SBIR-STTR Award

Formation of misfolded protein oligomers in neurons is an early and causative event in a variety of neurodegenerative diseases, such as Alzheimer's Disease (ß-amyloid and tau oligomers), Fronto-temporal lobe dementia (tau oligomers), and Parkinson's Disease (a-synuclein oligomers). These toxic oligomers share a common aggregation mechanism that involves formation of hydrogen bonds between individual monomers. A therapeutic that can disaggregate these oligomers, or prevent their formation from monomers, could therefore have extraordinary potential to treat a host of neurodegenerative diseases/disorders. Regarding Alzheimer's Disease (AD), currently available therapeutics (e.g., AChE inhibitors and memantine) only temporarily slow the rate of cognitive decline without affecting the disease process. This may be in large part because these drugs have not been shown to penetrate the brain's neurons to disaggregate toxic ß-amyloid (Aß) oligomers and tau oligomers therein. The critical importance of addressing the oligomeric forms of Aß and tau in AD pathogenesis, along with the failure of many clinical studies using anti-Aß aggregating drugs, highlight the need for new, innovative therapies. Since 2007, Dr. Gary Arendash (NeuroEM's PI) and his collaborators have been developing and testing a new non-pharmacologic intervention against AD - Transcranial Electromagnetic Treatment (TEMT). In multiple peer-reviewed papers, he has demonstrated in both in vitro and in vivo studies using AD transgenic mice that TEMT prevents and reverses Aß oligomerization/aggregation, both inside and outside neurons. These anti-aggregating effects demonstrate that TEMT penetrates the brain parenchyma and neurons to destabilize Aß aggregates. The result is a prevention/reversal of cognitive deficits in AD transgenic mice. This proposal's Aims will focus on administering TEMT through a new prototype head device developed for human TEMT administration against AD. To effectively validate and greatly extend our approach, Aim 1 will utilize assays for oligomeric forms of Aß, tau, and a-synuclein to specifically measure TEMT's effects on each of these three toxic oligomers in CSF samples placed within a human head mannequin. Aim 2 will then seek to optimize the TEMT parameters for maximum anti-oligomerization and investigate direct mechanisms of TEMT action. The successful execution of these Aims will provide validation of the "direct" anti-oligomerization effects of TEMT across toxic proteins involved in multiple neurodegenerative diseases. In a follow-up SBIR Fast Track application, NeuroEM will continue this work by: 1) investigating the "indirect" effects of TEMT in neuronal cell cultures over-expressing these oligomers and 2) performing a Phase II clinical trial involving TEMT administration to AD patients utilizing the optimal set of TEMT parameters. Thus, the extent of both direct and indirect TEMT actions across multiple pathologic oligomers will be determined, as will insight into the anti-oligomerization mechanisms of TEMT action - all this, utilizing a TEMT head device that we will utilize in a Phase I AD clinical trial starting in Summer 2016 that involves our current set of TEMT parameters.

Public Health Relevance Statement:
NARRATIVE Alzheimer's Disease (AD) is a neurodegenerative disease that primarily affects individuals over 65 years of age and is characterized by a progressive loss of memory due to the loss and dysfunction of neurons in brain areas important for cognition. In 2015, an estimated 5.4 million Americans had Alzheimer's disease (AD), which accounts for 70 percent of all cases of dementia. The formation of misfolded protein oligomers in neurons is an early and causative event in a variety of neurodegenerative diseases, including AD. Current therapeutics against AD (e.g., AChE inhibitors and memantine) only temporarily slows the rate of cognitive decline without affecting the disease process or addressing the oligomeric forms of ß-amyloid (Aß) and oligomeric tau in AD pathogenesis. NeuroEM has been developing and testing a new non-pharmacologic intervention against AD, Transcranial Electromagnetic Treatment (TEMT), which disaggregates Aß oligomers. This grant application will determine the anti-oligomerization effects of TEMT on three toxic oligomers (Aß, tau, and a-synuclein), optimize TEMT treatment parameters, and investigate TEMT's direct mechanism(s) of action - all of which are important for refining TEMT technology as NeuroEM moves into clinical trials with this promising neuromodulatory technology.

Project Terms:
tau oligomer; tau neurofibrillary tangle; tau filament; tau fibrillization; tau aggregate; tau accumulation; tau PHF; self-aggregate tau; paired helical filament of tau; microtubule associated protein tau deposit; microtubule associated protein tau aggregation; filamentous tau inclusion; abnormally aggregated tau protein; tau aggregation; Coupling; treatment effect; abeta oligomer; aß oligomer; amyloid beta oligomer; Amyloid ß oligomer; prototype; commercialization; brain parenchyma; misfolded protein; proteotoxin; proteotoxic protein; Affect; senile dementia of the Alzheimer type; primary degenerative dementia; dementia of the Alzheimer type; Primary Senile Degenerative Dementia; Alzheimers disease; Alzheimers Dementia; Alzheimer's; Alzheimer syndrome; Alzheimer sclerosis; Alzheimer disease; Alzheimer Type Dementia; Alzheimer; Alzheimer's Disease; inhibitor; inhibitor/antagonist; Biologic Assays; Bioassay; Assay; Biological Assay; Encephalon; Brain Nervous System; Brain; cell culture; Cell Culture Techniques; Clinical Study; Clinical Research; Clinical Trials; Cognition; Disorder; Disease; trisomy 21 syndrome; pseudohypertrophic progressive muscular dystrophy; morbus Down; congenital acromicria syndrome; chromosome 21 trisomy syndrome; Trisomy 21; Mongolism; Langdon Down syndrome; Downs Syndrome; Down's Syndrome; Down Syndrome; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; Electromagnetic; Electromagnetics; Foundations; Gel; Glass; Goals; Head; Modern Man; Human; H-bond; Hydrogen Bonding; In Vitro; indexing; Investments; Manikins; Mannequins; Memantine; Memantin; Transgenic Mice; Neurons; neuronal; Neurocyte; Neural Cell; Nerve Unit; Nerve Cells; Paper; Parkinson Disease; Primary Parkinsonism; Parkinsons disease; Parkinson's disease; Parkinson's; Parkinson; Paralysis Agitans; Patients; Peer Review; Problem Solving; Proteins; Technology; Testing; Work; soluble amyloid precursor protein; beta amyloid fibril; amyloid-b protein; amyloid beta; abeta; a beta peptide; Aß; Amyloid ß-Protein; Amyloid ß-Peptide; Amyloid ß; Amyloid Protein A4; Amyloid Beta-Peptide; Amyloid Alzeheimer's Dementia Amyloid Protein; Alzheimer's amyloid; Alzheimer's Amyloid beta-Protein; Alzheimer beta-Protein; Amyloid beta-Protein; Measures; τ Proteins; tau factor; tau; microtubule-bound tau; microtubule bound tau; MT-bound tau; tau Proteins; Area; Phase; Failure; insight; Ache; Individual; Funding; pathophysiology; Physiopathology; Dysfunction; Functional disorder; Letters; phase II protocol; phase 2 trial; Phase 2 Clinical Trials; Phase II Clinical Trials; a-synuclein; a-syn; non A4 component of amyloid precursor; non A-beta component of AD amyloid; alphaSP22; a-synuclein; a-syn; SNCA protein; SNCA; PARK4 protein; PARK1 protein; NAC precursor; alpha synuclein; Therapeutic; Frontotemporal Dementia; frontotemporal lobe degeneration associated with dementia; frontotemporal lobar dementia; fronto-temporal lobar dementia; fronto-temporal dementia; front temporal dementia; Frontal Temporal Dementia; Impaired cognition; cognitively impaired; cognitive loss; cognitive dysfunction; Disturbance in cognition; Cognitive function abnormal; Cognitive decline; Cognitive Impairment; Cognitive Disturbance; Frequencies; Event; Dementia; Amentia; Neurodegenerative Disorders; neurodegenerative illness; degenerative neurological diseases; degenerative diseases of motor and sensory neurons; Neurologic Degenerative Conditions; Neurodegenerative Diseases; Neuro-degenerative Disorders; Neural degenerative Disorders; Neural Degenerative Diseases; Nervous System Degenerative Diseases; Degenerative Neurologic Disorders; Degenerative Neurologic Diseases; American; dielectric property; monomer; neuroregulation; neuromodulatory; neuromodulation; neural regulation; neural control; beta pleated sheet; ß-pleated sheet; ß-Sheet; Beta Sheet; protein oligomer; Cognitive deficits; cognitive defects; Prevention; Devices; Pathogenesis; Memory Loss; memory decline; Sampling; Traumatic Brain Injury; traumatic brain damage; Brain Trauma; Intervention; interventional strategy; Intervention Strategies; Tauopathies; tauopathy; tauopathic neurodegenerative disorder; tau neuropathology; tau neurodegenerative disease; tau mediated neurodegeneration; tau induced neurodegeneration; tau associated neurodegenerative process; tau associated neurodegeneration; Innovative Therapy; prevent; preventing; Address; Age-Years; Applications Grants; Grant Proposals; in vivo; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Validation; Pathologic; Process; followed up; follow up; Active Follow-up; follow-up; protein mis-folding; pathologic protein folding; abnormal protein folding; aberrant protein folding; protein misfolding; τ aggregation; tau-tau interaction; tau polymerization; tau paired helical filament

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.

Public Health Relevance Statement:
NARRATIVE 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. NeuroEM Therapeutics has developed a bioengineering technology against Alzheimer's disease (Transcranial Electromagnetic Treatment; TEMT) that appears to be "disease- modifying" in showing cognitive enhancement in AD subjects. The goal of this SBIR Phase II research is to extend our completed Phase I research involving AD brain homogenates to "in vitro" studies utilizing various cell cultures in order to comprehensively evaluate the safety and mechanisms of TEMT action, leading to initiation of a pivotal clinical trial and de novo submission to the FDA.

Project Terms:
Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Biomedical Engineering; bio-engineered; bio-engineers; bioengineering; Blood; Blood Reticuloendothelial System; Brain; Brain Nervous System; Encephalon; Cause of Death; Cell Culture Techniques; cell culture; Cell Survival; Cell Viability; Cells; Cell Body; Clinical Trials; Communication; Disease; Disorder; Down Syndrome; Down's Syndrome; Downs Syndrome; Langdon Down syndrome; Mongolism; Trisomy 21; chromosome 21 trisomy syndrome; congenital acromicria syndrome; morbus Down; pseudohypertrophic progressive muscular dystrophy; trisomy 21 syndrome; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electromagnetics; Future; Goals; Government; Grant; Head; Health; Healthcare Systems; Health Care Systems; Heat shock proteins; stress protein; Hippocampus (Brain); Ammon Horn; Cornu Ammonis; Hippocampus; hippocampal; Human; Modern Man; In Vitro; indexing; Inflammation; Microtubules; Micro-tubule; Mitochondria; mitochondrial; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Organelles; Parkinson Disease; Paralysis Agitans; Parkinson; Parkinson's disease; Parkinsons disease; Primary Parkinsonism; Play; Production; Proteins; Publishing; Research; Role; social role; Safety; Technology; Translating; Work; Prosencephalon; Fore-Brain; Forebrain; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; τ Proteins; Clinical; Phase; Physiological; Physiologic; Microglia; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; peripheral blood; Failure; Oxidative Stress; alpha synuclein; NAC precursor; PARK1 protein; PARK4 protein; SNCA; SNCA protein; a-syn; a-synuclein; alphaSP22; non A-beta component of AD amyloid; non A4 component of amyloid precursor; a-syn; a-synuclein; Therapeutic; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; Frontal Temporal Dementia; front temporal dementia; frontal lobe dementia; fronto-temporal dementia; fronto-temporal lobar dementia; frontotemporal lobar dementia; frontotemporal lobe degeneration associated with dementia; Frontotemporal Dementia; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Impaired cognition; Functional MRI; fMRI; Functional Magnetic Resonance Imaging; Pulse; Physiologic pulse; Frequencies; Immunes; Immune; Treatment Period; treatment days; treatment duration; System; extracellular; Degenerative Neurologic Diseases; Degenerative Neurologic Disorders; Nervous System Degenerative Diseases; Neural Degenerative Diseases; Neural degenerative Disorders; Neurodegenerative Diseases; Neurologic Degenerative Conditions; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; neurodegenerative illness; Neurodegenerative Disorders; American; Ribosomal Peptide Biosynthesis; Ribosomal Protein Biosynthesis; Ribosomal Protein Synthesis; protein synthesis; Protein Biosynthesis; Isoforms; Protein Isoforms; protein oligomer; PBMC; Peripheral Blood Mononuclear Cell; Structure; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; Devices; Brain Trauma; traumatic brain damage; Traumatic Brain Injury; Pathogenicity; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; preventing; prevent; Culturing, in vitro Vertebrate, Primary; Primary Cell Cultures; Mononuclear; in vivo; Cell Culture System; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; pre-clinical; preclinical; preclinical study; pre-clinical study; cost; tau aggregation; abnormally aggregated tau protein; filamentous tau inclusion; microtubule associated protein tau aggregation; microtubule associated protein tau deposit; paired helical filament of tau; self-aggregate tau; tau PHF; tau accumulation; tau aggregate; tau fibrillization; tau filament; tau neurofibrillary tangle; tau oligomer; tau paired helical filament; tau polymerization; tau-tau interaction; τ aggregation; design; designing; protein aggregation; insoluble aggregate; protein aggregate; AD transgenic mice; Alzheimer's disease transgenic mice; Alzheimer's transgenic mice; treatment effect; abeta oligomer; Amyloid ß oligomer; amyloid beta oligomer; aß oligomer; neuronal survival; effective therapy; effective treatment; cognitive enhancement; phase 2 study; phase II study; mild cognitive impairment; mild cognitive disorder; experimental study; experiment; experimental research; cognitive benefits; stress reduction; Alzheimer's disease therapeutic; Alzheimer's therapeutic; Alzheimer's disease brain; Alzheimer's brain; Home