We propose to discover new drug candidates for Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel candidates by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drugs by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drugs to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches to drug discovery for AD.
The objective of this development candidate feasibility (DCF) proposal is to discover novel small molecule drug candidates for Alzheimer's Disease (AD) by screening purified human brain cells derived from induced pluripotent stem cells (hiPSC) from patients who have rare and aggressive hereditary forms of AD. The applicants have already demonstrated that such human brain cells exhibit a unique biochemical phenotype in a dish that indicates early development of AD. They propose to use this finding to develop a screening assay to find new drugs. Six milestones are proposed: 1) Scale production of purified human neurons from their existing hiPSC lines derived from familial AD patients; 2) Miniaturization and optimization of a high-throughput screening (HTS) assay to test for compound-induced decreases of a new and unique phenotype in human neurons; 3) Screening of carefully selected compounds; 4) Establishment of structure-activity relationships within one novel chemical series; 5) Prioritization of lead compound candidates using in vitro and in vivo pharmacological experiments; and 6) Demonstration of in vivo proof-of-concept by testing biochemical and pathological efficacy in a suitable human transgenic mouse model.
Objective and Milestones
- The detailed milestones are well conceived, logical, and focused.
- The profile outlined is scientifically and clinically achievable, although probably not within 3 years.
- The target product profile is reasonable, since the biochemical phenotype on which the applicant will base the assay is an established early biochemical marker of neurofibrillary tangle pathology, and thus, screening for a decrease in such activity may identify promising treatments in the early AD pathophysiological process.
Rationale and Significance
- As there are no current therapies to slow or stop disease progression of AD, the discovery of a disease-modifying drug with the envisaged properties would represent a highly important achievement in medicine and a crucial advance in the treatment of the disease.
- If successful, the proposed work has the potential to identify novel targets or compounds to move forward towards pharmaceutical development for the treatment of early AD.
- hIPSC from sporadic AD (SAD) showed similar pathologies, thus this approach may be more generalizable.
- Targeting the early AD pathophysiology may prove a valuable approach in preventing longer-term progressive degenerative processes.
Research Project Feasibility and Design
- The research plan is focused, well designed and fully supports the feasibility of the milestones and objectives.
- There is a good probability that at least one candidate compound will be identified for lead development.
- The referenced work and the preliminary data provide convincing evidence that the objectives of the research plan will be achieved.
- The ambitious timeline, and the risky nature of drug screening in general, suggest that it may not be feasible to complete the project within 3 years.
- One criticism of the plan is the limited use of cheminformatics approaches to further refine the list of compounds to screen by limiting candidates to those with good solubility profiles and predicted membrane permeability potential.
- Another recommendation is that if a hit or lead series is identified, the applicants should consider applying “Lipinski's Rule of 5” to filter candidates for further development.
- Reviewers felt that the applicants have not adequately considered the difficulty in developing compounds that can efficiently cross the blood-brain barrier, which would be critical for success of an AD drug.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI is a distinguished cell biologist, with an outstanding track record of achievement and is engaged in a number of studies addressing critical questions in AD research.
- A major concern was that there is a significant lack of expertise in medicinal chemistry.
Collaborations, Assets, Resources and Environment
- The research environment is outstanding and includes resources for early stage drug discovery such as the screening steps necessary for conducting these studies.
- There are no letters indicating specific collaborations or consulting agreements. Given the limited expertise of the applicants in drug discovery, this is a concern.
- The budget was viewed as appropriate for the proposed studies.
- There was some concern that the program is significantly understaffed for the work proposed.
Responsiveness to the RFA
- Human iPSCs are necessary to achieve the outcomes of the proposed research and a target for drug discovery has been identified. The project appears entirely responsive to the RFA.