Funded Programs Drug Discovery

Alzheimer\'s disease modeling with patient-specific stem cells

Summary:
Many diseases, including degenerative disorders like Alzheimer\'s disease, result from the destruction of specific cell types. In order to develop effective treatments for these disorders, it is essential that we understand why these cells are lost and how to prevent their loss. The development of cell reprogramming technologies to generate patient-specific stem cell lines offers an unprecedented opportunity to develop these models and to probe molecular and cellular aspects of the disease. Once reprogrammed stem cell lines have been created from a particular individual, their self-renewal and differentiation capacity allow the production of a renewable supply of the particular human cell types necessary to study functional ramifications of an individual\'s genotype. We have generated an initial set of pluripotent iPS lines with mutations from patients diagnosed with familial early onset Alzheimer\'s disease (FAD). In continuation of this work, we aim to apply these new advances in cell reprogramming to generate in vitro human models common to both familial and sporadic Alzheimer\'s disease which will open new avenues for drug discovery.

Small Molecule P2X7 Antagonists for AD Treatment

Summary:
Neuroinflammation, as characterized by activation of glia and elevated presence of inflammatory molecules, is a common component of the normal aging brain, yet is exacerbated in Alzheimer\'s disease and other neurodegenerative disorders. One of the characteristic pathological features of Alzheimer\'s disease is indeed a robust inflammatory response, involving microglia overactivation and release of pro-inflammatory signals, associated with extracellular deposition of amyloid-beta protein. Although assumed to be a local tissue response to combat the condition-specific pathology, neuroinflammation independently appears to actively contribute to CNS pathophysiology. Consideration of age-associated reactive gliosis in light of epidemiological studies reporting reduced risk of AD in patients with chronic use of anti-inflammatory drugs has stimulated intense research to investigate the implications of neuroinflammation leading to the identification of new promising molecular targets. The tight association between the P2X7 purinergic receptor and the key intracellular apparatus responsible for processing and release of the key pro-inflammatory cytokine IL-1beta; by microglia puts this molecular target at the very heart of CNS inflammation. In particular several studies have shown that P2X7R is an obligate participant in microglial activation caused by amyloid-beta.P2X7 antagonists can be useful in treating brain inflammation, and they may represent an innovative and relevant approach to treating AD and other neurodegenerative diseases involving microglia activation. The scope of project is the identification, through high-throughput screening, and early development, of bioactive molecules that limit microglia overactivation and neurotoxicity by specifically inhibiting the P2X7 receptor. These molecules will lay the ground for further development toward oral, selective drugs useful for treatment of Alzheimer\'s disease as well as of other neurodegenerative disorders.

Optimization of Aminothienopyridazine Inhibitors of Tau Aggression

Summary:
Protein misfolding and aggregation comprise the underlying common pathological mechanism of many neurodegenerative disorders. In the case of tauopathies, a group of neurodegenerative diseases, which include Alzheimer\'s disease, the aggregation of the microtubule-associated protein tau is believed to have pathological consequences via toxic gains and/or losses of functions. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other essential cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. As such, agents capable of preventing the misfolding and aggregation of tau hold considerable promise for the prevention and/or treatment of these serious diseases. We have recently identified a novel class of tau aggregation inhibitors, the aminothienopyridazines, which exhibit highly promising combinations of biological activity as well as drug-like properties (see Biochemistry 2009, 48, 32, 7732-45). The objective of this Proposal is to conduct a medicinal chemistry optimization program with the goal of identifying candidates that would be appropriate for efficacy studies in animal models of human tauopathies.

Antiamyloidogenic and Antiinflammatory effects of Proton Pump Inhibitors in AD model mice

Summary:
Despite the therapeutic potential of the link between cholesterol metabolism and Alzheimer\'s disease (AD) pathogenesis, the mechanisms by which lipid metabolism influence AD pathogenesis remain uncertain. To better understand those mechanisms we have been investigating the role of the transcription factors Nuclear Liver X Receptors (LXRalpha and LXRbeta) which regulate the expression of genes involved in metabolic pathways and transport of cholesterol. LXR ligands are considered one of the most promising targets for prevention and treatment of atherosclerosis and most recently together with ABCA1 have emerged as such for Alzheimer’s disease. The conventional wisdom is that the therapeutic potential and efficacy of synthetic LXR ligands depends on the transcriptional upregulation of their responsive genes, involved primarily in the regulation of lipid metabolism. Until now, however, LXR ligands for clinical use are not available on the market, nor have they been applied in a clinical trial. The data as outlined above, and the preliminary unpublished results generated in our laboratory, substantiated the design of a drug discovery study for identification of LXR ligands and their systematic evaluation in in vitro and in vivo model systems for AD pathogenesis and progression. Screening a small library of pharmacologically active compounds and off-patent drugs, we identified the Proton Pump Inhibitor (PPI) Lansoprazole as an LXR agonist. In secondary screens and counter-screening assays, we confirmed that Lansoprazole directly activates LXR, increases the expression of LXR target genes in brain-derived human cell lines, and increases Abca1 and Apo-E protein levels in primary astrocytes derived from wild type but not LXRalpha/beta double knockout mice. We are proposing further characterization of two PPIs Lansoprazole and Pantoprazole in an in vivo model of AD at two ages representing distinct stages in the pathogenesis of AD.

GMP Production of E64d

Summary:
Unfortunately, there are currently no drugs that can delay the progression of Alzheimer’s disease. This proposal focuses on a novel target, Cathepsin B, to prevent the accumulation of amyloid plaques in the brain. Cathepsin B has been shown previously to increase the generation of Abeta, related peptides and amyloid plaques. The compound presented in this proposal inhibits Cathepsin B activity and has previously been shown to be safe in human clinical trials for an unrelated indication. The goal of this proposal is to advance the compound through studies required by the Food and Drug Administration (IND enabling studies), the first step towards clinical trials.