7

Closing Remarks

Throughout the workshop, presentations and discussions focused heavily on deep mechanistic understanding of the cellular biology of neurodegenerative diseases. As illustrated in this summary, there remain many fundamental gaps in understanding about the causal mechanisms of neurodegenerative diseases and the roles of other cellular and molecular mechanisms in these diseases. Many participants noted the importance of further research within individual diseases. The observation of common mechanisms, pathologies, and genetics across different diseases suggests that it may be valuable—at least in cases where careful scrutiny and consideration of the evidence supports it—to move away from the tradition of studying individual diseases and instead consider whether they may be better understood as clinical variants of common cellular and molecular biological defects. Furthering understanding about the basic biology of the neurodegenerative diseases could help advance efforts to prevent and effectively treat them.

In the final session, the focus shifted toward broad trends and challenges in central nervous system (CNS) research and development. Participants suggested strategies for advancing research and development for neurodegenerative diseases. There was some debate about the extent to which there is hope and interest in therapeutics development for neurodegenerative diseases. Several participants expressed concern about large pharmaceutical companies’ lack of interest in pursuing CNS development. John Dunlop of AstraZeneca, however, described this as a misconception and highlighted several areas in which large companies are working on CNS diseases. He noted that companies are not just focused on Alzheimer’s disease, but also working on Parkinson’s disease, Huntington’s disease,



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7 Closing Remarks Throughout the workshop, presentations and discussions focused heavily on deep mechanistic understanding of the cellular biology of neurodegenera- tive diseases. As illustrated in this summary, there remain many fundamental gaps in understanding about the causal mechanisms of neurodegenerative diseases and the roles of other cellular and molecular mechanisms in these diseases. Many participants noted the importance of further research within individual diseases. The observation of common mechanisms, pathologies, and genetics across different diseases suggests that it may be valuable—at least in cases where careful scrutiny and consideration of the evidence sup- ports it—to move away from the tradition of studying individual diseases and instead consider whether they may be better understood as clinical variants of common cellular and molecular biological defects. Furthering understanding about the basic biology of the neurodegenerative diseases could help advance efforts to prevent and effectively treat them. In the final session, the focus shifted toward broad trends and chal- lenges in central nervous system (CNS) research and development. Par- ticipants suggested strategies for advancing research and development for neurodegenerative diseases. There was some debate about the extent to which there is hope and interest in therapeutics development for neuro- degenerative diseases. Several participants expressed concern about large pharmaceutical companies’ lack of interest in pursuing CNS development. John Dunlop of AstraZeneca, however, described this as a misconception and highlighted several areas in which large companies are working on CNS diseases. He noted that companies are not just focused on Alzheimer’s disease, but also working on Parkinson’s disease, Huntington’s disease, 65

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66 NEURODEGENERATION psychiatry, and chronic pain. Various participants mentioned the many biotech and medium-sized companies working on neurodegenerative dis- eases. Don Cleveland of the University of California, San Diego, described therapeutic approaches that target gene products known to be truly caus- ative of disease, such as the treatments based on antisense oligonucleotides presented by Frank Rigo of ISIS Pharmaceuticals, as “at least one ray of real optimism” in therapies for neurodegenerative disease. Participants went on to discuss various ways to encourage therapeutics development for neurodegenerative diseases. For example, they noted that small and medium biotech companies may do innovative science and then partner with or be absorbed by larger companies. Several participants discussed how National Institutes of Health funding could help support Phase II clinical trials in small companies, as well as models of collaboration between academic investigators and companies. In thinking about promising strategies going forward, several par- ticipants discussed the balance between going after a single receptor or single transcription factor versus embracing complexity. One participant noted that although the intrinsic complexity may be concerning to large pharmaceutical companies and a single focus may provide the appealing promise of clarity, the biological phenomena themselves may require a sys- tems approach. Similarly, a number of participants highlighted the difficult balance between pursuing a diversified strategy and the reality of finite budgets. Lennart Mucke of the Gladstone Institutes and the University of California, San Francisco, noted that with personalized medicine, the days of pursuing one blockbuster drug are coming to an end. He mentioned the example of Herceptin and said, “As we understand patient population het- erogeneity better, we will see that kind of personalized medicine approach expand. The pockets of investment will be smaller.” He went on to say, “We need to diversify our strategy in drug development. We need to be prepared for the possibility that most sporadic neurodegenerative disorders have a multifactorial etiology and will require a multipronged therapeutic approach.” Some participants highlighted large collaborative efforts, such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Parkinson’s Pro- gression Markers Initiative (PPMI). John Trojanowski of the University of Pennsylvania called ADNI a great success story, encompassing public– private partnership, data made publicly available, and excellent use of funding in a strategic way during difficult financial times. He asked, “Why can’t we do this again and again” for different diseases and biomarkers? Lucie Bruijn of the ALS Association encouraged this suggestion, and the group discussed differences in the levels of knowledge among the different diseases and how this might impact the appropriate timing for launching large collaborations.

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CLOSING REMARKS 67 While highlighting ADNI and PPMI and other large collaborative efforts, various participants also discussed the tension between encourag- ing large collaborations with agreed-upon strategic directions versus sup- porting investigator-initiated creative science. Story Landis, director of the National Institute of Neurological Disorders and Stroke, said that they have been sensitive to this issue and have been striving for “a reasonable bal- ance.” She noted that “there’s huge tension between hypothesis-driven and discovery science, basic translational and large Phase III clinical trials, and keeping that balance in the current fiscal climate is not as simple as it would be if there were a different fiscal climate.” Richard Hodes, director of the National Institute on Aging (NIA), also noted NIA’s efforts—in the context of difficult financial circumstances—to achieve a balance of subject matter, mechanisms, and approaches. He noted that it is necessary to pursue both “large science” and smaller research projects funded through RO1 grants. Hodes also remarked on the importance of ongoing discovery science to inform the development of biomarkers. During the last minutes of the workshop, a participant reemphasized the importance of the many open questions about cell biology that were raised over the course of 2 days of presentations and discussions. Lucie Bruijn of the ALS Association also emphasized the need for further careful exploration of the commonalities and differences among diseases, before launching large projects based on perceived commonalities across multiple diseases. In closing the workshop, Landis reminded the group of the pro- vocative questions process that Harold Varmus implemented as director of the National Cancer Institute, and challenged participants to design a similar set of questions focusing on neurodegenerative diseases and basic cell biology of neurons.

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