Converging on 9 Areas of Focus

Therapeutic Strategies

Projects in the Therapeutic Strategies category identify, evaluate and perfect potential therapies, whether drugs or other interventions, for Alzheimer’s disease. 

Very promising research is taking place in the University of California, San Diego lab of Steven Wagner, Ph.D., and the Harvard/Massachusetts General Hospital lab of Rudy Tanzi, Ph.D. Their approach has been to develop drugs that modulate an enzyme called gamma secretase, which is a critical contributor to Abeta production. Their effort has been so successful that the compounds they developed have been adopted by the National Institutes of Health (NIH) as part of its fast-track, high-priority “Blueprint” program. Tanzi and Wagner now have two viable clinical candidates that are entering clinical trials soon. 

We are very optimistic about the drug candidates developed by Wagner and Tanzi with the support of Cure Alzheimer’s Fund, as well as the complex chemistry necessary to justify biopharmaceutical investment.

Cure Alzheimer’s Fund is proud to provide leverage that accelerates the progress of potential interventions into clinical trials.

 

 

Project Description Researchers
A Combination of Anti-Abeta and Growth Factor Therapy for AD

We propose to test a combination of two potentially potent therapies for Alzheimer’s disease (AD): Brain-Derived Neurotrophic Factor (BDNF) and an anti-amyloid treatment (gamma secretase modulator, GSM). In numerous animal models, modulation of amyloid beta levels (by immunotherapy or secretase blockade/modulation) has exhibited an ability to reduce AD-related neuropathology and improve functional outcomes.

Development of Novel APP Dimerization Inhibitors That Lower Abeta Levels Diseases that affect learning and memory are of fundamental biological importance and are among the most challenging biomedical problems of our time. We recently demonstrated that compounds that inhibit amyloid precursor protein (APP) dimerization and enhance APP phosphorylation reduce the levels of Abeta, the peptide responsible for the neurotoxicity seen in Alzheimer’s disease.
Binding Site Characterization of a Novel Pyridazine-Derived Class of γ-Secretase Modulators

This research will identify the critical sites of interaction between novel pyridazine-derived soluble gamma secretase modulators (SGSMs) and their molecular target, as well as provide valuable information toward fostering an improved understanding of the mechanism by which these therapeutically relevant small molecules affect the production of specific Abeta peptide variants without inhibiting the enzyme’s activity. Despite the development of numerous potent SGSMs, the precise molecular target and the mechanism of action of this clinically relevant pyridazine series remain unknown.

Activation of the 26S Proteasome for the Treatment of Alzheimer’s Disease

One fundamental feature of Alzheimer’s disease (and several related neurodegenerative diseases) is the build-up in neurons of abnormal protein aggregates composed of the protein tau. One of the primary mechanisms that cells employ to prevent the accumulation of such misfolded, potentially toxic proteins is rapid degradation by the 26S proteasome, a degradative particle present in thousands of copies in all our cells. Our lab long has been investigating proteasome functions and molecular mechanisms.

Nanobodies to Cross the Blood-Brain Barrier

The blood-brain barrier (BBB) is a vital barrier between the bloodstream and the brain. This barrier tightly controls which molecules can enter the brain. As a consequence of this barrier, the majority of currently available drugs can’t enter the brain. Importantly, to treat Alzheimer’s disease, drugs need to reach the brain. The aim of this project is to generate a universal tool that can transport drug molecules to the brain.

Acceleration of FDA-Required GLP Gene Toxicity Studies with the GSM BPN-15606

As a result of an Ames positive result in a single salmonella strain (T98), the FDA is requiring that, prior to our pre-IND meeting with them, we perform a GLP Ames assay with a form of BPN-15606 (besylate salt form) that is equivalent to what will be used in our IND-enabling toxicity studies and Phase 1 clinical trials. In addition, the FDA recommended that we perform two additional in vivo gene toxicity assays in rodents: the Micronucleus assay and the Comet assay.

Identification of a Protective Human Immune Response for Alzheimer’s Disease

Immunotherapy is a leading strategy for preventing cognitive decline in Alzheimer’s disease. Administering a monoclonal antibody to beta amyloid aggregates in patients with mild cognitive impairment showed some positive impact on cognitive decline over the course of a year in a clinical trial, but effective dosages are tied to negative side effects.

The APOE Mimetic Therapeutic Peptide CN-105 Attenuates AD Pathology and Improves Functional Outcomes in a Murine Model of Alzheimer’s Disease

Increasing evidence suggests that brain inflammation plays an important role in mediating progression of Alzheimer’s disease (AD). In particular, it has been established that apolipoprotein E (APOE) plays a critical role in mediating neuroinflammation and disease pathology. We have developed specific APOE-based peptides that are rationally derived from the receptor-binding region of this protein, and we have demonstrated that these compounds are well tolerated, cross the blood-brain barrier, and reduce brain inflammation in preclinical models of AD and acute brain injury.

Lead Optimization and Lead Evolution of Potent SGSMs for the Treatment of Alzheimer’s Disease

This application outlines a highly focused extension of an NIH-funded Blueprint Neurotherapeutics (BPN) U01 program to create more potent, soluble, brain penetrant, nontoxic small molecules known as soluble gamma-secretase modulators (SGSMs) that act to enhance the activity/processivity of y-secretase, thereby reducing the levels of Aβ42 and to a lesser extent Aβ40 while increasing the levels of shorter Abeta peptides (e.g., Aβ38 and Aβ37)

Evaluation of AMX0035, a Neuroprotecting and M1-Deactivating Therapeutic, in an Immunological Model of AD (Part 2)

In Alzheimer’s disease (AD) and other neurodegenerative diseases (ND) such as ALS, neurological inflammation and cell death form a vicious cycle that is one of the main causes of decline. Mitochondrial and endoplasmic reticulum stresses mediate these pathways, accelerating inflammation and triggering apoptosis. Therefore, we developed a combination therapeutic of repurposed compounds to simultaneously reduce endoplasmic reticulum stress and mitochondrial dysfunction to halt the cycle of inflammation and cell death.

Evaluation of AMX0035, a Neuroprotecting and M1-Deactivating Therapeutic, in an Immunological Model of AD (Part 1)

In Alzheimer’s disease (AD) and other neurodegenerative diseases (ND) such as ALS, neurological inflammation and cell death form a vicious cycle that is one of the main causes of decline. Mitochondrial and endoplasmic reticulum stresses mediate these pathways, accelerating inflammation and triggering apoptosis. Therefore, we developed a combination therapeutic of repurposed compounds to simultaneously reduce endoplasmic reticulum stress and mitochondrial dysfunction to halt the cycle of inflammation and cell death.