Funded Programs Drug Discovery

Mitochondria-associated membranes in Alzheimer disease: a new target for drug discovery Investigator(s): Eric Schon, PhD Institution(s): Columbia University, New York, NY

Summary:
Alzheimer disease (AD) is characterized by the accumulation of protein fragments in the brains of affected patients ("plaques" and "tangles"), as well as by various biochemical alterations, including high circulating cholesterol, altered cellular lipid and calcium metabolism, and defects in the function of mitochondria (the energy "powerhouse" of the cell), but it has been unclear how all of these features combine to generate the disease. Dr. Schon and team have discovered that a protein called presenilin, which plays a critical role in the development of AD, is highly enriched in "mitochondria-associated membranes" (MAM), a specialized subcompartment of the cell that not only affects mitochondrial function, but is also required for the synthesis of lipids and cholesterol, as well as for maintaining proper cellular calcium levels. Furthermore, they have found that MAM function is severely perturbed in cells from AD patients. Dr. Schon believes that altered MAM function plays a fundamental role in the development of AD, and that if one were somehow able to "fix" the MAM, the inexorable cognitive decline that is so devastating to AD patients and their families could be halted. Accordingly, Schon and team propose to identify chemical compounds that will "rescue" aberrant MAM function in AD cells, as the first step towards developing a pharmacological approach to treating AD.

Phosphoprotein phosphatase 2A (PP2A): A novel therapeutic target for Alzheimer's disease Investigator(s): Jeffry Stock, PhD Institution(s): Signum Biosciences, Inc.

Summary:
Alzheimer's disease and related dementias have multiple causative factors that lead to signaling imbalances, loss of cell function, and ultimately neurodegeneration. Abnormal protein phosphorylation is a critical signaling imbalance resulting from the inappropriate activities of kinases and phosphatases. While drug discovery and development efforts have focused exclusively on inhibiting kinases, the activation of phosphatases remains an unexplored, yet promising strategy to restore normal protein phosphorylation. Signum Biosciences' lead drug candidate, SIG1012, elevates the activity of the major brain phosphatase, PP2A. Further development of SIG1012 and related compounds, offers a novel approach to restoring healthy protein phosphorylation.

Drug Discovery for Progranulin-Mediated Frontotemporal Lobar Degeneration Investigator(s): Philip Van Damme, MD, PhD Institution(s): VIB, Zwijnaarde

Summary:
After Alzheimer's disease, frontotemporal degeneration (FTD) is second most common dementia-type in individuals under 65 years. Degeneration in prefrontal and anterior temporal areas leads to variable clinical presentations of changes in personality and social conduct, and/or disturbances in language with impaired word retrieval and/or comprehension. In some patients, motor neuron degeneration as seen in amyotrophic lateral sclerosis (ALS) can be part of the clinical picture. The course is progressive with devastating effects on patients and their families. FTD is a familial disorder in up to 30-40% of cases. Recently, mutations in progranulin on chromosome 17q were found to be a common cause of familial FTLD. These mutations are inherited mostly in an autosomal dominant way and many of these mutations are null mutations, which result in a loss of gene expression. Therefore, progranulin deficiency is thought to cause neurodegeneration in these patients. Progranulin (PGRN) is a 68.5 kD secreted precursor protein which is cleaved into paragranulin and granulin A-G. Granulins (GRNs) are growth factors involved in wound healing and tumor growth and full length progranulin might exert different actions on its own. Since mutations in progranulin appear to be a common cause of neurodegeneration in FTD and little is known about its functions in the central nervous system, a whole new and promising field in neurodegeneration research is emerging. Recently, Van Damme and team found progranulin to have neurotrophic properties on neurons in culture. This makes PGRN the only neurotrophic factor identified to cause neurodegeneration in humans through genetic mutations. Reduced levels of PGRN in blood, CSF and brain from patients with null mutations support the hypothesis that impaired PGRN-induced support of neuronal survival may underlie neurodegeneration. The aim of this study is to identify compounds that can stimulate PGRN expression and restore normal PGRN levels in patients with PGRN mutations. Given that progranulin could have protective effects on neurons in general, compounds identified in this screen could have broad reaching applications to many neurodegenerative diseases.

Tau Clearance by Autophagy Investigator(s): W. Haung Yu, PhD Institution(s): Columbia University, New York, NY

Summary:
Macroautophagy is the principle cellular mechanism for the clearance of protein aggregates, such as tau, in cells. Uncleared tau can form "tangles" seen in the brain of FTD and Alzheimer's patients. It is an essential process in the maintenance of healthy neurons. Recent work has also shown that the use of rapamycin, an inducer of autophagy, can increase the longevity of laboratory mice, as well as clear protein aggregates. In this study, Dr. Yu and team propose to determine if stimulating macroautophagy can successfully clear aggregated/hyperphosphorylated tau from transgenic FTD mice.. This study will also identify if rapamycin can be used as a preventative agent (before pathology begins) or therapeutically (following onset of pathology). At the end of this study, the scientists will have identified whether targeting the autophagic pathway is a viable druggable option for reversing tauopathy in an animal model. If this proof-of-concept study is successful, the investigator will move forward with testing additional drug-like compounds that activate the same pathway. The study opens up a new mechanism with therapeutic potential for FTD and related dementias, like AD.

Early toxicology and ADME studies with our lead RAGE inhibitors Investigator: Rashid Deane, PhD Institution: University of Rochester, Rochester, NY

Summary:
In Alzheimer\'s disease (AD) a toxin called amyloid-beta peptide (Aß) is accumulated in the brain. Reduced Abeta clearance and/or its increased entry into the brain from the blood via transports may be responsible for Abeta brain accumulations. The main transporter for Abeta’s entry into the brain is called RAGE (Receptor for Advanced Glycation End products). RAGE binds to Abeta and transports it into brain, mediating a disease cascade. Dr. Deane and colleagues have shown that compounds which block Abeta/RAGE interaction, block the entry of Abeta into the brain, reduce Abeta related pathology, improve the regulation of cerebral blood flow and reduce cognitive decline. All of these outcomes should translate into therapeutically beneficial effects in AD. During these studies, it was suggested that ADME (absorption, distribution, metabolism and elimination) and early toxicology studies were needed. Based on these suggestions, studies are proposed for the lead compound (FPS2-BM). These studies will be out-sourced and conducted by vendors with expertise in these areas.