Disease Team Planning
Alzheimer’s Disease (AD) is a major health problem in the U.S. with 10% of people over the age of 65 and 50% of people over the age of 85 afflicted with disease. In spite of the magnitude of the problem, however, we lack a compelling mechanistic understanding of AD. As a result, we have no effective therapeutic agents for AD, with few if any on the horizon. While cellular therapy might some day be a viable therapy for AD, current data do not strongly support such an approach and the obstacles to implementing cellular therapy for AD include the lack of a compelling mechanism of neurodegeneration. We propose to recruit a disease team that will use human stem cells to accelerate the development and prioritization of drug-like therapeutic agents as well as developing targets for therapeutic agent development based on the mechanisms identified. Importantly, the resulting cellular and animal models can also be used as assays to screen chemical libraries to find novel drugs that may protect against the degenerative processes. These investigations will require significant interdisciplinary activity as they will need technologies, informatics, and computing beyond those typical of most stem cell biology laboratories. Our general plan is to use funds obtained for workshops, bringing in outside experts to consult, to define a pathway and set of processes and assays to test AD therapeutics, begin developing a disease team application, and to identify one or more private sector collaborators, who will commit to collaborating. Finally, although therapy development for AD might not be as conceptually mature as for some other diseases, the significance and social and financial impact of AD is massive. In addition, since clinical trials for AD are already proceeding in large number, the potential ability to design and use human cellular models to improve the therapy development and prioritization process is very likely to have a major impact on what agents enter, and hopefully succeed, in clinical trials in a 4-5 year period.
Statement of Benefit to California:
Alzheimer’s Disease (AD) is a major health problem in the U.S. with 10% of people over the age of 65 and 50% of people over the age of 85 afflicted with disease. In spite of the magnitude of the problem, however, we lack a compelling mechanistic understanding of AD. As a result, we have no effective therapeutic agents for AD, with few if any on the horizon. While cellular therapy might some day be a viable therapy for AD, current data do not strongly support such an approach and the obstacles to implementing cellular therapy for AD include the lack of a compelling mechanism of neurodegeneration. We propose to recruit a disease team that will use human stem cells to accelerate the development and prioritization of drug-like therapeutic agents as well as developing targets for therapeutic agent development based on the mechanisms identified. Because AD is such an expensive disease with major social and familial impact, progress in therapeutic development will not only strengthen California businesses, but may also provide some relief from the enormous costs of caring for people with AD.
Executive Summary This proposal will deal with devising new strategies to treat Alzheimer’s disease (AD). AD is a major health problem in the United States, and few therapeutic options are under development. This applicant suggests that current drug discovery mechanisms are not appropriate for studying AD, as animal models have not proven predictive of success in humans. The applicant proposes to use human stem cells in culture systems in which neurons and glia can be cultured together, both from sporadic disease patients and from patients with identified familial mutations. Using such culture platforms, the applicant will develop assays for drug screening and testing. During the planning process, the applicant will organize three meetings of a group of local scientists from different disciplines and three outside experts in AD to attend the second and third one-day retreats. Alzheimer’s Disease is a major medical problem with few therapeutic options, so this proposal has a very strong rationale, is extremely significant, and the science is very strong. In spite of these strengths, reviewers felt that the proposal was not yet sufficiently mature, as the project will not clearly lead to a clinical trial within five years. Reviewers commented that no specific translational target was identified and suggested that the disease target is too big, as there are potentially many different pathophysiological causes for different forms of AD. Another strength of this proposal is the quality of the PI and the members of the proposed team. The PI is among the leaders of this field and has significant expertise in both AD and stem cell biology. S/he has an outstanding publication record and has all the qualifications to lead this planning group. The proposed collaborators are also outstanding, and these investigators are likely to make significant advances in knowledge of AD. In addition, the scientific concept outlined in this proposal is compelling. The applicant provides a very good rationale for trying to add-on to existing trials and focus entirely on in vitro and proof-of-concept studies. Most reviewers appreciated the applicant moving away from unsatifying animal models of AD. The planning meetings seem well-conceived in regard to their agendas and to the questions to be asked. The applicant has set up specific goals for the meetings, such as (1) identification of team members through several retreats, (2) evaluation of the state of the current team described in the proposal, (3) identification of appropriate models. The main weakness of this proposal was that, although the significance of addressing AD is very high, most reviewers felt that it is not clear how this research approach will lead specifically into a clinical trial within 5 years so this proposal is not sufficiently mature. As the applicant acknowledges, the approach is high risk, likely long term, and there is no guarantee of this research leading to a therapy. One panelist pointed out that the team has strong infrastructure supporting the project (access to large databases, robotics, etc.), which should make progress to the clinic more rapid. However reviewers pointed out that it takes a long time to integrate discovery into a clinical trial and this proposal does not end in a clinical trial. In addition, there is not sufficient follow-up proposed for target molecules – there are collaborations proposed, but it was unclear that animal studies, ADME/toxicity studies, and so on were being considered. Other minor weaknesses pointed out by reviewers were the apparent lack of commitment by the PI, who will only dedicate 5% effort to the project, and that the relative lack of clinical expertise could be a problem for implementation and translation. Finally, reviewers wondered whether the PI had considered using reprogramming of somatic cells as part of the project, since the disease manifests in the adult. Programmatic Discussion: A motion was made to move this application to Tier 1 - Recommended for Funding. The panel was supportive of the quality of the science presented, the PI, the proposed team, and noted the lack of representation of AD in this category. However, the same issues discussed during the scientific review dominated the programmatic assessment, mainly that the project has no clear translational target and is not yet mature enough to move to the clinic. It was proposed that this project might be more appropriate for another funding initiative, such as CIRM’s upcoming Translational Award initiative or perhaps another team-based funding initiative for earlier-stage translational work, and the motion was withdrawn. Reviewer One Comments Concept: This proposal will deal with devising new strategies to treat Alzheimer’s disease (AD). As discussed by the applicant, this is a huge medical problem, thus this proposal deals with an extremely important disease. The concept is basically that the field lacks good systems to study the therapeutic effects of current drugs or new small molecules. In particular these are not being tested in human systems and the animal models of AD are not perfect and have not proven predictive of success in humans. They propose to use human stem cells in culture systems where neurons and glia can be cultured together, both from sporadic disease patients and those with identified familial mutation. Using such culture platforms they will develop assays for drug screening and testing. This is high risk research not being pursued by industry. To do this will involve a multi-disciplinary team approach. Principal Investigator: Dr. Goldstein is a distinguished scientist, a Howard Hughes Fellow and has an absolutely outstanding list of publications. He is clearly a scientific leader and has all the qualifications to lead such a planning group. Planning Approach: The applicant plans three meetings of a group of local scientists in San Diego from different disciplines, the majority of whom are well known in their fields. He also proposes to invite three outside experts in AD to attend the second and third one day retreats. These meetings seem well planned in regard to their agendas and to the questions to the asked. There is no doubt that these investigators, if funded by the major grant, are likely to make significant advances in our knowledge of AD. As they acknowledge however, the approach is high risk, likely long term and with no guarantee of this research leading to a therapy. The importance of the disease however perhaps trumps these concerns. Reviewer Two Comments Concept: - This proposal targets the use of hESCs as a cell-based therapy to treat Alzheimer’s Disease (AD), and thus has a very strong rationale and is extremely significant. Principal Investigator: - Dr. Goldstein (a senior Howard Hughes investigator) is among the leaders of this field, with an impressive publication track record and clearly capable of successfully fulfilling the aims of the team. - 5% effort, zero salary requested. Planning Approach: - The strength of this proposal relies on the significance of the topic, the quality of the PI, and the members of his team, which include: Dr. Lipton (Burnham Institute), Fred Gage (Salk Institute). The team members are appropriate for their areas of contribution. Reviewer Three Comments Concept: - concept is good and realistic however it is difficult to see how this is different from existing approaches and especially how this will lead specifically into a clinical trial within 5 years - very good rationale for trying to add-on to existing trials and focus entirely onto in vitro and proof-of-concept studies - Very significant problem – AD - Problem that the disease target is too big, potentially many different pathophysiological aspects that lead to different forms of AD Principal Investigator: - established investigator, HHMI, has significant expertise in both AD and stem cells, ES cell biology - outstanding environment - extensive experience as a leader, for instance UCSD stem cell center etc. - not MD, could be a problem for the implementation Planning Approach: - has set up specific goals, like (1) identification of team members through several retreats, (2) evaluation of the state of the current team described in the proposal, (3) identification of appropriate models; (plan the process of how the information is processed) - retreats are a good idea - goals are not very specific, not very outcome oriented