After decades of intensive research and drug development efforts, there are still no cures or substantially effective treatments for Alzheimer's disease (AD). Currently available medications, including cholinesterase inhibitors, NMDA receptor antagonists, and amyloid beta (Aß) monoclonal antibodies (mAbs), can only reduce certain symptoms or slightly slow down disease progression in mild to moderate AD patients; and their side effects, particularly those of Aß mAbs, further limit their benefit. The most recently reported efficacy and safety profile of another Aß mAb donanemab does not add much enthusiasm to the field. Studies of AD have been mainly focused on Aß plaques and tau protein-formed neurofibrillary tangles in the brain. However, in recent years, it is increasingly clear that the development of AD is the collective consequence of the toxicities induced by Aß plaques, tau protein-formed neurofibrillary tangles, and malfunctions of microglia. Nacetylcysteine (NAC) is a derivative of amino acid cysteine; it has been studied for its potential effects on AD, largely due to its antioxidant and anti-inflammatory activities, particularly its beneficial effects on microglia. However, NAC cannot penetrate the BBB and reach the brain sufficiently. To realize NAC's potential as an AD treatment, we developed a brain targeted NAC delivery system (TN-NAC). Our preliminary data demonstrate that TN-NAC can effectively cross the BBB, quench the elevated ROS, attenuate the activation of microglia, reduce Aß burden, and eliminate senescent cells in the brain in a 5xFAD mouse model, and improve the performance of the animals in behavior tests. Based on these exciting data, in this Phase I STTR study, we will test the feasibility to develop TN-NAC as a therapy for AD through two specific aims. In SA1 we will evaluate the toxicity and pharmacokinetic properties of TN-NAC in mice. The maximum tolerated dose (MTD) of TN-NAC will be first determined in mice; and then the PK properties of TN-NAC at various doses will be examined. In SA2 we will test the therapeutic efficacy of TN-NAC in a 3xTg-AD mouse model. We will assess the effects of TNNAC on biochemical, pathological, and behavioral alterations in the AD mice. We will also further evaluate the systemic toxicity of TN-NAC in AD mice. The successful completion of the proposed studies will serve as a milestone for the further development effort. A Go/No Go decision will be made based on 1) if TN-NAC can achieve sufficient blood and brain NAC concentrations at a certain dose without causing evident toxicity in mice; and 2) if TN-NAC at that dose can significantly attenuate AD pathology and behavioral impairment in the AD mice. A Go decision will lead us in a STTR Phase 2 study to: 1) using large animal models to find a dose range that can be extrapolated to humans and test the safety and efficacy of TN-NAC for the treatment of AD in a GLP setting using large animal models, and 2) carrying out cGMP manufacturing of TN-NAC for human studies. These studies will enable us to file an IND application to FDA.
Public Health Relevance Statement: NARRATIVE
Public Health Relevance: Alzheimer's disease is the sixth-leading cause of death in the United States and costs about $345 billion in 2023. This research will develop an AD brain targeted delivery system that can carry N- acetylcysteine into the brain to effectively quench the elevated ROS, attenuate the activation of microglia, reduce Aß burden, eliminate senescent cells, improve the survival of neurons in the brain, and stop the progression of Alzheimer's disease. The success of validating this concept will open a new era for treating Alzheimer's disease, which is consistent with the mission of the NIH. Terms: <3xTg; 3xTg-AD mice; 3xTg-AD mouse; AD dementia; AD pathology; Acetylcysteine; Acetylin; Aducanumab; Airbron; Alzheimer Type Dementia; Alzheimer beta-Protein; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Amyloid beta-Protein; Alzheimer's Disease; Alzheimer's amyloid; Alzheimer's brain; Alzheimer's disease brain; Alzheimer's disease pathology; Alzheimer's disease patient; Alzheimer's disease therapy; Alzheimer's pathology; Alzheimer's patient; Alzheimer's therapy; Alzheimers Dementia; Amino Acids; Amyloid (Aß) plaques; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Plaques; Amyloid Protein A4; Amyloid beta-Protein; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Animal Model; Animal Models and Related Studies; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Anticholinesterase Agents; Anticholinesterase Drugs; Anticholinesterases; Antiinflammatory Effect; Antioxidants; Area Under Curve; Attenuated; Aß; Aß burden; BBB crossing; BBB penetration; BIIB037; Behavioral; Binding; Bioavailability; Biochemical; Biological Availability; Blood; Blood - brain barrier anatomy; Blood Plasma; Blood Reticuloendothelial System; Blood-Brain Barrier; Brain; Brain Nervous System; Broncholysin; Brunac; Cause of Death; Cell Body; Cells; Cholinesterase Inhibitors; Clinical Treatment Moab; Clinical Trials; Cyclic GMP; Cysteine; Data; Deposit; Deposition; Development; Development and Research; Disease Progression; Dose; Drug Kinetics; Drugs; Effectiveness; Encephalon; Ensure; Fabrol; Fluatox; Fluimucetin; Fluimucil; Fluprowit; Formulation; GSH receptor; Galantamin; Galantamine; Galanthamine; Glutathione; Guanosine Cyclic Monophosphate; Half-Cystine; Half-Life; Health; Healthcare; Hemato-Encephalic Barrier; Hortega cell; Human; Hydrophobicity; In Vitro; Inflammatory Response; Injections; Investigational New Drug Application; L-Cysteine; Lead; Learning; Ligand Binding; Lycoremine; MT-bound tau; Macrophage; Maintenance; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Measures; Medication; Memantin; Memantine; Memory; Mercaptans; Mercapto Compounds; Mercapturic Acid; Mice; Mice Mammals; Microglia; Mission; Modern Man; Molecular Interaction; Monoclonal Antibodies; Muco Sanigen; Mucocedyl; Mucolator; Mucolyticum; Mucomyst; Mucosolvin; Mucret; Murine; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Receptors; MÏ; N-Acetylcysteine; NAC Zambon; NIH; NMDA receptor antagonist; Names; National Institutes of Health; Neo-Fluimucil; Neuritic Plaques; Neurofibrillary Tangles; Nicotinic Acetylcholine Receptors; Nicotinic Receptors; Oral; Oxidative Stress; Parvolex; Pathologic; Pb element; Penetration; Performance; Pharmaceutical Preparations; Pharmacokinetics; Phase; Physiologic Availability; Plasma; Plasma Serum; Play; Polymers; Primary Senile Degenerative Dementia; Process; Production; Property; Publishing; R & D; R&D; Reporting; Research; Respaire; Reticuloendothelial System, Serum, Plasma; Role; STTR; Safety; Senile Plaques; Serum Albumin; Small Business Technology Transfer Research; Sulfhydryl Compounds; Survey Instrument; Surveys; Symptoms; System; Technology; Therapeutic; Thiols; Tixair; Toxic effect; Toxicities; Treatment Efficacy; Treatment-related toxicity; United States; United States National Institutes of Health; a beta peptide; a-beta burden; abeta; abeta burden; abeta deposition; aduhelm; aminoacid; amyloid beta; amyloid beta deposition; amyloid beta plaque; amyloid burden; amyloid ß deposition; amyloid-b plaque; amyloid-b protein; anti-inflammatory effect; attenuate; attenuates; aß deposition; aß plaques; behavior test; behavioral impairment; behavioral test; beta amyloid burden; beta amyloid fibril; blood-brain barrier crossing; blood-brain barrier penetration; bloodbrain barrier; bloodbrain barrier crossing; bloodbrain barrier penetration; cGMP; cored plaque; cost; developmental; diffuse plaque; disulfide bond; donepezil; drug development; drug/agent; effective therapy; effective treatment; feasibility testing; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; gitter cell; glutathione receptor; health care; health care community; healthcare community; heavy metal Pb; heavy metal lead; impaired behavior; improved; intervention efficacy; intravenous administration; mAbs; manufacture; mesoglia; microglial cell; microgliocyte; microtubule bound tau; microtubule-bound tau; model of animal; monoclonal Abs; mouse model; murine model; name; named; naming; nano particle; nano-sized particle; nanoparticle; nanosized particle; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; neuronal survival; new approaches; novel approaches; novel strategies; novel strategy; oxidation; patient living with Alzheimer's disease; patient suffering from Alzheimer's disease; patient with Alzheimer's; patient with Alzheimer's disease; perivascular glial cell; phase 2 study; phase II study; polymer; polymeric; primary degenerative dementia; public health relevance; research and development; rivastigmine; safety testing; senescent cell; senile dementia of the Alzheimer type; side effect; site targeted delivery; social role; soluble amyloid precursor protein; success; sulfhydryl group; systemic toxicity; tangle; targeted delivery; tau; tau Proteins; tau factor; therapeutic efficacy; therapeutic evaluation; therapeutic target; therapeutic testing; therapeutic toxicity; therapy associated toxicity; therapy efficacy; therapy related toxicity; therapy toxicity; tool; treatment effect; treatment strategy; treatment toxicity; treatment-associated toxicity; ß-amyloid burden; ßamyloid burden; Ï Proteins
