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.