Executive Summary Alzheimer’s disease (AD) is the most common adult onset neurodegenerative disease affecting more than 5 million people in the United States. At present, there are neither cures nor effective therapies for the treatment of AD. The current application proposes to put together a clinically oriented research program using a suite of early stage and well developed technologies with the goal of developing a combination therapy strategy for improving memory and halting further progress of neurodegeneration. The investigators envision using stem cells (SCs) as a two track approach by first building on existing evidence that transplanting cells can aid in brain recovery by clearing amyloid plaques and delivering neurotrophic factors. The second track would then use SCs to speed drug development by incorporating human embryonic stem cells (hESCs) into toxicology and functional screens for drug candidates. This program is somewhat diverse and employs both an interventional approach with cell delivery as well as a somewhat unrelated in vitro approach. Conceptually, this proposal targets two cell-based strategies for the treatment of AD and other neurodegenerative diseases. With the focus on AD, the proposal has high significance as it represents a major unsolved problem that is clearly an appropriate target for SC-based approaches. However, when comparing this application to other similar ones in this RFA, this proposal was not clearly defined. The proposal was felt to be overly broad, with both a drug screening and a cell therapy approach. Furthermore, although both approaches are novel, they do not share much in the way of overlapping biology, as the biology necessary for transplantation is quite different than the biology associated with in vitro screening. This breadth may be problematic for team assembly and to keep the project(s) on track. Reviewers agreed that the drug screening approach is more realistic than the engraftment therapy approach. There was a consensus during the review discussion about the strength that the principal investigator (PI) brought to this application. The PI is an outstanding scientist with a very good track record in publications. The investigator proposes a core team that includes a neuropathologist with some clinical trial experience, a cell biologist, a pharmaceutical researcher with Investigational New Drug (IND) experience, an expert in AD models and assays, and an expert in establishing clinical trials in humans. None of these people however, have extensive experience in executing a large clinical trial. In that respect, reviewers thought the group would benefit from bringing in external advisors. Unfortunately, the core team is only loosely described, and there is little evidence in their description about the inclusion of an external advisory committee. In terms of the planning approach, the review panel agreed that the main objective is poorly defined and seems to be in a development phase. The planning approach had major shortcomings, including lack of milestones, poor definition of the responsibility and mission of each of the members of the group, and a poorly-integrated collaborative approach. The proposal describes a planning meeting and conference calls that will lead to the draft strategy, and suggests the addition of other members who might be necessary during the first months; however, actual goals, plans, and structures of meetings remain unknown. In summary, the panel felt that the proposal suffered from a lack of focus. The concept was overly broad and appeared very early in development. This was reflected in the planning approach, which was also judged to be in a development phase. Reviewer One Comments There are 2 approaches described in this proposal, a drug screening and a cell-replacement approach. The drug screening is far better and realistic than engraftment therapy. Although both approaches as noted in this limited description are novel, they do not share much in the way of overlapping biology as the biology necessary for transplantation is quite different than the biology associated with in vitro screening. There is little experience with drug discovery in the proposed team. The plan is superficial. The investigator proposes a team although this team is not well outlined. There is a core team that includes a neuropathologist with some clinical trial experience; a cell biologist; a pharmaceutical researcher with IND experience; an expert in AD models and assays; and an expert in establishing human research. None of these people however, have extensive experience with putting together a large clinical trial and to that end would certainly benefit by bringing in external advisors far more experienced in this round. Unfortunately, the core team is only loosely described and there is little evidence in their description about the inclusion of an external advisory committee. Moreover, a more clear definition of the types of meetings, milestones that would be achieved by meeting periodically is missing in their disease planning approach. As compared to other disease planning applications, this one is far more superficial with thin details about actual goals, plans, structures of meetings, identifying local as well as more national experts in all of the rounds. Reviewer Two Comments Concept: - This proposal targets cell-based strategies for the treatment of Alzheimer’s and other neurodegenerative diseases. - This represents the second AD grant in this pile, and enjoys a very high significance as it represents a major unsolved problem that is clearly an appropriate target for stem cell-based approaches. - The strength of the proposal includes, in addition to the significance of the project, the talent of the PI. Principal Investigator: - The PI got his/her PhD from the University of Oregon in 1979. He/She is an outstanding scientist with a very good track record in publications. - 10% effort with salary requested. - Moved in 2007 from Burnham Institute to Scripps Institute across the street. - Team includes people from UCD, Torrey Pines Therapeutics, UC Irvine, and the Burnham Institute. The strength of the team is not at the highest level, certainly when compared with the other Alzheimer’s proposal. Planning Approach: - This proposal was not as clearly defined as the others on the same topic in my pile, and there are major shortcomings, including lack of milestones, poor definition of the responsibility and mission of each of the members of the group, and a poorly-integrated collaborative approach. - The main objective is poorly defined and seems that it still is in its development phase. During the first months, there will be planning meeting and conference calls that will lead to the draft of a strategy and suggest the addition of other members who might be necessary. The rest remains unknown.