Saturday, April 20, 2024
4/20/2024
PROJECT SUMMARY / ABSTRACT Alzheimer’s Disease (AD) is the 6th leading cause of death in the U.S., costs the U.S. government over $200B every year, and has the potential to compromise the U.S. healthcare system within a few decades if an effective treatment or preventative is not found. Pharmaceutical research has been mostly fruitless, with over 150 drugs having disappointing results in clinical trials to prevent or treat AD, including several drug failures in 2019 alone. In recent years, it has become clear that the probable culprits of AD are toxic soluble “oligomers” of b-amyloid and tau proteins that aggregate inside neurons. Through extensive pre-clinical studies in AD transgenic mice, the PI and NeuroEM Therapeutics, Inc. have shown that Transcranial Electromagnetic Treatment (TEMT) penetrates the brain to disaggregate both of these toxic oligomers, while enhancing mitochondrial function and inducing consistent cognitive benefits. To translate these promising findings to clinical trials, NeuroEM has created a first-of-its-kind head device (the MemorEM) for in-home treatment. Published results from the company’s Pilot clinical trial in AD subjects have shown the device to provide considerable cognitive benefit, changes in Ab levels within CSF consistent with Ab disaggregation in the brain, and evidence of enhanced brain function in fMRI. In view of these pre-clinical and clinical findings, the FDA has recently granted the MemorEM device “Breakthrough Device” designation. Given these promising, FDA-acknowledged results, NeuroEM’s major thrust now is to identify a best set(s) of TEMT parameters for its pivotal clinical trial that are the safest and most efficacious for disaggregating toxic protein oligomers. NeuroEM’s SBIR Phase I grant elucidated the ability of TEMT to disaggregate three toxic protein oligomers (Ab, tau, and a-synuclein) in AD brain homogenates and began determination of the most efficacious TEMT parameters therein. Our proposed SBIR Phase II research is a logical extension of our SBIR Phase I findings by determining a best set of four TEMT parameters for Ab disaggregation, and doing so in “cell cultures” studies wherein intra- and extracellular physiologic endpoints can be evaluated for safety – both of these Phase II goals are important for NeuroEM’s Pivotal clinical trial, wherein NeuroEM’s MemorEM device will be utilizing this best set of parameters. Accordingly, Phase II studies are organized into two Specific Aims: Specific Aim 1: Utilizing N2a/APPswe cell cultures, wherein secretion and aggregation of Ab occurs, establish optimal TEMT parameters (e.g., frequency, power level, etc.) for disaggregation of Ab; then elucidate Ab-related effects of TEMT on N2a/APPswe cell viability, mitochondrial function, and protein production. Specific Aim 2: Utilizing three different primary cell cultures (hippocampal neurons, microglia, PBMC immune cells), evaluate indirect (non-Ab) TEMT actions on a variety of important physiologic systems to determine the safety and possible benefits of TEMT on: a) neuronal survival/structure, b) pro- and anti-inflammatory function in microglia, and c) immune modulation in PBMC cells. These two Specific Aims should thus identify a best set of TEMT parameters for use in our up-coming Pivotal clinical trial that do not deleteriously impact important physiologic functions/systems either directly (via Ab) or indirectly (non-Ab). Health Impact. There is presently no preventative or treatment for AD. If NeuroEM shows TEMT to be an effective disease-modifying AD therapeutic through its multiple mechanisms of action, 5.5 million Americans who currently suffer from AD would greatly benefit, as should the 5 million additional Americans who have Mild Cognitive Impairment (MCI), the prelude to AD.
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