disease and HD. He was the Louis C. Lasagna Professor of Experimental Therapeutics, and Professor of Neurology, Pharmacology and Medicine at the University of Rochester School of Medicine in Rochester, New York from 1990 to 2011, and Chair of the HSG from 1996-2014. Dr. Shoulson recently shared his journey and his hopes for the future of HD research with HD Insights. Beginning on page 2 is an edited transcript of the conversation.
HD INSIGHTS: How did you first become interested in HD?
SHOULSON: In 1973, I finished my residency in internal medicine and went to the NIH for a clinical research fellowship. I was part of the Public Health Service, and one of my jobs was working under Dr. Tom Chase, who ran the Experimental Therapeutics branch of the National Institute of Mental Health (NIMH), a research program involving patients with PD and HD. I had seen PD during my residency training, but I had never seen HD. In about two months I saw fifty to sixty HD patients and their families volunteering to participate in research. Shortly after, Dr. Chase was promoted to scientific director of the NIH Neurological Institute, and I, so to speak, inherited this wondrous research world for the next two years. I then returned to the University of Rochester for a formal neurology residency. By the time I joined the faculty in 1978, I had seen and cared for about 200 patients with PD and HD. So like most interesting things in life, these opportunities were just very serendipitous and fortuitous.
HD INSIGHTS: You eventually became involved in the Venezuela project, correct?
SHOULSON: Yes, from 1975 to 1977, I was involved in research at the NIH and met two really important people. One was Marjorie Guthrie, who was trying to get the word out about HD. I was in Washington, DC and watched her convince Congress and key thinkers in government of the importance of supporting HD research. She actually started a commission that I was part of, and that set the stage for the creation of the Total Functional Capacity scale that Dr. Stan Fahn and I developed between 1977 and 1980. While at the NIH, I also met Dr. Nancy Wexler, another important influence. Nancy had this crazy idea that perhaps we could use the “new genetics”—which at the time meant restriction fragment length polymorphisms (RFLPs)—to identify the HD gene in a large unexamined population of individuals with HD living along Venezuela’s Lake Maracaibo. In 1980, Nancy and Tom went to Venezuela, and when they returned he said, “This looks like HD we see in the USA.” Nancy recruited Dr. Anne Young, Dr. Jack Penney and me to the project. We were all junior faculty, Anne and Jack at the University of Michigan and I at the University of Rochester. I spent the next fourteen years traveling in February or March to Maracaibo, which was our headquarters for field research work. I sought to identify and characterize clinical phenotype and obtain biological samples, primarily blood, for DNA.
HD INSIGHTS: What did it feel like when you heard from Drs. Jim Gusella, Marcy MacDonald and colleagues that they had identified a genetic marker?
SHOULSON: We were surprised, because we had started in 1980, and by 1983 the linkage for the HD gene had been established and localized to the short arm of chromosome 4. Of course, establishing genetic linkage was different from identifying the gene itself. We were surprised at how quickly the linkage came, but also surprised at how long it took—ten more years—to identify and characterize the HD gene mutation.
HD INSIGHTS: After identifying the gene, you started thinking about forming the HSG, correct?
SHOULSON: Yes. Dr. Stan Fahn and I had experience organizing the PSG in the mid-1980s. In 1993, Dr. Jack Penney and I, supported by small grants from advocacy organizations, organized the first meeting of what was to become the HSG in Washington, DC. There were twenty of us from the US and Canada. The core leadership group also included Dr. Karl Kieburtz, who had recently completed our experimental therapeutics fellowship, and Dr. David Oakes, with whom I had worked closely in mounting the multicenter PSG “Deprenyl and tocopherol antioxidative therapy of parkinsonism” (DATATOP) trial.1 The big decision we had to make was whether to meet again. We spent the next four or five years developing and refining the Unified Huntington’s Disease Rating Scale (UHDRS) and applying it to clinical trials between 1994 and 1999. Thereafter, we took on the large-scale observational and clinical trials that helped set the standards for cooperative HD clinical research, such as “Prospective Huntington At Risk Observational Study” (PHAROS).2
HD INSIGHTS: What was the biggest challenge in forming the HSG?
SHOULSON: Well, I think the biggest challenge, besides the buy-in (“Are we going to do this?”), was actually doing something substantive. The old saying is, “The proof of the pudding is in the eating,” meaning that talking about things and doing them are often quite different. We talked about a unified clinical research scale, but realized we didn’t have anything like it and needed to develop such a tool. I remember that at a meeting in Boston in 1994, I got four groups together and locked each group in a room—figuratively speaking, of course—and said, “You have to come up with a scale for measuring the motor, cognitive, behavioral, and functional domains of HD.” That was really the beginning. There were many contributions and refinements thereafter to what became known as the UHDRS. After several pilot studies, we started in 2003 to apply the UHDRS in HSG clinical trials. So that was an important ten years between the talking and the doing.
HD INSIGHTS: What was the biggest success you experienced during your time leading the HSG?
SHOULSON: I think the biggest success or satisfaction from my point of view is how sustainable the HSG has been. Like the PSG, once people were involved, such as investigators, coordinators, social workers, neuropsychologists, and scientists, the HSG built commitment, cooperation, momentum and sustainability. Our other early accomplishments were PHAROS, the observational study that was started in 1999, then the landmark “Neurobiological Predictors of Huntington’s Disease” (PREDICT-HD) (see HD Insights, Vol. 7, p. 8) and “Cooperative Huntington’s Observational Research Trial” (COHORT) studies,3 followed in short order by the CARE-HD trial of Coenzyme Q10 in HD.4 Our most tangible accomplishment was planning, conducting and reporting the TETRA-HD HSG trial that led to the approval of tetrabenazine to treat chorea associated with HD.5 Another benefit of approval of tetrabenazine was that it signaled to innovators in industry that HD should not be neglected, but rather be thought of as an important unmet need and a market.
HD INSIGHTS: What was your biggest disappointment or failure?
SHOULSON: Well, we never had a strategic plan, which in retrospect, I think would have been useful. In some fashion, we were just kind of flying by the seat of our pants. Eventually, in 2012, we made the transition to an independent entity, HSG, Ltd. That was an important milestone, moving from childhood into adolescence. I just wish we had gotten through that childhood a little bit faster.
HD INSIGHTS: You recently accepted a position on the board of directors of Prana Biotechnology. Can you tell us why?
SHOULSON: Prana Biotechnology was developing the experimental drug PBT2, which had novel mechanisms and showed safety and signals of cognitive benefit in a European Alzheimer disease trial.6 Working closely with Dr. Steven Hersch, we developed the clinical research interest in examining PBT2 in HD, and an approach that became the HSG Reach2HD dose- ranging phase II trial under the leadership of Dr. Ray Dorsey, Dr. Julie Stout, Dr. Diana Rosas, and Elise Kayson. As recently reported, Reach2HD showed safety and tolerability and signals of cognitive benefit that may prove to be reproducible and clinically meaningful (see HD Insights, Vol. 7, p. 1). Once my leadership of the HSG concluded in April 2014, and upon an invitation from Prana, I accepted the position as a non-executive director in order to provide clinical research expertise and help ensure that PBT2 was developed to its full potential in HD. Prana has a dedicated group of scientists and developers who have come to appreciate the many unmet needs of HD and the opportunities that exist to relieve some of the burdens. I continue my full-time work in leading the regulatory science program at Georgetown University, which has reviewed and authorized my work with Prana. I am compensated by Prana, both as a member of the board and as a consultant, but I have no equity positions, stock options, or incentive packages. I am focused on fully developing PBT2 for HD, whatever the outcome of future studies might be.
HD INSIGHTS: What have you learned working directly for industry that you did not know before?
SHOULSON: I learned a bit about business development as a bystander over the years that I was leading the HSG and taking on industry-sponsored research. I now better appreciate the need to integrate clinical research and business development. These endeavors are often undertaken in parallel but separately. That may be a mistake. It is very natural to do them together. The people responsible for business development must appreciate the clinical entity and unmet needs that are the problems that bother our patients and families. Then too, the clinical researchers who know and care for the manifold problems need to know how to be entrepreneurial and capitalize on opportunities. While seemingly awkward, clinical and business development best proceed hand in hand.
HD INSIGHTS: What does the future hold for you?
SHOULSON: I enjoy what I’m doing now. My day job is at Georgetown University, where I direct the program in regulatory science of medicine. It is an outstanding opportunity. We have a Center of Excellence in Regulatory Science and Innovation (CERSI) that is supported by the FDA, conducts important research in regulatory science, and offers an online Master’s program in regulatory science, linked to the Georgetown-Howard Universities Clinical and Translational Science Award (CTSA).
Solid experimental evidence is key in making up one’s mind, whether making decisions as a regulator at the FDA, as a clinician or prescriber, or as a patient, family, or consumer. I find the commonality in decision-making about the safety and benefits of medical products to be very relevant and interesting. I have also become more interested in direct-to-consumer genetic testing, which the FDA regulates as a device. There are important issues about comprehension, literacy and numeracy of direct-to-consumer genetic tests as well as their accuracy, applicability and predictability. Regulatory science can provide a knowledge base to address these issues. Of course, genetic testing, choices and decision-making have been a centerpiece of HD interest for the past two decades. We have learned a lot about genetic testing that is guided by experience, data, laboratory quality, and knowledgeable clinicians, but this is not direct-to-consumer.
HD INSIGHTS: Where do you see direct-to-consumer genetic testing going in the future?
SHOULSON: I think it’s to be determined. You have to consider questions surrounding whether genetic testing should be treated as a medical device, because you usually use some kind of kit to do the testing. You have to ask, “Do we know enough about the scientific precision, predictability, and accuracy of the results? Do we know enough about the attitudes, beliefs, comprehension, expectations and resulting behaviors of the consumer as well as the clinicians to whom the consumers turn?” In other words, is direct-to-consumer genetic testing “good to go” as an over-the-counter medical product? I feel that we are not quite there yet, and there is a lot to learn. Consumers expect that their clinician will be able to guide them about the results of genetic testing, but that may not be in keeping with the knowledge and competencies of the clinician. It will take time to sort this out.
HD INSIGHTS: You have devoted forty years of your professional life to advancing knowledge and therapeutics for HD. What would you like to see happen in the future?
SHOULSON: It has been that long? In terms of HD, I think we need some substantive treatments, although I’m of the mind that substantive treatments come about incrementally and gradually. When you look back in ten or twenty years, it looks like a quantum leap. That certainly was true in developing HIV therapies. In HD, we have had the benefit of quickly improving understanding of the etiology, pathogenesis, and scientific foundations around HD. I expect incremental gains will be realized for our patients and their families.
HD INSIGHTS: When you are not working on therapeutic developments for HD, how do you spend your free time?
SHOULSON: I do a lot of traveling. Most is work-related, but I also do a lot with my wife Josie and family. We have a getaway place in Florida that’s right on the beach. I enjoy exercising, walking, and taking in the outdoors.
HD INSIGHTS: I hear you have a very young companion in some of your exercises.
SHOULSON: Oh, you mean my grandson Noah? Yes, he’s a joy. It’s really nice to experience this again. As a parent, it’s so interesting to watch your kids grow up. But when you get a chance to do it again with grandchildren, it’s fabulous, interesting and gratifying. A great environment for my encore career!
HD INSIGHTS: Thank you very much for all of your contributions to the HSG and to the HD field. The field certainly wouldn’t be where it is without you and your leadership over the past four decades.
1 Kieburtz K, McDermott M, Como P, et al. The effect of deprenyl and tocopherol on cognitive performance in early untreated Parkinson’s disease. Parkinson Study Group. Neurology.
3 Cooperative Huntington’s Observational Research Trial: NCT00313495. [Webpage]. 2014; clinicaltrials.gov/show/ NCT00313495. Accessed 10/7/2014.
4 Biglan KM, Dorsey ER, Evans RV, et al. Plasma 8-hydroxy-2′- deoxyguanosine Levels in Huntington Disease and Healthy Controls Treated with Coenzyme Q10. JHD. 2012;1(1):65-69.
5 Dorsey R, Biglan K, Eberly S, et al. Use of Tetrabenazine in Huntington Disease Patients on Antidepressants or with Advanced Disease: Results from the TETRA-HD Study. PLoS currents. 2011;3:Rrn1283.
6 Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet neurol. 2008; 7(9): 779-786.