2009 Annual Report I. Table of Contents Pages Cover 1 Table of Contents 2 Overview of the Activities of the Taube-Koret Center for HD Research 3–5 Oversight of the Taube-Koret Center for HD Research Biographies of our Advisors 6 Report from Dr. Pagno Paganetti 7–10 Report from Dr. Norbert Bischofberger 11–13 Publications and Presentations of the Taube-Koret Center for HD Research Bibliography of Publications 14 HD-related Academic Seminars 15 HD-related Industry Consultations and Seminars 16 Taube-Koret Center for HD Research and the Community Press releases 17–22 News stories 23–33 The Taube-Koret Center for HD Research and 34 HD Families Appendix of Publications 35–113 2 II. Overview of the Activities of the Taube-Koret Center for Huntington’s Disease Research for 2009 We are pleased to provide this annual report describing the activities of the Taube-Koret Center for Huntington’s Disease Research during 2009. The Center was established in 2009 with a joint gift from Taube Philanthropies and the Koret Foundation. It has been a very exciting year. I am delighted to say that we exceeded all five of the scientific and financial goals we set for the first year of operation. Our progress in each area is described in detail below. Goal 1. Establish the Taube-Koret Center for Huntington’s Disease Our initial goal was to establish a Center focused on developing therapeutics for Huntington’s disease (HD). We proposed to develop an infrastructure that would be capable of identifying and validating drug targets for HD and of discovering compounds that modify HD and have the potential to become drugs. The new Center is housed in rented space within the Gladstone Center for Translational Research at 1700 Owens Street and in existing space within the main research building of the J. David Gladstone Institutes at 1650 Owens Street. The new laboratories have been outfitted with equipment to evaluate potential HD drug targets and to synthesize potential new therapeutics. Substantial capabilities, including special robotics, have been added to our existing laboratories to carry out high-throughput screens to find new therapeutics. One silver lining of the global financial crisis last year was that it enabled us to purchase equipment and set up these laboratories for less than it would otherwise have cost. Goal 2. Integrate industrial experience and capability into the academic framework In addition to the physical resources necessary to find HD therapeutics, we added critical human resources. Dr. Stephen Freedman provides assistance in prioritizing drug targets, designing screens, developing hits into lead programs, and negotiating relationships with potential industry partners. His decades of drug experience with Merck and Elan have proven to be extremely helpful. In addition, we recruited experts in medicinal chemistry to help us develop leads into potential drugs and established relationships with an array of contract research organizations that can perform critical steps in drug development that are not cost- effective to establish in house. We also recruited two external advisors of international reputation and drug discovery experience to provide a detailed scientific review of our program. Throughout the year, they have provided advice and oversight. In December, at our request, they made a site visit to review the program. The review meeting with Dr. Paolo Paganetti (Novartis) and Dr. Norbert Bischofberger (Gilead) was highly successful and added considerable input to our future direction. The detailed reports are provided below. Goal 3. Implement a critical review process and focus on programs most likely to succeed Recognizing that our resources are limited, we implemented a hard-nosed strategy to periodically re-prioritize our programs as results from our experiments become available. Programs that fail to meet performance criteria are dropped, and resources are redeployed to more promising leads. Programs that meet performance criteria and progress to the point that they interest industry are favored. They lead to partnerships that bring in additional resources from our industry partners, which also allow us to redeploy resources of the Center to other 3 promising leads. Industry partners will eventually be needed to carry leads forward into clinical trials, which require resources that are currently beyond those of the Center. We began the year with 11 programs, spanning target identification, validation, and lead development. By year’s end, one program was dropped because it failed to meet performance milestones. Another program had progressed to the point that it garnered interest by two competing biotechnology companies, who delivered term sheets to form a partnership. Three new lead programs have been added. Goal 4. Use a publication strategy to validate the scientific excellence of the Center, stimulate scientific discussion and promote scientific awareness in the Huntington’s disease field The scientific productivity of the Center during its first year has been exceptional. The Muchowski and Finkbeiner laboratories published 10 peer-reviewed papers describing results from their HD research programs. These studies revealed a range of pathogenic mechanisms in HD and therapeutic strategies. These include ground-breaking work on misfolding and abnormal clearance of huntingtin, critical neurobiology of cellular mechanisms to rid cells of protein aggregates, excessive neuroinflammation, new potential drugs to protect neurons against neurodegeneration induced by polyglutamine stretches, and new methods to use neurons to find therapeutics. A bibliography and copies of all the original publications from the Center in 2009 are enclosed. Publication is the major mechanism for achieving international renown for our HD research program. Other mechanism are to accept invitations to speak about the work from the Center all over the world and to participate in service to the National Institutes of Health (NIH) and on scientific advisory boards (SABs) of drug companies working on HD. Drs. Muchowski and Finkbeiner both helped to guide NIH HD programs in 2009 and provided SAB service and consultation to 11 biotechnology and pharmaceutical companies. As a result of these and other activities, the Center has been featured in the popular press. Some of these news stories can be found in this annual report. Goal 5. Leverage additional external funding to support the overall mission of the center Another important strategic feature of Center is our commitment to attract additional resources to leverage the investment by our donors. We were unusually successful in 2009, raising an additional $7.85M to support our HD therapeutics programs. A $1.7M grant from the prestigious Keck Foundation will enable us to establish a facility to study electrical activity in the region of the brain affected by HD in mice while they are awake and behaving. A $3.7M Grand Opportunity grant from the NIH will enable us to generate inducible pluripotent stem cells from skin tissue of adults with HD and use them to create human neurons we will use to search for new therapeutics. Further, the award itself provides additional recognition for the Center as one of the world’s leading sites for HD research. The remaining $2.45M came from the NIH in a series of smaller grants. We might never duplicate the fund raising success we experienced in 2009, but it was an encouraging start for the new Center nonetheless. 4 The Taube-Koret Center for Huntington’s Disease Research was established to facilitate the development of therapeutics for HD. We proposed a novel strategy to bridge the gap between academia and industry and to create a pipeline for therapeutics. This year, we expected to be heavily focused on building the infrastructure to develop therapeutics. However, we are pleased to report the unexpected news that two of our lead programs have already attracted industry interest. The fact that these programs have warranted industry interest is an important validation for the overall strategy of the Taube-Koret Center for Huntington’s Disease Research. The need for HD therapeutics is clear. Overall, we are very pleased with the success of the Taube-Koret Center for HD Research during its first year of operation. We remain as committed as ever to the primary goal of the Center—to develop therapies that prevent, treat, and eventually cure HD. Steven Finkbeiner, M.D., Ph.D. Paul Muchowski, Ph.D. Director, Taube-Koret Center Co-Director, Taube-Koret Center for Huntington’s Disease Research for Huntington’s Disease Research Associate Director, Senior Investigator Associate Investigator Gladstone Institute of Neurological Gladstone Institute of Neurological Disease Disease Professor, Departments of Neurology Associate Professor, Department and Physiology of Biochemistry and Biophysics UCSF UCSF 5 III. Reports of the External Advisors to the Taube-Koret Center for Huntington’s Disease Research We seek to be transparent and accountable in our management of the gifts entrusted to us by the donors, which enabled us to establish the Taube-Koret Center for Huntington’s Disease Research. As part of this effort, we recruited expert external advisors to the Center to provide an outside perspective on our performance. Short biographies of our advisors can be found below. The advisors provided advice and oversight throughout 2009. On December 15, 2009, we organized a day-long meeting on-site with our external advisors, who reviewed the structure of the Center and our major lead programs. Their reports are reproduced verbatim below. Biographies of the External Advisors to the Taube-Koret Center for Huntington’s Disease Research Paolo Paganetti, PhD Head of Huntington’s Disease Research Novartis Dr. Paganetti received his PhD from the University of Zurich, Switzerland in the lab of Prof. M.E. Schwab, in the Brain Research Institute. His postdoctoral research was done with Prof. Schwab and Prof. R.H. Scheller, HHMI and Stanford University. He joined Novartis in 1992 as a lab head and has occupied positions with increasing responsibilities. Within the neuroscience disease area, Dr. Paganetti was part of the Alzheimer’s disease team responsible for drug discovery programs for compounds reducing Ab-peptide secretion and inhibiting the aspartic protease BACE. Currently, he leads the Huntington’s disease team and is involved in several external research collaborations. He was mentor for six postdoctoral fellows, four PhD students and seven research assistants and leads a lab with five associates. Dr. Paganetti received the Novartis Leading Scientist award in 2003 and was appointed senior research investigator II in 2006. He is author of over 60 scientific publications. Norbert W. Bischofberger, PhD Executive Vice President, Research and Development and Chief Scientific Officer Gilead Sciences Dr. Bischofberger joined Gilead Sciences in 1990 and has served as executive vice president for research and development since 2000 and chief scientific officer since 2007. He oversees all of Gilead’s research discovery, preclinical & clinical development, pharmaceutical development and API manufacturing. Before joining Gilead, Dr. Bischofberger was a senior scientist in Genentech’s DNA Synthesis Group from 1986 until 1990. He received a PhD in organic chemistry from Zurich's Eidgenossische Technische Hochschule and performed postdoctoral research in steroid chemistry at Syntex. He also performed additional research in organic chemistry and applied enzymology in Professor George Whiteside’s lab at Harvard University. 6 Paolo Paganetti, PhD Senior Research Investigator II Novartis Institutes for BioMedical Research Novartis Pharma AG Basel, Switzerland External Evaluation Taube-Koret Center for Huntington’s Disease Advisory Meeting of December 15, 2009 I had the great pleasure to actively participate at the advisory board meeting of the Taube-Koret Center for Huntington’s Disease as an external advisor. I was astonished by the clear and concise presentations of top scientific quality made by Dr. Steve Finkbeiner and Dr. Paul Muchowski and the other presenters, as well as by the focused drug discovery activities and the quality of the translational research advancing rapidly at the Center. The objective of the Taube-Koret Center is to find a cure for Huntington’s disease (HD) by 2020. HD is a progressive neurodegenerative genetic disorder that affects muscle coordination and some cognitive functions. Caused by a dominant mutation in a gene located on chromosome 4 encoding for the huntingtin protein, HD is inherited with a 50% risk by any child of an affected parent. Mutated huntingtin with a CAG repeat expansion (for polyglutamine) provokes a gradual damage to the brain by mechanisms not fully understood. Clinical symptoms usually begin with subtle changes in physical skills, personality, or cognition in middle age. Lethal complications such as pneumonia or heart disease result in a life expectancy of ~20 years after onset of clinical symptoms. HD is an orphan disease with no cure available, but with treatments improving some symptoms. Approved in 2008, Tetrabenazine has specific use for reducing the severity of chorea in HD. There is a lot of confidence that a pharmacological intervention reducing the amount of mutant huntingtin in the brain would lead to an effective cure for HD. On the other hand, the length of the CAG repeat accounts for only 50% of the variation in age of onset and rate of disease progression, implying that other “modifying” genes or to environmental factors influence the disease mechanism and explain the remaining variation. The drug discovery activities progressing at the Taube-Koret Center are targeting both intervention nodes making the aim to find a cure for HD within the proposed timeline an achievable mission. Fulfilling this goal requires a deep understanding of the pathogenic mechanisms of HD and the application of this knowledge to develop more effective methods of early detection and treatment. This is crucially dependent on advances in genomics, cell biology, chemistry and computational science. The most modern tools and techniques in these areas have been developed by the scientists of the Taube-Koret Center or are accessible through affiliated Institutes (Gladstone and UCSF to only mention the two most important) or well established scientific and technical collaborations. This is an excellent basis for propelling basic science and drug discovery, in particular because 7 the Taube-Koret Center will bridge these two disciplines and fill an historic gap in the discovery of new therapies. The Taube-Koret Center has been created this year and is directed by is by Dr. Steven Finkbeiner and Dr. Paul Muchowski, two world-wide recognized scientists who have made critical contributions to advancing basic knowledge by dissecting pathomechanisms underlying the development and progression of Huntington’s disease. This is not only evident by an impressive number of recent peered reviewed publications in top-ranked scientific journals, but also by a well running network of collaborations that is among the most impressive existing in the field. Clear recognition for this achievement is demonstrated by the fact that their work has attracted financial support through a handful of grants for a yearly funding that surpasses by more than fivefold the initial investment made by the donors who made the creation of the Taube- Koret Center possible. In this report, I would like to give a feedback on different projects that attracted my attention during the meeting and include some recommendations. Drug Target Identification Identification of new drug targets for a cure of HD at the Taube-Koret Center is based on well-established unbiased screening capabilities in cultured cells. Dr. Muchowski has long-standing expertise in successfully applying yeast to identify genetic modifiers of the toxic properties of mutant huntingtin. Dr. Finkbeiner has developed over the last 10 years a powerful automated microscopy screening model with mammalian neurons in cultures that not only has proven its use as a screening assay but represent a world- wide unique test paradigm for drug target validation in vitro. In addition to other target screening and validation techniques, already these two models (yeast and primary neurons) led the researchers at the Center promising starting point for drug discovery. Such candidate drug target genes are currently validated not only with the mentioned in vitro test assays but through a battery of in vivo mouse lines. These models are recognized by the scientific community as golden standard for HD-relevant pathological and clinical measures and thus of robust translational medicine potential. In this contest, at The Gladstone Institute there are excellent facilities for neurobehavioral and neuropathological studies to which as good access. Medicinal Chemistry Medicinal chemistry with best pharmaceutical practice and decades of know-how is present at the Center including computational chemistry and other modern techniques. Although small, these capacities have already delivered series of proprietary small molecular weight compounds with proven in vitro and in vivo activities. It is suggested to make appropriate use of these assets in the different programs and seek external partners with the adequate resources to accelerate the most advanced programs. Partnering will also allow access capabilities not yet available at the Center and leverage the investments made to date by the donors as pointedly recognized by the presenters. 8 Animal Models Use of animal experiments needs careful evaluation. Their importance as a powerful translational medicine tool is obvious. On the other hand, in the field of neurodegenerative disorders efficacy studies in mouse models often acquire proportion similar to those of clinical trials with long study length, substantial costs and often requiring a large number of animals because only few measurable endpoints are available. The scientists at the Center are well aware of these issues and beside pharmacokinetic studies of compound distribution, gave high priority to demonstrate target engagement, as well as adequate safety margins by the experimental drugs. For programs directly aiming at reducing the load of toxic huntingtin in the brain, the link with mechanism of action and efficacy is well accepted. In contrast, for putative toxicity modifiers the link between brain pathology, animal behavioral endpoints and clinical efficacy is weaker and may require significant tailoring for each program. The search for powerful biomarkers of disease onset and progression is one of the priority activities in the HD field and the Center has established privileged relationship with the most important HD center in the US and Europe. KMO Program Dr. Muchowski has demonstrated a relation between this target and HD in several cellular and animal models by tenaciously championing this program to steady progress. This year, the Center has unequivocally validated the target in vivo making KMO world-wide one of maybe two-three preclinically validated targets. This contribution is outstanding and of excellent quality. The animal data indicate that KMO inhibition will affect disease progression, prolonging survival and rescuing some of the pathological measurements. Further morphological analysis of brain atrophy and striatal markers, such as DARP32, may represent an additional asset of the program, as well as attempts to better understand the mechanism of action possibly also in peripheral tissues. Dose chronically one or more of the KMO metabolites may also contribute in elucidating the mechanism. Overall, there was good agreement on the path forward, such as integrating the key enzymatic tests within the Center, convincing enzymatic studies, the need for an efficient measure for short-term mouse compound screen and a mechanistic readout in corticospinal fluid. In the near future, the established IP position needs an aggressive protection strategy as the design of adequate partnering plans. The preliminary positive outcome in animal models of other neurodegenerative disorders, such as Alzheimer’s disease, is remarkable and of wonderful potential. Autophagy Program Macroautophagy is a cellular defense mechanism for degradation of defective organelles and toxic protein aggregates that has attracted recently a lot of attention by the scientific community and drug discovery researchers. Also neurons make us of autophagy but the regulatory mechanisms in these cells are poorly understood as the classical inducing treatment paradigms are ineffective. Dr. Finkbeiner has made perfect use of his automated microscopy technique by screening a large number of marketed drugs and identifying a small molecular weight drug which efficiently induce mutant huntingtin degradation by autophagy in neurons. This discovery is of upmost importance and combined with the identification of a marketed drug with proven safe clinical use, 9 this program pushes the Center in unique competitive advantage. The path forward was endorsed by all participants: a concise medicinal chemistry program with the aim of obtaining a small increase in potency to allow validation of the hypothesis in vivo, proof of concept could also be envisaged in peripheral tissues and thus limit the program should not be limited to CNS active compounds, demonstration of a specific mechanism and not related to the known biology of the current leads. The well progressed partnering negotiation for licensing biology and chemistry to one of the two companies Proteostatis or LINK is fully supported. Additional Programs IDO/TDO represents a very attractive back-up program to KMO. It is expected that the identified modulatory compounds, as well as use of the knock-out mice, are adequate to rapidly validate this program in vivo. Additional exploratory activities to assess the possible role of inflammatory cytokines in the brain with the potential to produce a biomarker strategy as well as therapeutic approach are well founded. Mgmt, a DNA repair enzyme identified in the yeast screen, if validated, has a lot of potential since compounds in advance clinical trials exist for oncology indications. Also here, compound treatment and knock-out mice are adequate to rapidly validate this program in vivo. CB2 and Nrf2 are in an early exploratory phase, and their potential as drug targets difficult to assess at the present date. Huntingtin modifying strategies have an excellent rationale, and the programs on polyglutamine conformation and phosphorylation have great potential. It is unfortunate that the compound leads identified in the screen can not be pursued with the necessary determination for lack of resources. If a reprioritization would endanger more advanced program, then partnering seems the best solution. General comment When testing strategies reducing toxic huntingtin, it is advised to analyze additional neurodegeneration-linked proteins, such as alpha synuclein or tau, in the HD models. Integration of human models in the current screen would further increase the value of the screening models developed at the Center. 10
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