Funded Programs Drug Discovery

Phosphoprotein phosphatase 2A (PP2A): A novel therapeutic target for Alzheimer\'s disease; For Clinical Development of SIG1012

Summary:
Dr. Braithwaite and the team at Signum Biosciences are working to develop the natural product, SIG1012, a minor component of coffee, for clinical application in Alzheimer\'s disease (AD). SIG1012 restores normal activity of an important cellular protein called PP2A (protein tyrosine phosphatase 2a). PP2A returns tau from a diseased form to its normal state, preventing the accumulation of tau into neurofibrillary tangles seen in the brain of AD patients. Signum has previously provided SIG1012 to mouse models with neurofibrillary tangles and observed a delay in onset of symptoms and decreased mortality. The studies proposed below are designed to develop SIG1012, a PP2A demethylation inhibitor present in coffee, into the clinic as rapidly and effectively as possible providing proof-of-concept for the mechanism and accelerating the availability of the compound to the Alzheimer\'s Disease population.

Combining Enhanced Neurotransmission and Inhibition of Beta Amyloid Toxicity in Treating Cognitive Disorders in Alzheimer\'s Disease.

Summary:
ADispell research has revealed a novel mechanism that explains the onset of Alzheimer\'s Disease and has discovered lead compounds that interact with that mechanism in a way that has potential to halt disease advancement. ADispell is working with this novel discovery, licensed from Cornell University, that identical binding sites exist on the ion channels of the neurons in the brain and on the amyloid peptide, raising the possibility that one drug might affect the two major mechanisms believed to be involved in Alzheimer\'s. This unique approach has led to the identification of two lead compounds that have been tested successfully for both sites in vitro. ADispell now is planning to perform in vivo testing.

Genome Wide RNAi Screen to Identify Inhibitors of Tau Expression

Summary:
Alzheimer\'s disease (AD) is the main cause of aging-related dementia, and its prevalence is rising as the number of elderly in our population increase. The disease currently afflicts over 5 million Americans, a number that is predicted to triple by 2050. With the increasing longevity of many populations around the world, AD is a medical problem of mounting social and economic impact. The predicted increase in AD cases could make our health care system collapse. Thus, there is an urgent need to deepen our understanding of this most common of all neurodegenerative disorders and develop better strategies to prevent and reverse it, neither of which is currently possible. Abeta peptides are widely thought to cause AD, and many new AD treatments in clinical trials aim to lower the production of Abeta or increase its removal. However, the efficacy and long-term safety of these treatments are unknown. Therefore, it is important to search for alternative approaches to treat AD progression. Using mouse models of AD, we discovered that even a partial reduction of the protein tau can prevent Abeta from causing cognitive deficits and related neuronal abnormalities. Importantly, tau reduction had no significant side effects when implemented early during development, suggesting that drugs that either reduce tau levels or inhibit its actions could prevent AD or block its relentless progression. In this proposal, we will unravel the molecular pathways that regulate tau expression, with the ultimate goal of identifying drugs that can inhibit tau expression and prevent AD. We will screen a genome-wide RNAi library to identify modulators of tau transcription, translation and degradation. Some of these novel targets could be used in the future to identify drugs that can prevent the development and progression of AD by lowering neuronal tau levels or blocking the biological activities of this intriguing protein.

Hsp90 Inhibitors for Alzheimer\'s Disease

Summary:
Alzheimer\'s disease (AD) affects more than 5 million Americans and is a progressive neurodegenerative disorder that causes cognitive dysfunction, memory loss, and eventual death. Currently, no drugs have been shown to halt disease progression. Efforts to develop effective AD treatments have focused on approaches to attenuate the functions of Abeta; either by preventing its expression or facilitating its removal from the brain. A promising target has recently been identified, the chaperone protein heat shock protein 90 (Hsp90). Hsp90 has important roles in promoting disaggregation of misfolded proteins and protein degradation. In addition, recent evidence indicates a role of Hsp90 in maintaining functional stability of neuronal proteins even when they are abnormal, therefore allowing the accumulation of toxic aggregates. The majority of effort on Hsp90 inhibitors has been for cancer applications. This proposal is to optimize existing Hsp90 inhibitors for brain penetration in order to develop their potential for AD. These inhibitors can be tested in future studies for efficacy in animal models of AD and then further developed in preclinical studies with the goal of advancing unique molecules as a new generation of drugs to treat AD.

Preclinical TDP43 Mouse Model

Summary:
The availability of TDP43 animal model offers an exciting opportunity for preclinical work in neurodegenerative diseases. Relevant to Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Alzheimer\'s Disease (AD), and Parkinson\'s Disease (PD), the newly available mouse model represents a new tool for drug screening. Many reports have focused on the need for the establishment of best practices in the use of such animal models. The ALS Therapy Development Institute (ALS TDI) has developed and published best practices and guidelines for use of the SOD1 mouse model, and seeks to do the same for the TDP43 model. The outcome of the project will standardize the use of the model, improve the interpretability of preclinical results and, improve the attrition rate of costly clinical trials. ALS TDI is uniquelrative research community. The Institute is prepared with over 14,000 square feet of laboratory space in Cambridge, Massachusetts, an animal capacity of 3000, and a dedicated colony of TDP43 mice available for studies. ALS TDI\'s staff of 25 full time scientists brings to bear the experience of conducting over 300 animal studies, testing over 100 therapeutic candidates for ALS since 2001. It\'s 2008 publication, Design, power, and interpretation of studies in the standard murine model of ALS, speaks to the Institute\'s expertise relevant to this project.