Funding opportunities

Stem cell based small molecule therapy for Alzheimer's disease

Funding Type: 
Early Translational III
Grant Number: 
Principle Investigator: 
Funds requested: 
$1 673 757
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective; a drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. Our laboratory has developed a drug discovery scheme based upon using hESCs to screen drug candidates. We have recently identified a very potent drug that is exceptionally effective in rodent models of AD. However, this molecule needs to be optimized for human use. In this proposal, we will harness the power of hESCs to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.
Statement of Benefit to California: 
Over 6 million people in the US suffer from Alzheimer’s disease (AD). Unless a viable therapeutic is identified it is estimated that this number will increase to 16 million by 2050, with a cost of well over $1 trillion per year, overwhelming California and national health care systems. Among the top 10 causes of death, AD (6th) is the only one with no treatment available to prevent, cure or slow down the condition. An enormous additional burden to families is the emotional and physical stress of having to deal with a family member with a disease which is going to become much more frequent with our aging population. In this application we use new human stem cell technologies to develop an AD drug candidate based upon a strong lead compound that we have already made that stimulates the multiplication of nerve precursor cells derived from human embryonic stem cells. This approach presents a unique opportunity to expand the use of human embryonic stem cells for the development of a therapeutic for a disease for which there is no cure, and could lead to a paradigm shift in the treatment of neurodegenerative disease. Since our AD drug discovery approach is fundamentally different from the unsuccessful approaches used by the pharmaceutical industry, it could also stimulate new biotech. The work in this proposal addresses one of the most important medical problems of California as well as the rest of the world, and if successful would benefit all.
Review Summary: 
This Development Candidate Feasibility (DCF) application builds on a novel approach to discover and develop a new class of drugs for Alzheimer's disease (AD). The applicant has recently identified a potent molecule with neurogenic and neuroprotective activities that appears to enhance memory and ameliorate AD pathology in rodent models. Using human embryonic stem cell (hESC)-derived human neural precursor cells (hNPCs) as a screening platform, the applicant proposes to specifically tailor derivatives of their initial candidate for use in humans. Specific aims are 1) to use medicinal chemistry approaches to improve key properties of the initial molecule; 2) to assess pharmacokinetic profiles and stability of new derived compounds; and 3) to determine dosing and demonstrate proof of concept for efficacy in a model of AD. Objective and Milestones - This proposal meets the objective for a Development Candidate Feasibility Award and if successful, will achieve preclinical proof of concept. - Project milestones are logical and realistic, with clearly defined criteria for success. - The target product profile (TTP) is scientifically and clinically reasonable, but may not completely address the key attributes for the proposed development candidate. In particular, the compound may improve cognition but not prove efficacious as a disease-modifying treatment for AD. Rationale and Significance - Alzheimer's Disease represents one of the most significant unmet medical needs. A compound with the envisaged properties would represent a highly important achievement in medicine and could become a crucial game changer in the treatment of AD. - The scientific rationale is strong: drug candidates that can both stimulate neurogenesis and provide neuroprotection in the innately toxic environment of an AD brain represent a novel and untried approach. Research Project Feasibility and Design - The project builds on a strong body of preliminary data, much of which has been published and passed significant peer review. - Reviewers cautioned that structure activity relationship (SAR) studies might not yield a series with all the desired activities and drug-like properties, especially for use in the central nervous system. The possibility of achieving milestones with SAR would be increased if more than one scaffold were utilized. - The SAR studies may prove more challenging than anticipated if more than one molecular target contributes to the mechanism of action(s) for the initial candidate. Careful analysis of desired effects in vivo will be required to focus the program on the most attractive feature. - It was unclear to reviewers whether the initial target of six compounds represented an optimized set of compounds. If not, this might be too low. Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team - The PI and his/her collaborators are skilled and experienced medicinal chemists capable of designing and synthesizing new compounds; their proficiency is supported by their publications and the preliminary data. - The research team might benefit from including experts in neuroscience medicinal chemistry programs and from industry. Collaborations, Assets, Resources and Environment - The environment in which the proposed research will be conducted is excellent. Resources and institutional support are outstanding. Responsiveness to the RFA No relevant concerns were highlighted by reviewers under this review criterion.

© 2013 California Institute for Regenerative Medicine