There is a very large and rapidly growing unmet need for disease-modifying drugs for Alzheimer's disease (AD) as its prevalence is increasing worldwide due to demographic shifts in the aging population. AD is the third most costly disease in the US with direct costs over $200 billion annually. The proposed phase IIB program is for the continued development of small molecule drugs specifically inhibiting tau aggregation at the earliest steps of tau monomer self-association into oligomers that were discovered during the phase II program. A decrease in tau oligomer accumulation in neurons should also inhibit the formation of higher order aggregates. These drugs may also be effective in reducing extracellular tau oligomers that are not irreversibly linked. A decrease of tau oligomers in the extracellular compartment holds promise to eliminate the associative impairment of memory formation and the propagation of pathology to healthy neighboring neurons. Therefore, it is anticipated that therapeutic intervention that diminishes extracellular tau oligomers should lead to both an improvement in memory and a slowing or arresting of disease progression in AD patients. Symptomatic improvement in memory may be used as an early indication of drug efficacy in preclinical and clinical studies. In Phase II of the project, the assay was converted t a high throughput compound-screening platform, validated, and used to screen a diverse compound library. Antibody fragments for tau oligomers were selected and cloned (Tian et al. 2012). The proposed phase IIB program Specific Aims are: """""""" Perform secondary screen in cell assays for inhibition of tau oligomer accumulation """""""" Improve the potency of selected compounds in the primary and secondary assays """""""" Validate the tau oligomer target in an acute mouse model of memory formation """""""" Select compounds in the acute mouse model for testing in a chronic tauopathy model """""""" Develop regulatory strategy The anticipated outcome of the proposed Phase IIB program is the selection of at least three or more lead candidate compounds targeting tau oligomers for evaluation in animal models of AD and tauopathies. To attain this result, secondary screening in cell models of tau oligomer formation and medicinal chemistry will be used to optimize and select compounds for testing in the acute mouse model of tau-induced memory dysfunction. Following validation of the model for the tau oligomer target, selected active compounds will be screened and candidates chosen for further development. At the conclusion of the proposed program, a detailed regulatory strategy will be written to guide preclinical up to the IND submission and Ph 1 clinical trials. Key Words: Alzheimer's disease, tauopathy, neurodegenerative disease, drug discovery, tau, oligomer, cell model, mouse model, memory
The proposed phase IIB program is for the continued development of small molecule drugs specifically inhibiting an important protein that plays a role in Alzheimer's disease (AD) that forms protein aggregates known as tangles. A high throughput screening assay was implemented to discover compounds that could inhibit tau self-association and aggregation as starting structures for drug development for AD. These drugs may be effective in both improving cognitive function and in preventing the spread of pathology within the brain thereby arresting the disease. Standard lead optimization work will be carried out in the program to identify compounds for in vivo mouse studies. The mouse model that will be used to test compounds was developed by the team and it will test the ability of lead compounds to restore memory formation in this model. The Company is engaged in active discussions with potential pharmaceutical companies as commercialization partners for the purposes of accelerating this exciting program into clinical studies. The SBIR program has been essential for these studies and in transitioning the company from an early stage, high risk venture to an established successful;commercial entity.
|FÃ¡, M; Puzzo, D; Piacentini, R et al. (2016) Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory. Sci Rep 6:19393|
|Tian, Huilai; Davidowitz, Eliot; Lopez, Patricia et al. (2015) Isolation and characterization of antibody fragments selective for toxic oligomeric tau. Neurobiol Aging 36:1342-55|
|Tian, Huilai; Davidowitz, Eliot; Lopez, Patricia et al. (2013) Trimeric tau is toxic to human neuronal cells at low nanomolar concentrations. Int J Cell Biol 2013:260787|