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RN1-00538-1: ES-Derived Cells for the Treatment of Alzheimer's Disease
Recommendation: Recommended if funds available
Scientific Score: --
First Year Funds Requested: $418,530
Total Funds Requested: $2,120,833
Public Abstract (provided by applicant)
Alzheimer’s disease is the most common cause of dementia in the elderly, affecting over 5 million people in the US alone. Boosting immune responses to beta-Amyloid (Aβ) has proven beneficial in mouse models and Alzheimer’s disease (AD) patients. Vaccinating Alzheimer’s mice with Aβ improves cognitive performance and lessens pathological features within the brain, such as Aβ plaque loads. However, human trials with direct Aβ vaccination had to be halted to brain inflammation in some patients. We have demonstrated that T cell immunotherapy also provides cognitive benefits in a mouse model for Alzheimer’s disease, and without any detectable brain inflammation. Translating this approach into a clinical setting requires that we first develop a method to stimulate the proliferation of Aβ-specific T cells without triggering generalized inflammatory response, as happens with vaccinations. Adaptive immune responses are provided by T cells and B cells, which are regulated by the innate immune system through antigen presenting cells, such as mature dendritic cells. We propose to leverage the power of embryonic stem (ES) cells by engineering dendritic cells that express a recombinant transgene that will specifically activate Aβ-specific T cells. We will test the effectiveness of this targeted stimulation strategy using real human T cells. If successful, this approach could provide a direct method to activate beneficial immune responses that may improve cognitive decline in Alzheimer’s disease.
Statement of Benefit to California (provided by applicant)
Alzheimer’s disease is the most common cause of dementia in the elderly, affecting more than 5 million people in the US. In addition to being home to more than 1 in 8 Americans, California is a retirement destination so a proportionately higher percentage of our residents are afflicted with Alzheimer’s disease. It has been estimated that the number of Alzheimer’s patients in the US will grow to 13 million by 2050, so Alzheimer’s disease is a pending health care crisis. Greater still is the emotional toll that Alzheimer’s disease takes on it’s patients, their families and loved one. Currently, there is no effective treatment or cure for Alzheimer’s disease. The research proposed here builds on more than 7 years of work showing that the body’s own immune responses keep Alzheimer’s in check in young and unaffected individuals, but deficiencies in T cell responses to beta-amyloid peptide facilitate disease progression. We have shown that boosting a very specific T cell immune response can provide cognitive and other benefits in mouse models for Alzheimer’s disease. Here we propose to use stem cell research to propel these findings into the clinical domain. This research may provide an effective therapeutic approach to treating and/or preventing Alzheimer’s disease, which will alleviate some of the financial burden caused by this disease and free those health care dollars to be spent for the well-being of all Californians.
Review
SYNOPSIS: The applicant has previously shown that beta amyloid – specific T cell immunotherapy can provide beneficial effects in a mouse model for Alzheimer’s disease (AD). The research proposed here builds upon this previous study and preliminary studies included in the application. The overall objective of the study plan is to develop rational protocols for the production of beta amyloid (Aβ) specific T cells by using embryonic stem (ES) cell technology to produce Aβ-presenting dendritic cells to specifically amplify the desired Aβ-specific T cell population.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: The overarching goal of this proposal is to target proliferation of Aβ-specific T cells using recombinant fusion proteins containing fragments of Aβ. The applicant has shown that an infusion of Aβ-specific immune T-cells from normal donor mice significantly improved cognitive performance of AD mice. To bring this finding to the clinical stage, the applicant is proposing to produce T cells that recognize Aβ by exposing T-cells isolated from adult donors to dendritic cells differentiated from ES cells transfected with Aβ fusion gene. The study plan unfolds in three phases:
The first specific aim is to create a series of amyloid beta fusion constructs in expression vectors that will be introduced into human embryonic stem cells (hESCs), and then screened for amyloid beta fusion protein expression.
The second specific aim is to differentiate hESCs through the myeloid lineage to attain dendritic cells that express these amyloid beta fusion constructs. Several different routes towards production of dendritic cells are proposed. Ideally, dendritic cells would be isolated from the ES cells differentiated along the lymphoid lineage; however, at the present time, lymphoid differentiation from ES cells is difficult. Accordingly, the PI proposes to obtain dendritic cells from differentiation of ES cells through the myeloid lineage. However, differentiation of ES cell could be affected by the transfection of Aβ fusion gene and the differentiation conditions to produce dendritic cells from ES cells are not fully established. Thus, the applicant needs to show at least in the preliminary study the production of dendritic cells from ES cells. In the third and final stage of research, the applicant will use the antigen presenting dendritic cells to activate T cells obtained from organ donors. Plans for obtaining the spleens from six anonymous organ donors have been put into place.
The reviewers gave this proposal high marks for novelty, innovation and potential scientific and clinical impact, but noted, as did the applicant, that the proposal is high risk. The study plan is carefully considered and is linear, logical and easy to read. The applicant should be complemented on a well-done and helpful cartoon which pictorially illustrated the three specific aims that will be investigated. Potential problems have been recognized and alternative strategies have been proposed wherever possible.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The applicant received Bachelor’s and Ph.D. degrees from a Canadian university and then embarked on a series of postdoctoral training experiences that included studies in Europe and California research institutions. In 2002, the applicant joined the faculty of the institution as an Assistant Professor. The applicant cites a total of nearly twenty peer-reviewed research publications but the bulk of these papers have appeared in lower tier specialist journals.
The applicant appears to have many of the skills needed to do this work, although he/she has very limited experience with hESCs (the applicant does have experience with mouse ES cell culture in neurosphere production). The applicant acknowledges problems with a research focus in the past, but now it appears that AD is the major thrust. It is hard to know just how well set up the lab is to do the work; one reviewer was concerned that there was no experience to produce blood cells on the research team. The PI seems to be working independently with no named collaborators and with no one in particular at the institution.
The applicant has provided a career development plan but the plan is rather worrisome in that scientific interests seem unrealistically broad (Alzheimer’s disease, Parkinson’s disease, mental retardation, autism) and there are no concrete plans for advisory committees, mentorship etc.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: A letter from the Vice Chancellor for Research at the institution states that the applicant has a “significant” allocation of research space and equipment and that roughly 75% of his/her time will be available for research. The Vice Chancellor notes that the normal expectation is that assistant professors will receive promotion to the rank of tenured associate professor within five to seven years. The applicant is currently in year five of the appointment as an Assistant Professor. While the institution appears to want to get into the business of stem cells and perhaps ES cells more specifically, the commitment to the applicant seems somewhat weak and generic. There is no formal mentoring plan presented.
DISCUSSION: The reviewers agreed that the proposal was lucid, articulate, and well-written. The applicant was however, not exceptional in that he/she has not been highly productive and has shown a lack of focus over the course of his/her career. The institutional environment is acceptable, but the PI has been there for 5 years, and at the institution it is up or out in 7 years. The institutional commitment is modest, and no formal mentoring plan was indicated for the PI. There was much discussion about whether it is possible to get dendritic cells from hESC as this is the major risk of the research proposal. If this can’t be accomplished, then the proposal can’t be done.
PROGRAMMATIC DISCUSSION: A motion was made to move this application into Tier 2 — Recommended for Funding if Funds are Available. The applicant is not exceptional on paper, but may be well-positioned to do what is proposed. Although the applicant’s career has been lengthy and not particularly productive, it has been linear in progress. This is essentially an application on a clinically relevant target (AD) from a well-trained immunologist. Panelists also noted that the stem cell program at the institution is developing; there is increasing expertise in stem cell science. The panel noted that AD was an important target for stem cells and that this was considered a lucid, well reasoned, albeit risky proposal. The motion to move this application into Tier 2 passed.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- None