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. Dr. Braithwaite and team have previously provided SIG1012 to mouse models with neurofibrillary tangles and observed a delay in onset of symptoms and decreased mortality. Ongoing AD related studies include the assessment of cognitive and biomarker endpoints in AD mouse models. Together, these studies are designed to efficiently transition into clinical trials and explore cognitive and CSF biomarker endpoints in humans.

Interaction between Abeta and Fibrinogen: A New Therapeutic Target for Alzheimer\'s Disease

Summary:
Dr. Strickland’s lab and others have presented evidence of a vascular contribution in Alzheimer’s disease (AD). Many AD patients suffer from altered brain blood flow, damaged cerebral vasculature, and abnormal hemostasis which can result in brain cell dysfunction and death. However, the mechanism underlying a vascular contribution in AD is still unknown. The protein, fibrinogen, is the primary component of blood clots. Previous studies from Dr. Strickland’s laboratory demonstrated that fibrinogen accumulates in the damaged vasculature of AD mice. Depleting fibrinogen improved the Alzheimer-like symptoms in the mice, indicating a potentially critical role for fibrinogen in AD. Further experiments confirmed that Aβ binds to fibrinogen resulting in blood clots that are more persistent and could cause blood brain barrier damage, neuroinflammation, reduced blood flow, and neuronal death. Therefore, Dr. Strickland and team propose to screen for novel molecules that block the interaction between Aβ and fibrinogen to restore normal blood clotting as a novel therapeutic approach to AD.

Identification of Small Molecules That Can Prevent Mitochondrial Dysfunction Associated with the Generation of Apolipoprotein E Fragments in Neurons

Summary:
Alzheimer\'s disease (AD) is a devastating neurodegenerative disease that affects 5 million people worldwide, and that number will climb to 15 million people by 2050. The cost to the health community in the US is $172 billion annually, and worldwide the costs are over $600 billion. While the death rate for most major diseases in the US is declining, the rate of mortality from AD is increasing by almost 50%. No treatment for AD effectively blunts disease progression. Consequently, there is an urgent need for new, effective treatments of this disease. The protein apoE4 is the major genetic risk factor for AD. ApoE4 carriers account for 65--80% of AD cases. ApoE4 increases the occurrence and lowers the age of onset of AD, and considerable evidence suggests that it has a fundamental role in the neurodegeneration and pathophysiology of AD. One major cellular site of apoE4\'s action in neurodegeneration is the mitochondria. This organelle is the main powerhouse of the cell, and insults to its function can cause neurodegeneration. We showed that apoE4 and its toxic fragments bind to the mitochondria in neurons. This results in a loss of the enzymes needed to produce energy and to a gradual loss of the ability of the mitochondria to function normally. We propose that \"mitotoxicity\" is one of the main ways that apoE4 causes neurodegeneration, and drugs blocking this pathway might prevent AD progression. We developed new methods to discover drugs that block the interaction of apoE4 toxic fragments with the mitochondria. We propose to use those methods to identify unique compounds that block apoE4\'s toxic effects on mitochondria. The compounds that we find will be developed in future studies into drugs to prevent apoE4-induced neurotoxicity to treat AD.

Selective GABA a5 ligands for cognitive enhancement in patients with Mild Cognitive Impairment

Summary:
AgeneBio, Inc. is developing new therapies for memory loss in Mild Cognitive impairment (MCI), a condition that often progresses to Alzheimer\'s disease. The company\'s intellectual property and research is based on work supported by the National Institute on Aging over the past 15+ years. That work has identified a novel entry for therapy in MCI to correct a condition of excess neural activity in circuits critical for memory. A highly restricted subtype of inhibitory mechanism, the GABA alpha 5 receptor, is localized to the memory system neurons that are hyperactive. It is also known that these receptors mediate tonic inhibition. Thus, boosting GABA alpha 5 function may remediate over activity in the memory system, as supported by our preliminary preclinical data on the use of such compounds to treat memory impairment in aged rats. The support of the ADDF will be used to further advance development of therapies directed at this target for age-related cognitive impairment. A well-characterized animal model of neurocognitive aging will be used to test a series of GABA treatment of impaired memory. These pharmacological studies will also use a selective inverse agonist to validate mechanism of action of the test compounds. This work will provide the basis for lead compound identification of a GABA alpha 5 agonist, a potential first in class therapy for MCI.

Optimization and Pre-Clinical Proof-of Concept of a New Drug Lead Candidate Series for Alzheimer\'s Disease

Summary:
The number of people suffering from Alzheimer\'s disease (AD) is projected to grow from 5 to over 13 million by 2050 in the US alone, yet currently available drugs still only provide modest symptomatic relief at best. Moreover, these few drugs are not able to slow the progression of AD, or, critically, to protect the brain against the severe tissue damage that is part of the disease process. There thus remains an urgent need to develop innovative new drug strategies that intervene in the biochemical processes that underlie AD. In this context, this project seeks to optimize and evaluate new drug candidate molecules for treating AD based on a novel molecular target that we have recently discovered. This drug target, called protein disulfide isomerase, or PDI, is involved in pathological processes that are triggered by misfolded proteins like Abeta that are a central to the disease process in AD.