Volume 4

HD Insights Volume 4 (PDF)

Editor’s Letter

Welcome to the fourth edition of HD Insights!

We started the venture of this periodical in 2011 and we have received great feedback on the first three issues. We electronically distribute every issue to over 1300 investigators, researchers, clinicians, and industry leaders from around the globe. In addition to electronic distribution, in 2011, 300 hard copies were distributed at the Huntington Study Group meeting in Indianapolis, Indiana, USA. In 2012, 700 hard copies were distributed at the European Huntington Disease Network meeting in Stockholm, Sweden; and also in 2012, 300 hard copies were distributed at the Huntington Study Group Meeting in Seattle, Washington, USA.

Past issues of HD Insights are available at www.hdinsights.org . They include interviews with leaders in the field such as Dr. Nancy Wexler, Professor of Neuropsychology at Columbia University, and Dr. Walter Koroshetz, the Deputy Director of the NINDS. There are articles on how many people in the world have HD; the therapeutic promises and challenges of antisense oligonucleotides; profiles of companies developing therapies for HD, such as Prana Biotechnology and Isis Pharmaceuticals; and status updates of HD clinical trials, the only comprehensive status report of HD clinical trials globally.

In this issue and the previous issue, we have included features on HD research in Chile and Japan. If you or one of your colleagues are interested in contributing a piece that highlights HD research in your part of the globe, please email me at editor@hdinsights.org . To receive a free subscription to HD Insights, simply email subscribe@hdinsights.org . If you have feedback for HD Insights, if there are features you would like to see in the next issue, if you want to contribute an article, or if you are eager to support this periodical, please email me.

The continuation of this periodical into 2013 has again been made possible by a generous unrestricted educational grant from Lundbeck.

Together we can advance research and eventually therapeutics for Huntington disease.

Dorsey_feat

 

 

 

 

 

 

 

Ray Dorsey, MD

Editor, HD InsightsTM


 

Editorial Board Members

Ray Dorsey, MD — Editor, Johns Hopkins University

Donald Kennedy, PhD — Stanford University

Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute

Rodrigo Osorio — Agrupacion Chilena de Huntington

Bernard Ravina, MD — Biogen Idec

Ralf Reilmann, MD — University of Munster S

arah Tabrizi, MBChB, PhD — University College London

Leslie Thompson, PhD — University of California Irvine

Huntington Study Group

Shari Kinel, JD — HSG Executive Director

Liz McCarthy, BA — HSG Administrative Manager

Jillian Lowell, BS — HSG Event Planner

Contributors

Hitoshi Okazawa, MD, PhD

Justo Garcia de Yebenes, MD

Lise Munsie, PhD

Paige Nichols, BA

Publication Staff

Kristin Darwin, BS — Deputy Editor

Robin Taylor — Production Editor

Martin Holmes — Technical Editor

Todd Bernhard — Copy Editor

Vinayak Venkataraman, BS — Website Designer

Dave Kolko — Distribution Specialist


For more information on HD Insights, or to receive a free subscription, please visit us at www.HDInsights.org  or email us at editor@hdinsights.org

HD Research Around the World: Japan

Past, Present, and Future

japanBy: Hitoshi Okazawa, MD, PhD

Huntington disease (HD) is rare in Japan. Its incidence is one-tenth of that observed in western countries, and as a result, the number of researchers studying HD in Japan is relatively low.

Dr. Ichiro Kanazawa, former chair of the Department of Neurology at the University of Tokyo, was the first to initiate research on the molecular genetics and biology of HD in Japan. After Gusella and colleagues identified the HD causative gene in 1993, Dr. Kanazawa and Dr. Nobuyuki Nukina and colleagues used immunohistochemistry and western blot techniques to generate a polyclonal antibody against the expected mutant protein (mHtt), and confirmed the difference in length of the polyglutamine repeat sequence in mHtt compared to Htt, and its expression in the brain1.

When post-genome research on HD started, Nukina discovered the involvement of the heat shock protein 40 family (Hsp40) and heat shock protein 70 family (Hsp70) in the pathogenesis of HD2. He developed a unique therapeutic approach based on selective autophagy3, and discovered the regulation of selective autophagy via the phosphorylation of p624. My group studies the functional side of mHtt. The polyglutamine repeat sequence is important for transcription-related proteins. Oct-3/ Oct-4, an octamer transcription factor, is now recognized as the most important transcription factor for embryonic stem cells and induced pluripotent stem cells5. Many transcription factors possess these polyglutamine sequences, and the tract sequence has been suggested as a motif for protein–protein interaction. Using this knowledge, my group identified a novel mediator of polyglutamine diseases, namely polyglutamine-binding protein-16, 7, which the European Consortium of Xlinked Mental Retardation subsequently recognized as the cause of a spectrum of mental retardations8.

Much of the current HD research in Japan is focused on therapy. Therapeutic research trends include the activation of selective autophagy; inhibition of mHtt; functional recovery of target physiological proteins; and use of induced pluripotent stem cells. Some of these approaches have reached the preclinical stage. Dr. Nukinaʼs group has identified that trehalose has a therapeutic effect in HD9. Dr. Nagai (National Center of Neurology and Psychiatry) and colleagues discovered that polyglutamine-binding peptide-1 (an artificial peptide distinct from the endogenous polyglutamine-binding protein-1 referred to above) showed a protective effect against aggregation10, 11.

Meanwhile, my group has used genomics and proteomics to screen pathological mediators of HD. Using genomics, we determined that Hsp70 plays a critical role in neuron subtype-specific vulnerability12. Using proteomics, we found that high-mobility group protein B, a DNA architectural protein, is involved in HD pathology13. In collaboration with Dr. Erich Wanker (Max-Delbrück Center for Molecular Medicine, Germany) and by using an interactomics approach, we discovered that Ku70, a DNA damage repair protein, plays a role in HD pathology14. More recently, we discovered that DNA damage repair by VCP/TERA/p97 is involved in the pathology of many polyglutamine diseases15. These targets of mHtt are functionally disturbed in HD, and the foci of their functions cluster around transcription and DNA damage repair, although other functions of these molecules, such as autophagy, may also be relevant. Functional rescue of these molecular targets has proved very successful in mice models of HD. Viral vector-mediated supplementation of high-mobility group protein B1, Ku70, and some other molecules has been very successful in mice model treatment for HD, spinocerebellar ataxia type 1, and other diseases. Details of such research will be published in the future.

DNA double strand break is increased in striatal neurons of human HD patients.14

DNA double strand break is increased in striatal neurons of human HD patients.14

Lifespan elongation by Ku70. Double transgenic mice have a 30% longer lifespan.14

Lifespan elongation by Ku70. Double transgenic mice have a 30% longer lifespan.14

 Colocalization of mutant huntingtin and Ku70 in astriatal neuron of R6/2 mouse.14


Colocalization of mutant huntingtin and Ku70 in astriatal neuron of R6/2 mouse.14

 

 

 

 

 

 

 

 

 

 

Moreover, mice models of HD treated with the above-mentioned genes have shown longer survival than other reported treatments. Due to limited social and financial support for HD research in Japan, HD research groups collaborate closely with each other and with research groups studying other neurodegenerative diseases. In order to advance HD research in Japan, there must be closer collaboration with researchers in countries that have a higher incidence of HD and consequent stronger support for HD research. International collaboration with pharmaceutical companies is also essential.

Dr. Okazawa would like to thank all friends around the world for their current and future support.


 

1 Yazawa I, Nukina N, Hashida H, et al. Abnormal gene product identified in hereditary dentatorubralpallidoluysian atrophy (DRPLA) brain. Nat Genet 1995 May; 10(1):99-103.

2 Jana NR, Tanaka M, Wang GH, et al. Polyglutamine lengthdependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-

3 Bauer PO, Goswami A, Wong HK, et al. Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein. Nat Biotechnol 2010 Mar;28(3): 256-63. doi: 10.1038/nbt.1608. Epub 2010 Feb 28.

4 Matsumoto G, Wada K, Okuno M, et al. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 2011 Oct;44(2):279-89.

5 Okamoto K, Okazawa H, Okuda A, et al. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 1990 Feb;60(3):461-72.

6 Waragai M, Lammers CH, Takeuchi S, et al. PQBP-1, a novel polyglutamine tract-binding protein, inhibits transcription activation by Brn-2 and affects cell survival. Hum Mol Genet 1999 Jun; 8(6):977-87. 7 Okazawa H, Rich T, Chang A, et al. Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death. Neuron 2002 May;34(5):701-13.

8 Kalscheuer VM, Freude K, Musante L, et al. Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet. 2003 Dec; 35(4):313-5. Epub 2003 Nov 23.

9 Tanaka M, Machida Y, Niu S, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 2004 Feb;10(2):148-54.

10 Nagai Y, Tucker T, Ren H, et al. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem 2000 Apr; 275(14):10437-42.

11 Nagai Y, Fujikake N, Ohno K, et al. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet 2003 Jun; 12(11):1253-9.

12 Tagawa K, Marubuchi S, Qi ML, et al. The induction levels of heat shock protein 70 differentiate the vulnerabilities to mutant huntingtin among neuronal subtypes. J Neurosci 2007 Jan; 27(4):868-80.

13 Qi ML, Tagawa K, Enokido Y, et al. Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases. Nat Cell Biol 2007 Apr; 9(4):402-14.

14 Enokido Y, Tamura T, Ito H, et al. Mutant huntingtin impairs Ku70-mediated DNA repair. J Cell Biol 2010 May 3; 189(3):425-43.

15 Fujita K, Nakamura Y, Oka T, et al. A functional deficiency of TERA/VCP/p97 contributes to impaired DNA damage repair in multiple polyglutamine diseases. Nature Commun In press.

Research Round-Up

By: Lise Munsie, PhD

In the lab. . .

Future clinical treatments for HD are likely to vary from patient to patient and involve multiple therapies to address all symptoms of the disease. Investigators are seeking to find novel ways to assess HD pathology, and they continue to research the molecular mechanisms of HD.

in the labSathasivam and colleagues describe aberrant splicing of Htt that leads to mRNA translation of an Htt exon1 fragment in the presence of the expanded polyglutamine tract1 that is characteristic of mHtt. Their results suggest that mHtt may be present at exon1 as a result of direct translation, not proteolytic cleavage.

Steinert and colleagues used a drosophila larva neuromuscular junction model to investigate glutamatergic synaptic transmission in HD2. Their manuscript describes vesicle defects in the presence of exon1 mHtt and reports that an overexpression of Rab11 at the endosomal recycling system rescues both synaptic and behavioral defects in this model.

Previous work has implicated the Rhes protein with the progression of HD. Rhes protein is a GTP binding protein enriched in the striatum. Baiamonte and colleagues crossed Rhes knockout mice with the R6/1 HD mouse model to study the effects of Rhes on the progression of HD3. The cross resulted in a delay in the behavioral symptoms of HD.

Lu and Palacino created a human neuronal model of HD4. Overexpressed Htt exon1 fragments recapitulated disease by causing protein aggregation and neurodegeneration in a neuronal population derived from induced pluripotent stem cells. The authors’ results support previously published data that suggests that soluble mHtt is a main toxic species.

In transition. . .

Promising pre-clinical data has emerged in the field of HD research.

in transitionMethylene blue, previously tested in Alzheimer’s disease, shows therapeutic potential in HD and is being tested for efficacy in HD readouts by a group at the University of California, Irvine. Sontag and colleagues report that methylene blue can inhibit the in vitro aggregation of mHtt and can also lead to functional improvements in the drosophila and R6/2 mouse models of HD5.

Human samples acquired by the TRACK-HD study have been used to develop an assay that detects levels of Htt in peripheral immune cells. Weiss and colleagues report the use of time-resolved Förster resonance energy transfer to quantify both total Htt and mHtt levels6. The assay detects differences in mHtt levels in different leukocyte populations. This study also reports that mHtt levels in monocytes were associated with rates of caudate and whole brain atrophy and ventricular expansion. Sawiak and colleagues created a public database of their ex vivo brain imaging from cohorts of both R6/2 and YAC128 HD mouse models7. Almost 400 datasets containing structural data and tissue maps for each individual brain are available. As in vivo data is obtained it will be added to this free online resource. Datasets may be accessed at http://dspace.cam.ac.uk/ handle/1810/243361 and may be viewed using online freeware. Medical imaging is at the forefront of biomarker research in HD. The availability of large datasets will aid investigators to make correlations between mouse models of HD and human brain imaging being undertaken for studies in neurodegenerative disease.

In the clinic. . .

A variety of therapeutic approaches are entering clinical trials for HD.

The drug PBT2, developed by Prana Biotechnology Ltd, has shown to improve cognition in Alzheimer’s disease8 and is now also a clinical trial candidate for HD. PBT2 is an 8-hydroxyquinoline analog that has affinity for transition metals, and may be able to liberate metals that contribute to pathology in HD. In a recent PloS One publication9, investigators report the alleviation of symptoms in a Caenorhabditis elegans model of aggregation, and the improvement of motor symptoms and a decrease in striatal atrophy in the R6/2 mouse model of HD, in response to PBT2. A phase II study of PBT2 for patients with early to mid-stage HD is ongoing10.

The ‘NEST-UK’ consortium at the University of Cambridge recently reported on the safety of using fetal striatal cell transplants to repair damaged cells in the striatum of HD patients11. Transplants were performed in five patients with mild HD symptoms and postoperative follow-up continued for up to 10 years. This follow-up was unable to detect any significant changes in either the Unified Huntington’s Disease Rating Scale or the Mini-Mental State Examination. However, this study does prove the safety of the protocol and lays the foundation for larger-scale studies of this intervention. Case reports have also featured the benefits and side effects of deep brain stimulation for HD12. Deep brain stimulation has been moderately successful for HD motor symptoms and has been shown to be safe for HD patients.


 

1 Sathasivam K, Neueder A, Gipson TA, et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 2013 Feb; 110(6):2366-70.

2 Steinert JR, Campesan S, Richards P, et al. Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington’s disease. Human molecular genetics 2012 Jul; 21(13): 2912-22.

3 Baiamonte BA, Lee FA, Brewer ST, et al. Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington’s disease. PloS one 2013; 8(1):e53606.

4 Lu B, Palacino J. A novel human embryonic stem cell-derived Huntington’s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration. FASEB journal 2013 Jan.

5 Sontag EM, Lotz GP, Agrawal N, et al. Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington’s disease models. The Journal of Neuroscience 2012 Aug; 32(32):11109-19.

6 Weiss A, Trager U, Wild EJ, et al. Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. The Journal of Clinical Investigation 2012 Oct; 122(10): 3731-6.

7 Sawiak SJ, Wood NI, Carpenter TA, Morton AJ. Huntington’s disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy. PloS one 2012; 7(12):e53361.

8 Faux NG, Ritchie CW, Gunn A, et al. PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 2010;20(2):509-16.

9 Cherny RA, Ayton S, Finkelstein DI, et al. PBT2 Reduces toxicity in a C. elegans model of polyQ aggregation and extends lifespan, reduces striatal atrophy and improves motor performance in the R6/2 mouse model of Huntington’s disease. J Huntington’s Dis 2012;1(2):211-9.

10 http://clinicaltrials.gov/ct2/show/NCT01590888? term=reach2hd&rank=1

11 Barker RA, Mason SL, Harrower TP, et al. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J Neurol Neurosurg Psychiatry 2013 Jan.

12 Velez-Lago FM, Thompson A, Oyama G, et al. Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington’s disease. Stereotact Funct Neurosurg 2013 Jan; 91(2):129-33.

Lundbeck: Building Hope for HD with Casa De Hogar

Lundbeck.svgLundbeck was pleased to donate a large supply of tetrabenazine to the Hereditary Disease Foundation to provide to the Casa De Hogar (House of Love and Hope), a unique clinic in Venezuela that provides care for people affected by HD.

The Casa De Hogar clinic provides treatment, food, and care at no cost to thousands of family members with HD who live along the shores of Lake Maracaibo, Venezuela. Venezuela has one of the largest known families affected by HD, and HD has been in this family for generations. The clinic continues to be an important part of the HD community, serving as a model for patient care, despite extreme challenges of poverty.

The clinic was built over a ten-year period and opened its doors in 1999. It was established by the Hereditary Disease Foundation in collaboration with local Venezuelan authorities in gratitude to the families whose help was critical to researchers who identified the HD gene in 1983 and isolated it in 1993. These discoveries provided the knowledge which enables doctors to genetically test for HD, and has paved the way for the varied and promising HD research being conducted today. The clinic is now home to over 65 people and provides care and food to many more from the surrounding community.

“As we approach our fifth year of involvement with this degenerative neurological disease, we are inspired by the resilience of this local HD community and continue to look for meaningful ways to support their needs,” said Staffan Schüberg, president of Lundbeck in the United States. “We’ve provided financial assistance to the Hereditary Disease Foundation to aid the clinic over the past three years through our ‘Build Hope for HD’ online awareness campaign, and we’re proud to expand our support with this product donation.”

In total, the Build Hope campaigns have resulted in $220,000 in donations from Lundbeck. Funds have been used to renovate and update the clinic’s facilities, purchase new hospital equipment, and assist in the general day-today operations of the facility.

Meet the Compound: Huntexil

 

Image courtesy of ChemSpider

Image courtesy of ChemSpider

VITAL SIGNS

NAME: Huntexil® (Pridopidine/ACR16)

CHEMICAL FORMULA: C15H23NO2S

MOLECULAR MASS: 281.41 g/mol.

TYPE OF COMPOUND: Dopamine stabilizer

MECHANISMS OF ACTION: Functional antagonism of dopamine type 2 receptors and strengthening of cortical glutamate functions in the central nervous system.


 

Two previous studies that feature Huntexil® are the MermaiHD study and the HART study.

The MermaiHD study was a 26-week, double-blind, controlled trial of 437 HD patients conducted in 2008 through 2009 at 32 centers in Europe1. Study participants were randomized to receive either placebo (n=144) or doses of 45mg (n=148) or 90mg (n=145) of Huntexil per day. The primary outcome measure was the modified motor score, a subset of the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. The 90 mg per day group improved 1.0 points on the modified motor score compared to placebo from baseline to week 26, but the improvement was not statistically significant. The 90 mg per day group showed a statistically significant improvement of 3.0 points in total motor score compared to placebo. Changes in other motor outcomes were not significant across groups.

The HART study was a 12-week, double-blind, controlled trial of 227 HD patients conducted in 2009 through 2010 at 27 centers in Canada and the United States2. Study participants were randomized to receive placebo (n=58) or doses of 20 mg (n=56), 45 mg (n=55), or 90 mg (n=58) of Huntexil per day. As in the MermaiHD study, the primary outcome measure was the modified motor score, but the improvement of 1.2 points on the modified motor score of the 90mg per day group compared to placebo was not statistically significant. The 90mg per day group showed statistically significant improvement of 2.8 points in total motor score compared to placebo. No significant changes in cognition were observed during this 12- week study. In both studies, Huntexil was safe, and well tolerated by participants2,3.


 

Commentary

Justo Garcia de Yebenes, MD

Huntexil is a dopamine stabilizer that was synthesized by Prof. Arvid Carlsson. It can activate dopamine receptors in hypodopaminergic status, and can also block these receptors in cases of dopamine hyperactivity. Huntexil has previously been tested in vitro and in vivo. It showed a good side-effect profile and its pharmacological effect is primarily on extrasynaptic dopamine receptors. Huntexil was first trialed in small groups of Scandinavian HD patients. After four weeks of treatment the results of these studies were primarily an improvement of the modified UHDRS. Following these short-term studies, the MermaiHD trial was organized. Previous studies showed no effect of Huntexil on chorea, dystonia and ocular movements, and so the evaluation of these clinical deficits was thought to ‘dilute’ the significance of the results. For this reason the modified UHDRS was chosen as the primary end-point of the study. That choice eventually proved to be a mistake because the periods of treatment required for improvement of the previously mentioned clinical deficits differ. The results of the study essentially showed no effect of Huntexil treatment at 45 mg per day and a borderline effect of treatment at 90mg per day, using as the defined primary end-point, the modified UHDRS. Additional analysis taking in consideration the number of the patient’s CAG repeats, age, or the total motor score on the UHDRS, showed unequivocal improvement for the group treated with Huntexil at 90 mg per day. Future studies are warranted. With the experience of this study, future studies should be long-term studies, with doses of pridopidine at 90 mg or more per day, using the total UHDRS motor scale as a primary end point, or a more sensitive and global motor scale, if such a rating scale is ever developed.


 

1 de Yebenes JG, Landwehrmeyer B, Squitieri F, et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebocontrolled trial. Lancet Neurol 2011 Dec;10(12):1049-57.

2 A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord 2013 Feb 28.

3 Squitieri F, Landwehrmeyer B, Reilmann R, et al. One-year safety and tolerability profile of pridopidine in patients with Huntington disease. Neurology 2013 Feb 27.

Meet the Investigator

Dr. Michael Hayden

Dr. Michael Hayden

VITAL SIGNS

NAME: Michael Hayden, CM, OBC, MB, ChB, PhD, FRCP(C), FRSC CURRENT

Dr. Michael Hayden was recently appointed as the President of Global Research and Development and Chief Scientific Officer at Teva Pharmaceuticals. Dr. Hayden is the most highly cited author in Huntington disease. He is the founder and director of the Centre for Molecular Medicine and Therapeutics in Vancouver, and founder of three biotechnology companies (NeuroVir, Xenon Genetics, and Aspreva Pharmaceuticals).

POSITION: President of Global Research and Development and Chief Scientific Officer at Teva Pharmaceuticals

OTHER POSITIONS: Killam Professor of Medical Genetics at the University of British Columbia, Canada Research Chair in Human Genetics and Molecular Medicine, Founder and director for the Center for Molecular Medicine and Therapeutics in Vancouver, Canada, Program director of the Translational Laboratory in Genetic Medicine at the National University of Singapore, Founder of NeuroVir, Xenon Genetics, Inc., and Aspreva Pharmaceuticals, Inc

EDUCATION: MB, ChB, PhD, University of Cape Town, Post-doctoral fellowship, Harvard University

HOBBIES: Collecting art, photography, and enjoying creativity in other domains.

FAVORITE ARTIST: Ben Shahn, who was born in Lithuania and became a social activist in America. He is known for his works of social realism.

 

Meet the Company

tevahome

 

 

 

 

 

 

 

VITAL SIGNS

NAME: Teva Pharmaceutical Industries, Ltd.

HEADQUARTERS: Petah Tikva, Israel

STOCK PRICE AS OF 3/5/13: $37.25

52 WEEK RANGE: $36.63 – $46.38

MARKET CAPITALIZATION: $31.92B

EMPLOYEES: ~46,000

HD INSIGHTS: How did you first become interested in Huntington disease (HD)?

MICHAEL HAYDEN: My interest in HD goes back to my life as a medical student in the middle of the 1970s, when I first saw patients in South Africa who had HD. At the time, HD was not diagnosed because it was thought not to occur in Africa. I realized that not only did HD in fact occur in Africa, but in people of Caucasian or mixed-race background it occurred at a similar rate to that seen in Europe. By contrast, HD was rare in the black populations of Southern Africa. I was drawn to HD. I traveled to every one of the 16 psychiatric and neurological hospitals in South Africa. I examined every single patient with chorea, and from this I compiled a list of 400 to 500 patients with a family history of HD. People in South Africa with HD were discriminated against. Many were of mixed race. Our cardinal observations were that there was a high frequency of juvenile HD in South Africa, and the incidence of HD in people of Caucasian and mixed-race background was similar to the incidence of HD in Europe. We traced the introduction of the HD gene mutation back to Dutch settlers who came to South Africa in the mid-1600s. We started documenting the difficult social and psychological impact of HD on the family. In 1978 we started the first HD clinic in Africa, and we provided an integrated model of HD – comprehensive neurology, psychiatry, social work and physiotherapy. The clinic was integrated in every way; not only by virtue of the specialties to treat HD patients, but also racially. This was the first multiracial clinic at the Groote Schuur Hospital in Cape Town, where ten years previously the first human heart transplant had been done. We wanted to provide support for all families with HD irrespective of their race and irrespective of their past. In the late 1970s we also formed the first lay HD organization in Africa. Just as we established a multiracial clinic for HD, I wanted to integrate the experience of medical students of different racial backgrounds in hospital wards in Cape Town. Generally, white medical students did not see black patients and black medical students were barred from seeing white patients. Inevitably at that time, this put me into conflict with the authorities. I met Marjorie Guthrie in San Diego in 1977 at the Second International Congress on HD. Marjorie and I became close buddies. I told her that I was very worried about my future. I had to choose which struggle I was going to dedicate my life to – was it the struggle to change South Africa, or was it the struggle to have an impact on families with HD and do something for them? Marjorie persuaded me to come to the United States, and helped organize my move. The late Senator Ted Kennedy wrote a letter to the Immigration Department to support my application for immigration on a Green Card. I thought that after I left South Africa I could never go back, and needed to find a home. Senator Kennedy recommended that I go to Boston, so I interviewed at the Children’s Hospital and was accepted into the genetics program. I arrived in Boston in June 1980 as a post-doc. At that time there were no reference books on HD. There had not been a single monograph on HD. I took my thesis of 1979 which formed the basis of the first single-author monograph on HD. This was published while I was in Boston in 1981. I dedicated the monograph to my research assistant at the time, who later became my wife, and Marjorie. Those were the two people who really had played a key role in me being able to complete that work.

INSIGHTS: What was the next step for you?

HAYDEN: As I came to the end of my fellowship, I was asked to go to Vancouver, Canada. Judith Hall, President of the American Society of Human Genetics, was there, Tom Perry Sr., a major researcher in HD, was there. Marjorie encouraged me to look at this opportunity. They welcomed me, and the HD family welcomed me. I had a deeply ingrained commitment to HD. I had seen the plight and difficulties but had also witnessed the courage and dignity of HD patients. I established my lab to make inroads into HD. We have had huge support from families all over North America. In 1986 we did the first predictive test for HD, and contributed to the guidelines for HD predictive testing. We worked on really understanding how, at a molecular and biochemical level, HD occurs. The key question was: How do we develop therapies for HD? We created a full-length animal model for HD. We did the first PET scans in patients, and we created an integrated HD clinic, the first in Canada, that today sees patients contributing to trials around the world. We defined the epidemiology and the incidence of HD, showing that it is more frequent than people have realized in the past. We also defined mechanisms that lead to HD, which is ongoing work for my lab in Vancouver and Singapore too. Many of my post-docs have now gone on to be leaders in the lab in Singapore with a major focus on HD.

INSIGHTS: Why did you make the transition to Teva?

HAYDEN: I could only go to a certain point with academic lab work. To develop therapies for HD, I would have to be open to other possibilities. I worked very hard trying to engage pharma. I met with large pharmaceutical companies, informing them about the importance of this disease, but I was not able to convince them to make the investments needed to commit to developing medicines that could possibly change the course of the lives of patients and families. Then I was approached to consider the job of President of Global R&D at Teva. During the recruitment process we discussed my launching a focus on neurodegeneration using HD as the model. I think that HD could inform studies on many forms of neurodegeneration, including Alzheimer’s disease. We needed to start somewhere, and the CEO, Jeremy Levin, was willing and enthusiastic to commit to that. And so I joined. My labs continue to do basic research that can feed the pipeline with new ideas. I go back to Vancouver very frequently as well as to Singapore to support that work. The very first acquisition with me at Teva was the purchase of a Phase III asset, the drug Huntexil from Neurosearch. This drug was not going to change the course of HD, but provide symptomatic relief. We are now working to start definitive trials with Huntexil in the next few months.

INSIGHTS: What about other approaches for HD?

HAYDEN: As president of R&D at Teva, we have a commitment to refocus the pipeline to diseases of the central nervous system, including MS, Parkinson’s, Alzheimer’s, Pain and, of course, HD. We are hiring people from around the world who know about HD. Teva is a company committed to making a change in the lives of patients with neurodegenerative disorders.

INSIGHTS: What do you think are the greatest future opportunities for new treatments for HD?

HAYDEN: We believe that the inflammatory pathways are important targets. Inflammation is an early feature of this disease, and it occurs both centrally and peripherally. The neurons may be secondarily involved. Astrocytes and microglia secrete various inflammatory cytokines that could cause damage. We are looking into drugs that influence those pathways. In the end, it is likely that you will need combination therapy for this disease: To retard disease progression and also to protect neurons that are already damaged. In HD, the cellular and biochemical disease process starts very early, and often, by the time you have clinical symptoms, there has already been a lot of damage.

INSIGHTS: Dr. Hayden, thank you for your time. Do you have any final thoughts?

HAYDEN: HD is now recognized as being present globally. It is present wherever people have migrated, and the burden of the disease is very similar irrespective of politics, irrespective of race, irrespective of borders and boundaries. The impact on people’s lives is profound. We have the chance to do something. This is an opportunity to impact the lives of patients not only with HD, but also with other forms of neurodegenerative disease.