TAU-targeting therapy for alzheimer's disease and other tauopathies

Abstract

The present disclosure provides methods for preventing or treating a neurodegenerative disorder in a subject, where the neurodegenerative disorder is one characterized by a deposition of abnormal tau protein in the brain of the subject. The method generally includes administering to the subject a therapeutically effective amount of a drug that is a tau propagation antagonist.

Description

PATENT Attorney Docket No.079445-014310PC-1488493 Client Ref. No. S22-503 TAU-TARGETING THERAPY FOR ALZHEIMER'S DISEASE AND OTHER TAUOPATHIES CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority from U.S. Provisional Application No. 63 / 560,302 filed March 1, 2024, the full disclosure of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND

[0002] Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and a leading cause of dementia worldwide, representing one of the most significant global health challenges of the 21st century. The disease is characterized by a gradual decline in cognitive function, memory, and executive abilities, eventually leading to severe impairment and death. With an aging global population, the prevalence of AD is rising rapidly, creating an escalating burden on healthcare systems and families. Despite decades of research, effective treatments to halt or reverse disease progression remain elusive, underscoring the urgent need for innovative therapeutic strategies.

[0003] One of the primary pathological hallmarks of Alzheimer’s disease is the development of intraneuronal neurofibrillary tangles (NFTs). These tangles are composed predominantly of hyperphosphorylated tau protein, a microtubule-associated protein that, under normal conditions, plays a critical role in stabilizing neuronal microtubules. In AD, tau becomes abnormally modified, misfolds, and aggregates into insoluble fibrils, which accumulate within neurons as NFTs. The presence of NFTs correlates strongly with neuronal dysfunction and cognitive decline, highlighting their central role in the disease process.

[0004] The propagation of tau pathology is thought to contribute significantly to the progression of AD. Misfolded tau appears to spread in a prion-like manner, transferring from one neuron to another and seeding the aggregation of normal tau in recipient cells. This pathological tau propagation follows a stereotypical pattern, progressing through anatomically KILPATRICK TOWNSEND 794102311connected brain regions. As tau pathology spreads, it disrupts neuronal circuits and accelerates neurodegeneration, exacerbating the clinical symptoms of the disease.

[0005] In healthy neurons, tau serves essential physiological functions that are critical for maintaining cellular stability and function. Tau binds to and stabilizes microtubules, which are vital for axonal transport and intracellular trafficking of organelles and molecules. Additionally, tau plays a role in maintaining the structural integrity of the cytoskeleton and supporting synaptic plasticity, which is crucial for learning and memory. The loss of these normal tau functions due to aggregation and mislocalization contributes to the widespread neuronal dysfunction observed in Alzheimer’s disease.

[0006] There are no currently available therapies for treating AD and other tauopathies. As a result, a clear need exists for techniques that can mitigate abnormal tau aggregation and propagation that can lead to or exacerbate related neurological disorders. The present application addresses this need, providing associated solutions and other technical advantages. BRIEF SUMMARY

[0007] This summary provides a high-level overview of various aspects of the disclosure and introduces some of the concepts that are described and illustrated in the present document and the accompanying figures. The summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. Covered embodiments of the disclosure are defined by the claims, not this summary. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures, and each claim. Some of the exemplary embodiments of the present disclosure are discussed below.

[0008] In one aspect, the disclosure provides a method for preventing or treating a neurodegenerative disorder in a subject. The prevented or treated neurodegenerative disorder is one characterized by a deposition of abnormal tau protein in the brain of the subject. The method includes administering to the subject a therapeutically effective amount of a drug that is a tau propagation antagonist.

[0009] In another aspect, the disclosure provides a pharmaceutical composition. The pharmaceutical composition includes a tau propagation antagonist. The pharmaceutical composition further includes a permeation enhancer. KILPATRICK TOWNSEND 794102311

[0010] In another aspect, the disclosure provides a nasal drug delivery system. The nasal drug delivery system includes a pharmaceutical composition. The pharmaceutical composition includes a tau propagation antagonist. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 presents an immunostaining image visualizing binding of normal tau protein to microtubules within cells.

[0012] FIG. 2 presents an immunostaining image visualizing formation of aggregates of abnormal tau protein propagated to cells, and showing no binding of tau to microtubules within the cells.

[0013] FIG.3 presents a photograph of an electrophoresis gel with a left lane corresponding to normal tau and a middle lane corresponding to propagating tau

[0014] FIGS. 4A-C present a series of images from bimolecular fluorescence complementation (BiFC) assay tests of individual monomer tau proteins (FIGS. 4A and 4C) and dimer tau proteins (FIG.4B).

[0015] FIG. 5 presents schematic chemical structures (left) of tau proteins that form dimers and mutagenized tau proteins that do not. The figure further presents partial chemical structures (middle) of regions of the non-mutagenized and mutagenized tau proteins exhibiting attractive, repulsive, and unattractive behavior towards one another. The figure further presents immunostaining images (right) showing aggregate formation with the non-mutagenized tau but not with the mutagenized tau.

[0016] FIG. 6 presents an immunostaining still image from a video visualizing COS-7 cells cultured in the presence of propagating tau.

[0017] FIG. 7 presents an immunostaining still image from a video visualizing COS-7 cells cultured in the presence of propagating tau and a tau propagation antagonist drug identified in candidate screening.

[0018] FIG.8 presents an immunostaining still image from a video visualizing neuronal cells cultured in the presence of propagating tau. KILPATRICK TOWNSEND 794102311

[0019] FIG.9 presents an immunostaining still image from a video visualizing neuronal cells cultured in the presence of propagating tau and a tau propagation antagonist drug identified in candidate screening.

[0020] FIG.10 presents an illustration of an exemplary procedure for preparing seed tau for in vitro screening of drugs to determine their effectiveness as tau propagation antagonists.

[0021] FIG. 11 presents a series of immunostaining still images from videos showing the effects of cetrorelix and CCK-8 on tau propagation.

[0022] FIG. 12 presents results from an immunoblot assay demonstrating increasing intracellular degradation of abnormal tau by increasing concentrations of tau propagation antagonist drug identified in candidate screening.

[0023] FIG. 13 presents a photograph of a gel showing degradation of multimeric tau from AD mouse brain in response to the administration of tau propagation antagonist drug identified in candidate screening.

[0024] FIG.14 presents a series of transmission electron microscopy (TEM) images showing that the tau propagation antagonist drugs identified in candidate screening can abolish fibril tau tangle structures.

[0025] FIG. 15 presents an illustration of an exemplary procedure for the in vivo testing of tau propagation antagonist drugs in model mice.

[0026] FIG. 16 presents an illustration of an exemplary procedure for the intranasal administration of tau propagation antagonist drugs to allow them to bypass the blood brain barrier.

[0027] FIG.17 presents graphs plotting probability of survival data for control (Vehicle, thin line) and test (Drug, thick line) administrations to first (upper graph) and second (lower graph) cohorts of PS-19 hemizygous model mice.

[0028] FIG.18 presents graphs plotting probability of survival data for control (Vehicle, thin line) and test (Drug, thick line) administrations to first (upper graph) and second (lower graph) cohorts of PS-19 homozygous model mice.

[0029] FIG. 19 presents graphs plotting weight data for vehicle control (V) and cetrorelix (D) administrations to first (upper graph) and second (lower graph) cohorts of PS-19 model mice. KILPATRICK TOWNSEND 794102311

[0030] FIG. 20 presents a series of photographs showing that drugged PS-19 model mice retain their cognitive performance and motor capabilities as demonstrated by nest building.

[0031] FIG. 21 presents a photograph showing that drugged PS-19 model mice retain their general social behavior as demonstrated by interactions rather than avoidance.

[0032] FIG.22 presents an image of a T maze used in an exemplary procedure for measuring the spatial working memory of mice.

[0033] FIG. 23 presents exemplary data analyses for results of a T Maze Spontaneous Alternation experiment.

[0034] FIG.24 presents graphs plotting percent alternations data for vehicle control (V) and cetrorelix (D) administrations to first (upper graph) and second (lower graph) cohorts of PS-19 model mice challenged in a T Maze Spontaneous Alternation experiment.

[0035] FIG.25 presents a graph plotting Novel Location Discrimination Index values based on data from the experiment of FIG.24.

[0036] FIG.26 presents a graph plotting Novel Object Discrimination Index values based on data from the experiment of FIG.24.

[0037] FIG. 27 presents an image of an electrophoresis gel showing that administration of cetrorelix to PS-19 model mice reduces the level of multimeric tau in the brains of the mice.

[0038] FIG. 28 presents an image of an electrophoresis gel showing that administration of sincalide to PS-19 model mice reduces the level of multimeric tau in the brains of the mice.

[0039] FIG. 29 presents immunohistochemical images of hippocampus samples following administration of vehicle control (PBS) or cetrorelix (Drug-D) administrations to PS-19 model mice.

[0040] FIG. 30 presents a graph plotting data related to counts of neurons from the experimental samples of FIG.29.

[0041] FIG.31 presents a series of images prepared with IBA 1 antibody staining to visualize activated microglia in brain samples from normal control mice, mice treated with vehicle, and mice treated with cetrorelix (D) or sincalide (K).

[0042] FIG. 32 presents photographs of a mouse receiving nasal administration of a tau propagation antagonist drug. The photographs are overlayed with information visualizing the KILPATRICK TOWNSEND 794102311location of the administered drug within the mouse brain at different time points following the drug administration. DETAILED DESCRIPTION I. INTRODUCTION

[0043] The tau protein, a member of the microtubule-associated protein (MAP) family, plays a pivotal role in maintaining the structural integrity and dynamic stability of neuronal microtubules. Microtubules are critical cytoskeletal components that facilitate intracellular transport, axonal elongation, and neuronal signal transduction. Tau achieves these functions by binding to microtubules and promoting their assembly, stabilization, and spatial organization within axons. Under physiological conditions, the activity of tau is tightly regulated through post-translational modifications, such as phosphorylation, which modulate its microtubule- binding affinity and solubility. However, pathological alterations can lead to tau dissociation from microtubules and subsequent aggregation into insoluble fibrillar structures. These aggregates, including paired helical filaments (PHFs) and neurofibrillary tangles (NFTs), are hallmark features of tauopathies. Abnormal tau aggregation disrupts neuronal cytoskeletal integrity, impairs axonal transport, and contributes to synaptic dysfunction, neuroinflammation, and neuronal death, thereby driving the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, progressive supranuclear palsy, and corticobasal degeneration.

[0044] The development of effective therapeutics for tau-associated disorders is complicated by the dual role of tau protein in neuronal physiology and pathology. While aggregated / fibril tau is a key driver of neurodegeneration, normal tau function is indispensable for microtubule stability and axonal transport. Therapeutic interventions must selectively target pathological tau conformations while preserving the structural and functional integrity of normal tau. Achieving this specificity has proven to be challenging with existing approaches. Furthermore, therapeutic design must account for the need to minimize off-target effects and avoid disrupting the delicate homeostasis of the neuronal cytoskeleton. The inherent complexity of tau’s physiological and pathological roles necessitates a nuanced approach that balances efficacy and safety. KILPATRICK TOWNSEND 794102311

[0045] The present disclosure provides methods and compounds that are surprisingly effective in addressing two interrelated therapeutic objectives in addressing tauopathies: (1) reducing or preventing the intercellular propagation of pathological tau and (2) mitigating the intracellular toxicity of aggregated tau species. Accumulating evidence suggests that misfolded tau can propagate between cells in a prion-like manner, acting as a template to induce conformational changes in native tau in recipient cells. Halting this propagation is essential for limiting the spread of tau pathology across neuronal networks. Simultaneously, for therapeutic strategies to be highly effective they must also focus on neutralizing or degrading intracellular tau aggregates to mitigate their cytotoxic effects, which include proteostatic imbalance, mitochondrial dysfunction, and activation of apoptotic signaling pathways. Addressing both intercellular propagation and intracellular toxicity is critical to developing disease-modifying treatments that can slow, arrest, or potentially reverse the progression of tauopathies, thereby improving clinical outcomes for affected individuals.

[0046] Provided herein are methods involving bio-reagents that can block or inhibit the tau propagation and toxicity features associated with neurodegenerative disorders such as Alzheimer’s disease (AD). The examples of the disclosure demonstrate the identification and testing of multiple FDA-approved drugs suitable for use with the provided methods. The disclosure thus provides the ability to advantageously repurpose these drugs for beneficially effective treatments, e.g., AD therapy. II. DEFINITIONS

[0047] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present disclosure. For purposes of the present disclosure, the following terms are defined.

[0048] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a drug” optionally includes a combination of two or more drugs, and the like.

[0049] As used herein, the terms “about” and “approximately,” when used to modify an amount specified in a numeric value or range, indicate that the numeric value as well as KILPATRICK TOWNSEND 794102311reasonable deviations from the value known to the skilled person in the art, for example ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value.

[0050] As used herein, the term “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0051] As used herein, the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited. As used herein, the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified. As used herein, the phrase “consisting essentially of” limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature.

[0052] The term “optional” or “optionally” means that the subsequent described event, circumstance or substituent may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0053] The terms “first,” “second,” “third,” and the like when used herein with reference to elements or properties, are simply to more clearly distinguish or identify multiple elements or properties, and are not intended to indicate an order or other serial or numerical limitation, or to require that each of the multiple elements or properties are present.

[0054] Unless otherwise stated, the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may be labeled with isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (125I), carbon-13 (13C), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0055] As used herein, the term “neurodegenerative disorder” refers to a disorder resulting from a loss and / or reduction of function and / or viability of neurons in the peripheral nervous system and / or central nervous system of a subject, e.g., neurons within the brain of the subject.

[0056] As used herein, the terms “abnormal tau,” “propagating tau,” and “pathogenic tau” are used interchangeably to refer to tau protein that exhibits sequence mutations, post- translational modifications, structural conformations, or biochemical properties deviating from KILPATRICK TOWNSEND 794102311the characteristics of healthy and physiologically functional tau protein. Such modifications include, but are not limited to, hyperphosphorylation, truncation, acetylation, ubiquitination, glycosylation, nitration, or aggregation into insoluble fibrils, oligomers, or paired helical filaments (PHFs). Abnormal tau is associated with loss of its microtubule-stabilizing function and the acquisition of neurotoxic properties, as observed in pathological states such as neurodegenerative tauopathies. This term encompasses tau species implicated in the disruption of cellular homeostasis, synaptic dysfunction, or neuronal death. Abnormal and propagating tau further exhibits the ability to disseminate between cells, tissues, or regions of the nervous system, thereby contributing to the progressive spread of tau pathology.

[0057] As used herein, the term “tau propagation antagonist” refers to a molecule, compound, biologic, or agent that inhibits, reduces, or prevents the formation and / or seeding of tau aggregates, fibrils, or multimers and / or the dissemination of tau protein or tau aggregates between cells, tissues, or regions within the central nervous system. This inhibition may be achieved by, for example, interfering with one or more mechanisms including, but not limited to, the extracellular release or secretion of tau protein, the uptake or internalization of tau protein by recipient cells, the interaction between tau protein and cellular receptors, the templated misfolding or aggregation of endogenous tau protein induced by pathogenic tau species, or the seeding, assembly, stabilization, or degradation of tau aggregates. Tau propagation antagonists are thus characterized by their ability to mitigate the spatial and temporal progression of tau pathologies.

[0058] As used herein, the terms “treat,” “treating,” and “treatment” refer to a procedure resulting in any indicia of success in the elimination or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of one or more symptoms. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination or laboratory test.

[0059] As used herein, the term “administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous, intrathecal, intraventricular, intracerebral, KILPATRICK TOWNSEND 794102311intracerebroventricular, intraparenchymal, retinal, subretinal, or intravitreal administration, or the implantation of a slow release device e.g., a mini osmotic pump, to the subject.

[0060] As used herein, the term “therapeutically effective amount” refers to the quantity of a composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Within the context of the present disclosure, the term “therapeutically effective” refers to that quantity of a composition that is sufficient to delay the manifestation, arrest the progression, or relieve or alleviate at least one symptom of a disorder treated by the methods of the present disclosure.

[0061] As used herein, the term “subject” refers to a vertebrate, and preferably to a mammal. Mammalian subjects for which the provided composition is suitable include, but are not limited to, mice, rats, simians, humans, farm animals, sport animals, and pets. In some embodiments, the subject is human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is above 10 years of age, e.g., above 20 years of age, above 30 years of age, above 40 years of age, above 50 years of age, above 60 years of age, above 70 years of age, or above 80 years of age. In some embodiments, the subject is less than 80 years of age, e.g., less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age.

[0062] As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like. One of skill in the art will recognize that other pharmaceutically acceptable excipients and carriers are useful in the present disclosure. III. METHODS OF TREATMENT OR PREVENTION

[0063] Provided herein are methods of preventing or treating a neurodegenerative disorder in a subject. More specifically, the methods are effective in preventing or treating neurodegenerative disorders characterized by a deposition of abnormal tau protein in the KILPATRICK TOWNSEND 794102311nervous system of a subject, e.g., in the brain of the subject. Accordingly, examples of neurodegenerative disorders suitable for being prevented or treated with the provided methods include Alzheimer’s disease (AD), frontotemporal dementia (FTD) with tau pathology, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), argyrophilic grain disease (AGD), primary age-related tauopathy (PART), globular glial tauopathy (GGT), and tau-related subtypes of neurodegeneration with brain iron accumulation (NBIA).

[0064] The provided methods involve administering a therapeutically effective amount of a drug to the subject in need of prevention or treatment of the neurodegenerative disorder, i.e., in need of prevention or treatment of deposition, aggregation, and / or propagation of abnormal tau. The administered drug is a tau propagation antagonist that interferes with this deposition, aggregation, and / or propagation, and thus prevents or treats the neurodegenerative disorder. In some examples, the mechanisms by which the administered drug interferes with the toxic effects of abnormal tau rely on a new understanding and appreciation of structural properties of abnormal tau described herein. Furthermore, in some examples, the administered drug is advantageously an agent that has previously received regulatory approval for use in other therapies, where the agent has not previously been recognized as having the efficacy against tauopathies that is described in this disclosure.

[0065] In some examples, the provided methods include arresting or regressing the formation of fibrils within neurons in the brain of the subject to whom the tau propagation antagonist is administered. In certain examples, the methods include selecting the identity of the drug and / or the therapeutically effective amount of the drug to have particular efficacy in arresting of regressing the neuronal fibril formation. This ability of the therapeutically effective amount of the drug is advantageous since fibrillar tau aggregates are a hallmark of the neurodegenerative processes underlying tauopathies. Tau fibrils, including paired helical filaments (PHFs) and straight filaments, can contribute directly to neuronal dysfunction by disrupting cytoskeletal integrity, impairing axonal transport, and inducing synaptic deficits. Additionally, tau fibrils can act as seeds for templated misfolding, propagating pathological tau species to neighboring cells and exacerbating the spread of tau pathology across brain regions. By targeting the formation or accumulation of fibrils, the drug can mitigate the downstream effects of tau aggregation, including neuroinflammation, oxidative stress, and neuronal apoptosis, thereby preserving cellular homeostasis and synaptic connectivity. Furthermore, arresting fibril formation reduces the reservoir of pathogenic tau species available for propagation, potentially KILPATRICK TOWNSEND 794102311halting the spatial and temporal progression of tau pathology. This mechanism of action is therefore beneficial for addressing the underlying pathophysiology of tauopathies, as it targets a central driver of disease progression rather than merely alleviating symptoms.

[0066] In some examples, the provided methods additionally or alternatively include inhibiting assembly of dimers or oligomers of the abnormal tau protein in the brain of the subject to whom the tau propagation antagonist is administered. In certain examples, the methods include selecting the identity of the drug and / or the therapeutically effective amount of the drug to have particular efficacy in inhibiting the abnormal tau protein dimerization or oligomerization. This ability of the therapeutically effective amount of the drug is advantageous since these small, soluble aggregates are demonstrated herein as being critical drivers of neurotoxicity and disease progression. As shown in this disclosure, dimers and oligomers of abnormal tau exhibit enhanced pathological activity compared to monomeric forms. These species also serve as precursors to larger aggregates, such as fibrils, which contribute to widespread neurodegeneration. By effectively inhibiting the formation of tau dimers and oligomers, the drug can prevent the accumulation of these toxic intermediates, thereby reducing neuronal stress and preserving cellular function. This mechanism of action further limits the availability of seeding-competent tau species, curbing the propagation of tau pathology across brain regions. Inhibiting the early stages of tau aggregation can therefore beneficially halt the pathological cascade at its origin, providing a significant means of disease modification in tauopathies.

[0067] In some examples, the provided methods additionally or alternatively include degrading dimers or oligomers of the abnormal tau protein in the brain of the subject to whom the tau propagation antagonist is administered. In certain examples, the methods include selecting the identity of the drug and / or the therapeutically effective amount of the drug to have particular efficacy in degrading the abnormal tau protein dimers or oligomers. This ability of the therapeutically effective amount of the drug is advantageous since the multimers can serve as precursors to larger fibrillar aggregates and as propagators of templated misfolding in neighboring cells. By actively degrading these toxic forms of tau, the drug can reduce their intracellular and extracellular burden, thereby alleviating neuronal stress, restoring cellular homeostasis, and preventing further aggregation and propagation. Targeting dimers and oligomers for degradation also mitigates their contribution to neuroinflammation and oxidative damage, addressing multiple downstream effects of tau pathology. KILPATRICK TOWNSEND 794102311

[0068] In some examples, the provided methods additionally or alternatively include blocking transport of the abnormal tau protein into neurons in the brain of the subject to whom the tau propagation antagonist is administered. In certain examples, the methods include selecting the identity of the drug and / or the therapeutically effective amount of the drug to have particular efficacy in blocking abnormal tau protein uptake by neurons. Because these pathogenic tau species act can as seeds that induce the misfolding and aggregation of endogenous tau, preventing the uptake of abnormal tau into neurons can advantageously slow or stop the abnormal tau from amplifying and spreading tau pathology across interconnected brain regions.

[0069] Surprisingly, in some examples the drugs shown herein to be effective in blocking or inhibiting tau include ones having physical properties and characteristics typically generally not considered favorable for compounds targeting the treatment of neurodegenerative disorders. For example, according the well-known “Lipinski Rule of Five,” desirable physiochemical properties for a central nervous system (CNS) drug include a molecular weight no greater than 400 g / mol, and an ability to penetrate the blood brain barrier (BBB). However, some of the drug compounds of the provided methods have molecular weights significantly greater than 400 g / mol, and do not cross the blood brain barrier. For instance, the tau propagation antagonist can be a drug having a molecular weight that is, for example, at least about 500 g / mol, e.g., at least about 700 g / mol, at least about 1000 g / mol, at least about 1400 g / mol, at least about 2000 g / mol, at least about 2800 g / mol, or at least about 4000 g / mol.

[0070] In some examples, the drug of the provided methods includes or consists of cetrorelix, a synthetic 10-membered oligopeptide. Cetrorelix is gonadotropin-releasing hormone (GnRH) antagonist, and has been previously used in the area of assisted reproduction for inhibiting premature luteinizing hormone surges. This compound has a molecular weight of 1431 g / mol, and does not penetrate the blood brain barrier. As disclosed herein, cetrorelix binds tau with a binding energy of -9.19635 kcal / mol.

[0071] The scope of the invention encompasses administration of cetrorelix in all forms, including pharmaceutically acceptable salts thereof, isoforms thereof, sequence variants comprising one, two, three, four, or more amino acid substitutions, and variants comprising modified amino acids. In one embodiment, cetrorelix comprises a composition comprising a compound having the structure: KILPATRICK TOWNSEND 794102311.

[0072] In one embodiment, cetrorelix comprises acetyl-D-3-(2 -naphtyl-alanine-D-4-chlorophenylalanine-D-3-(3 -pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide. In various embodiments, the cetrorelix or variant thereof may comprise a composition selected from those described in United States Patent Number 4,800,191, entitled “LHRH antagonists;” United States Patent Application Publication Number US 2022 / 0233631, entitled “Stable formulation of cetrorelix;” European Patent Number EP0947200, entitled “Compositions comprising Cetrorelix acetate for the treatment of female infertility and gonadal protection;” United States Patent Number 7,214,662, entitled “Injectable solution of an LHRH antagonist;” United States Patent Application Publication Number US 2013 / 0303464, entitled “Stable ready-to-use cetrorelix injection;” or United States Patent Number 4,690,916, entitled “Nona and decapeptide analogs of LHRH useful as LHRH antagonists.”

[0073] In other examples, the drug of the provided methods includes or consists of sincalide, a synthetic 8-membered oligopeptide. Sincalide, which is also known as CCK-8, contains the C-terminal fragment of cholecystokinin, and in prior uses was primarily administered by injection to aid in diagnosing disorders of the gallbladder and pancreas. This compound has a molecular weight of 1143 g / mol, and does not penetrate the blood brain barrier. As disclosed herein, sincalide binds tau with a binding energy of -10.66449 kcal / mol.

[0074] The scope of the invention encompasses administration of sincalide in all forms, including pharmaceutically acceptable salts thereof, isoforms thereof, sequence variants comprising one, two, three, four, or more amino acid substitutions thereof, and variants comprising modified amino acids. In one embodiment, sincalide comprises a composition comprising a compound having the structure: KILPATRICK TOWNSEND 794102311, or 1-De(5-oxo-L-proline)-2-de-L-glutamine-5-L-methioninecaerulein, 3-[[2-[[2-[[2-[[2-[[2- [(2-amino-3-carboxy-propanoyl)amino]-3-(4-sulfooxyphenyl)propanoyl]amino]-4- methylsulfanyl-butanoyl]amino]acetyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4- methylsulfanyl-butanoyl]amino]-3-[(1-carbamoyl-2-phenyl-ethyl) carbamoyl]propanoic acid. In various embodiments, sincalide or sincalide derivative administered in the practice of the invention comprise a composition described in any of: United States Patent Number 3,723,406, entitled “Novel peptides having cholecystokinin activity and intermediates therefor;” United States Patent Application Publication Number US 2020 / 0030406, entitled “Sincalide Formulations;” or United States Patent Number 3,937,819, entitled “Method of stabilizing an injectable composition of a cholecystokinin active octapeptide.”

[0075] The provided method includes administering one or more tau propagation antagonists using any suitable approach for delivery to the target neurons of the brain. Remarkably, the inventor of the present disclosure has unexpectedly determined that the tau propagation antagonists cetrorelix and sincalide may be administered intranasally, which advantageously provides a convenient and non-invasive means to administer these agents to the central nervous system. Accordingly, the present disclosure also provides nasal drug delivery systems that include the tau propagation antagonist. KILPATRICK TOWNSEND 794102311

[0076] In some examples, the tau propagation antagonist drug is administered according to the provided method in a therapeutically effective amount that has an average dose that is between about 0.1 μg / kg / day and 10 mg / kg / day, e.g., between about 0.1 μg / kg / day and about 1 mg / kg / day, between about 0.1 μg / kg / day and about 100 μg / kg / day, between about 0.1 μg / kg / day and about 10 μg / kg / day, between about 0.1 μg / kg / day and about 1 μg / kg / day, between about 1 μg / kg / day and about 10 mg / kg / day, between about 1 μg / kg / day and about 1 mg / kg / day, between about 1 μg / kg / day and about 100 μg / kg / day, between about 1 μg / kg / day and about 10 μg / kg / day, between about 10 μg / kg / day and about 10 mg / kg / day, between about 10 μg / kg / day and about 1 mg / kg / day, between about 10 μg / kg / day and about 100 μg / kg / day, between about 100 μg / kg / day, and about 10 μg / kg / day, between about 100 μg / kg / day and about 1 mg / kg / day, or between about 1 mg / kg / day and about 10 μmg / kg / day.

[0077] In some examples, the tau propagation antagonist drug is administered according to the provided method over a period time that includes a first dose of the drug and a last dose of the drug that are at least about 1 week apart, e.g., at least about 2 weeks apart, at least about 3 weeks apart, at least about 4 weeks apart, at least about 5 weeks apart, at least about 6 weeks apart, at least about 7 weeks apart, at least about 8 weeks apart, at least about 3 months apart, at least about 4 months apart, at least about 5 months apart, at least about 6 months apart, at least about 7 months apart, at least about 8 months apart, at least about 9 months apart, at least about 10 months apart, at least about 1 year apart, at least about 2 years apart, at least about 3 years apart, at least about 4 years apart, at least 5 years apart, or more. The frequency of the individual doses administered between the first and last doses can also be selected to provide the prevention or treatment method with its desired efficacy. For example, the doses can be administered multiple times per day; daily; weekly; monthly; 2, 3, 4, 5, or 6 days per week; 2 or 3 weeks per month; or at other intervals.

[0078] The provided methods can be suitable for preventing or treating a neurological disease or disorder categorized as a Class I tauopathy. For example, the tauopathy can be one associated with tau isoforms 3R and 4R. Class I tauopathies that can be prevented or treated with the methods disclosed herein include, for example, Alzheimer’s disease, Down’s syndrome, Parkinson’s dementia complex of Guam, Niemann-Pick disease type C, chronic traumatic encephalopathy (CTE), and certain subsets of Frontotemporal dementia with parkinsonism-17 (FTDP-17). KILPATRICK TOWNSEND 794102311

[0079] The provided methods can also be suitable for preventing or treating a neurological disease or disorder categorized as a Class II tauopathy. For example, the tauopathy can be one predominantly associated with tau isoform 4R. Class II tauopathies that can be prevented or treated with the methods disclosed herein include, for example, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), globular glial tauopathy (GGT), ageing-related tau astrogliopathy (ARTAG), and certain subsets of FTDP- 17.

[0080] The provided methods can also be suitable for preventing or treating a neurological disease or disorder categorized as a Class III tauopathy. For example, the tauopathy can be one predominantly associated with tau isoform 3R. Class III tauopathies that can be prevented or treated with the methods disclosed herein include, for example, Pick’s disease and certain subsets of FTDP-17.

[0081] The provided methods can also be suitable for preventing or treating a neurological disease or disorder categorized as a Class IV tauopathy. For example, the tauopathy can be one predominantly associated with tau isoform ON3R. Class IV tauopathies that can be prevented or treated with the methods disclosed herein include, for example, myotonic dystrophy.

[0082] In some embodiments, the provided method further includes obtaining a test sample from the subject. The test sample can include, for example, a blood sample, a tissue sample, a urine sample, a saliva sample, a cerebrospinal fluid sample, or a combination thereof. In some embodiments, the provided method further includes determining the level of one or more biomarkers in the obtained test sample. Determining the presence or level of biomarkers(s) can be used to, as non-limiting examples, determine response to treatment or to select an appropriate composition for the prevention or treatment of the disease.

[0083] In some embodiments, the provided method further includes comparing the determined level of the one of more biomarkers in the obtained test sample to the level of the one or more biomarkers in a reference sample. The reference sample can be obtained, for example, from the subject, with the reference sample being obtained prior to the obtaining of the test sample, e.g., prior to the administering to the subject of the therapeutically effective amount of the provided materials. In this way, the reference sample can provide information about baseline levels of the biomarkers in the sample before the treatment, and the test sample can provide information about levels of the biomarkers after the treatment. KILPATRICK TOWNSEND 794102311

[0084] Alternatively, the reference sample can be obtained, for example, from a different subject, e.g., a subject in which the treatment is not provided according to the provided methods. In this way, the reference sample can provide information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment. The reference sample can also be obtained, for example, from a population of subjects, e.g., subjects in which the treatment is not provided according to the provided method. In this way, the reference sample can provide population-averaged information about baseline levels of the biomarkers without treatment, and the test sample can provide information about levels of the biomarkers with treatment.

[0085] The reference sample can also be obtained from an individual or a population of individuals after treatment is provided according to the provided methods, and can serve as, for example, a positive control sample. In some embodiments, the reference sample is obtained from normal tissue. In some embodiments, the reference sample is obtained from abnormal tissue.

[0086] Depending on the biomarker, an increase or a decrease relative to a normal control or reference sample can be indicative of the presence of a disease, or response to treatment for a disease. In some embodiments, an increased level of a biomarker in a test sample, and hence the presence of a disease, e.g., an infectious disease or cancer, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least, 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7- fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5- fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11- fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold higher in comparison to a negative control. In other embodiments, a decreased level of a biomarker in the test sample, and hence the presence of the disease, increased risk of the disease, or response to treatment is determined when the biomarker levels are at least 1.1-fold, e.g., at least 1.2-fold, at least 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, or at least 20-fold lower in comparison to a negative control. KILPATRICK TOWNSEND 794102311

[0087] The biomarker levels can be detected using any method known in the art, including the use of antibodies specific for the biomarkers. Exemplary methods include, without limitation, polymerase chain reaction (PCR), Western Blot, dot blot, ELISA, radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, FACS analysis, electrochemiluminescence, and multiplex bead assays, e.g., using Luminex or fluorescent microbeads. In some instances, nucleic acid sequencing is employed.

[0088] In certain embodiments, the presence of decreased or increased levels of one or more biomarkers is indicated by a detectable signal, e.g., a blot, fluorescence, chemiluminescence, color, or radioactivity, in an immunoassay or PCR reaction, e.g., quantitative PCR. This detectable signal can be compared to the signal from a reference sample or to a threshold value.

[0089] In some embodiments, the results of the biomarker level determinations are recorded in a tangible medium. For example, the results of diagnostic assays, e.g., the observation of the presence or decreased or increased presence of one or more biomarkers, and the diagnosis of whether or not there is an increased risk or the presence of a disease, e.g., an infectious disease or cancer, or whether or not a subject is responding to treatment can be recorded, for example, on paper or on electronic media, e.g., audio tape, a computer disk, a CD-ROM, or a flash drive.

[0090] In some embodiments, the provided method further includes the step of providing to the subject a diagnosis and / or the results of treatment. IV. PHARMACEUTICAL COMPOSITIONS

[0091] Also provided herein are pharmaceutical compositions useful preventing or treating a neurodegenerative disorder in a subject. Accordingly, the provided pharmaceutical compositions are suitable for use with the methods described in Section III. Each pharmaceutical composition may include one or more tau propagation antagonists of the present disclosure, and a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient. In some examples, the pharmaceutical composition is useful for arresting or regressing formation of fibrils with neurons in the brain of a subject. In some examples, the pharmaceutical composition is additionally or alternatively useful for inhibiting assembly of dimers or oligomers of the abnormal tau protein in the brain of the subject. In some examples, the pharmaceutical composition is additionally or alternatively useful for degrading dimers or oligomers of the abnormal tau protein in the brain of the subject. In some examples, the KILPATRICK TOWNSEND 794102311pharmaceutical composition is additionally or alternatively useful for blocking transport of the abnormal tau protein into neurons in the brain of the subject.

[0092] In therapeutic applications, the pharmaceutical composition can be administered to a subject already suffering from a neurodegenerative disorder, in an amount sufficient to cure or at least partially arrest the symptoms of the neurodegenerative disorder, or to cure, heal, improve, or ameliorate the condition. In prophylactic applications, the pharmaceutical composition can be administered to a subject with a propensity or risk of developing a neurodegenerative disorder in order to prevent the occurrence of the condition or disease. The pharmaceutical composition can be administered to a subject before the onset of symptoms, or during or as soon as possible after the onset of the symptoms.

[0093] The pharmaceutical compositions described herein are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically or prophylactically effective. The dosage amount can be, for example, any of those described in Section III. The quantity to be administered depends on a variety of factors including, e.g., the age, body weight, physical activity, and diet of the individual, and the stage or severity of the neurodegenerative disorder. In certain embodiments, the size of the dose may also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration in a particular individual. It should be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and may depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0094] In certain embodiments, the dose of the drug may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, pellets, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, gels, aerosols, foams, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. In preferred examples, the dose of the drug has a form suitable for intranasal administration.

[0095] As used herein, the term “unit dosage form” refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of the drug calculated to produce the desired onset, tolerability, and / or therapeutic20 KILPATRICK TOWNSEND 794102311effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule). In addition, more concentrated dosage forms may be prepared, from which the more dilute unit dosage forms may then be produced. The more concentrated dosage forms thus will contain substantially more than, e.g., at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, or more times the amount of the drug.

[0096] Methods for preparing such dosage forms are known to those skilled in the art. The dosage forms typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like. Appropriate excipients can be tailored to the particular dosage form and route of administration by methods well known in the art.

[0097] In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient. Examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols, e.g., Carbopol 941, Carbopol 980, Carbopol 981, etc. In some embodiments, the pharmaceutical composition includes one or more of a diluent, adjuvant, or carrier in a formulation suitable for administration, e.g., administration to a human or other mammals. Suitable diluents, adjuvants, or carriers can include, for example, lipids, e.g., liposomes, e.g., liposome dendrimers; liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like; gum acacia; gelatin; starch paste; talc; keratin; colloidal silica; urea; and the like. Additional examples of suitable diluents include distilled water, buffered water, physiological saline, PBS, Ringer’s solution, dextrose solution, and Hank’s solution. The pharmaceutical composition can also include additional substances to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, wetting agents, and detergents. In addition, auxiliary, thickening, lubricating, and coloring agents can alternatively or additionally be used. Pharmaceutical compositions can be formulated into preparations in solid, semisolid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. KILPATRICK TOWNSEND 794102311

[0098] The pharmaceutical composition can also include any of a variety of stabilizing agents, such as an antioxidant for example. When the pharmaceutical composition includes a polypeptide, the polypeptide can be complexed with various well-known compounds that enhance the in vivo stability of the polypeptide, or otherwise enhance its pharmacological properties (e.g., increase the half-life of the polypeptide, reduce its toxicity, and / or enhance solubility or uptake). Examples of such modifications or complexing agents include sulfate, gluconate, citrate, and phosphate. The nucleic acids or polypeptides of a composition can also be complexed with molecules that enhance their in vivo attributes. Such molecules include, for example, carbohydrates, polyamines, amino acids, other peptides, ions (e.g., sodium, potassium, calcium, magnesium, manganese), and lipids.

[0099] In some examples, the provided pharmaceutical composition includes one or more permeation enhancers. The permeation enhancers can beneficially improve the absorption of the drug across the nasal epithelium by transiently altering the permeability of the mucosal membrane. This can allow for direct transport to the brain via the olfactory and trigeminal nerve pathways. Other advantages resulting from the use of permeation enhancers can include reducing systemic exposure, minimizing off-target effects, and quickening the onset of therapeutic effects. Examples of permeation enhancers suitable for use with the provided methods, compositions, and systems include non-ionic surfactants such as alkyl maltosides (e.g., dodecyl maltoside (DDM) and tetradecyl maltoside (TDM)); bile salts such as sodium taurocholate, sodium deoxycholate, and sodium cholate; fatty acids such as oleic acid, capric acid, and lauric acid; cyclodextrins; alkylglycosides; saponins; and organic solvents. In particular examples, the permeation enhancer includes DDM and / or TDM.

[0100] In addition to the identity of the one or more permeation enhancers of a provided pharmaceutical composition, the concentration of the permeation enhancers in the composition can be selected to provide the drug administration with its advantageous efficacy in preventing or treating a neurodegenerative disorder. The concentration of permeation enhancer in an administered pharmaceutical composition can be, for example, between about 0.02 wt% and about 2 wt%, e.g., between about 0.02 wt% and about 0.8 wt%, between about 0.02 wt% and about 0.3 wt%, between about 0.02 wt% and about 0.1 wt%, between about 0.02 wt% and about 0.05 wt%, between about 0.05 wt% and about 2 wt%, between about 0.05 wt% and about 0.8 wt%, between about 0.05 wt% and about 0.3 wt%, between about 0.05 wt% and about 0.1 wt%, between about 0.1 wt% and about 2 wt%, between about 0.1 wt% and about 0.8 wt%, KILPATRICK TOWNSEND 794102311between about 0.1 wt% and about 0.3 wt%, between about 0.3 wt% and about 2 wt%, between about 0.3 wt% and about 0.8 wt%, or between about 0.8 wt% and about 2 wt%.

[0101] In alternative implementations, the tau propagation antagonist may be administered in or as a pharmaceutical composition that facilitates crossing of the blood brain barrier (BBB), for example, comprising the tau propagation antagonist in combination with a drug delivery composition, wherein the drug delivery compositions encompasses any moieties, materials, or other compositions of matter that facilitate the delivery of the tau propagation antagonist across the blood brain barrier. The pharmaceutical compositions may encompass any form of combination of the tau propagation antagonist and the delivery composition, including functionalization of the tau propagation antagonist with the delivery composition, conjugation of the tau propagation antagonist to the delivery composition, admixture of the tau propagation antagonist with the delivery composition, encapsulation or infusion of the bisphosphonate tau propagation antagonist within the delivery composition, or any other combination. For example, the delivery composition may comprise ligands that facilitate transcytosis across the BBB through brain endothelial cells to the basolateral side, such as anti-transferrin receptor antibodies or antigen-binding fragments thereof, for example OX26 antibodies, Angiopep2 or like polypeptides, ApoE proteins and mimetics thereof, diphtheria toxin, and surfactants. Additional targeting moieties include BBB-crossing peptides, such as those described in Van Dorpe et al., Brainpeps: The blood-brain barrier peptide database, Brain Structure and Function, 2012, 217(3), 687-718. In one implementation, the delivery compositions comprise carriers to which the tau propagation antagonist is conjugated, encapsulated within, or otherwise combined with to facilitate crossing of the BBB and / or delivery to target RPE cells. Exemplary carriers include: liposomes; extracellular vesicles or synthetic mimetics thereof, such as exosomes; red blood cells modified with a tau propagation antagonist; microspheres, such as poly(lactic-co-glycolic acid) (PLGA) microspheres; and other drug delivery nanoparticles such as PLGA-PEG nanoparticles, alginate or chitosan nanoparticles, silica nanoparticles, and iron oxide nanoparticles. The carrier molecules or compositions may further be functionalized with ligands that promote crossing of the BBB or BRB, such as anti-tfR antibodies, Angiopep2 or like polypeptides, ApoE proteins and mimetics thereof; diphtheria toxin, and surfactants, as described above. In one embodiment the delivery composition comprises or is incorporated within an implant, for example, a drug-eluting implant placed within the target tissue, e.g. the brain.23 KILPATRICK TOWNSEND 794102311

[0102] The provided pharmaceutical composition can be administered to a subject in various dosage frequencies. e.g., the frequencies described in Section III. In some embodiments, the provided pharmaceutical composition is administered in accordance with an acute regimen. In certain instances, the composition is administered to the subject once. In other instances, the composition is administered at one time point, and administered again at a second time point. In yet other instances, the composition is administered to the subject repeatedly (e.g., once or twice daily) as intermittent doses over a short period of time (e.g., 2 days, 3 days, 4 days, 5 days, 6 days, a week, 2 weeks, 3 weeks, 4 weeks, a month, or more). In some cases, the time between administrations is about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, a week, 2 weeks, 3 weeks, 4 weeks, a month, or more. In other embodiments, the composition is administered continuously or chronically in accordance with a chronic regimen over a desired period of time. For instance, the composition can be administered such that the amount or level of the compound is substantially constant over a selected time period. V. KITS

[0103] In another aspect, the disclosure provides kits for preventing or treating a neurodegenerative disorder in a subject. The provided kits generally include a drug that is a tau propagation antagonist. The kit typically contains containers, which may be formed from a variety of materials such as glass or plastic, and can include for example, bottles, vials, syringes, and test tubes. A label typically accompanies the kit, and includes any writing or recorded material, which may be electronic or computer readable form providing instructions or other information for use of the kit contents. In certain examples, the kit includes a nasal drug delivery system, where the system contains s pharmaceutical composition as described in Section IV..

[0104] In some embodiments, the kits can further include instructional materials containing directions (e.g., protocols) for the practice of the methods described herein (e.g., instructions for using the kit for enhancing the cardiac function of a subject. While the instructional materials typically include written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this disclosure. Such media include, but are not limited to, electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.24 KILPATRICK TOWNSEND 794102311VI. EXEMPLARY EMBODIMENTS

[0105] The following embodiments are contemplated. All combinations of features and embodiments are contemplated.

[0106] Embodiment 1: A method for preventing or treating a neurodegenerative disorder in a subject, the neurodegenerative disorder characterized by a deposition of abnormal tau protein in the brain of the subject, the method comprising administering to the subject a therapeutically effective amount of a drug that is a tau propagation antagonist.

[0107] Embodiment 2: An embodiment of embodiment 1, wherein the method further comprises arresting or regressing formation of fibrils within neurons in the brain of the subject.

[0108] Embodiment 3: An embodiment of embodiment 1 or 2, wherein the method further comprises inhibiting assembly of dimers or oligomers of the abnormal tau protein in the brain of the subject.

[0109] Embodiment 4: An embodiment of any one of embodiments 1-3, wherein the method further comprises degrading dimers or oligomers of the abnormal tau protein in the brain of the subject.

[0110] Embodiment 5: An embodiment of any one of embodiments 1-4, wherein the method further comprises blocking transport of the abnormal tau protein into neurons in the brain of the subject.

[0111] Embodiment 6: An embodiment of any one of embodiments 1-5, wherein the drug has a binding energy to the abnormal tau protein that is at most -5 kcal / mol.

[0112] Embodiment 7: An embodiment of any one of embodiments 1-6, wherein the drug has a molecular weight that is at least 500 g / mol.

[0113] Embodiment 8: An embodiment of any one of embodiments 1-7, wherein the drug does not cross the blood brain barrier of the subject.

[0114] Embodiment 9: An embodiment of any one of embodiments 1-8, wherein the drug comprises cetrorelix, sincalide (CCK-8), or a combination thereof.

[0115] Embodiment 10: An embodiment of any one of embodiments 1-9, wherein the administering comprises intranasal administration. KILPATRICK TOWNSEND 794102311

[0116] Embodiment 11: An embodiment of any one of embodiments 1-10, wherein the administering comprises administration of a pharmaceutical composition comprising the drug and a permeation enhancer.

[0117] Embodiment 12: An embodiment of embodiment 11, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

[0118] Embodiment 13: An embodiment of embodiment 10 or 11, wherein the permeation enhancer has a concentration in the pharmaceutical composition that is between 0.02 wt% and 2 wt%.

[0119] Embodiment 14: An embodiment of any one of embodiments 1-13, wherein the therapeutically effective amount of the drug comprises an average dose of the drug that is between 0.1 μg / kg / day and 10 mg / kg / day.

[0120] Embodiment 15: An embodiment of any one of embodiments 1-14, wherein the therapeutically effective amount of the drug is administered with a first dose and a last dose that are at least 1 week apart.

[0121] Embodiment 16: An embodiment of any one of embodiments 1-15, wherein the neurodegenerative disorder comprises Alzheimer’s disease.

[0122] Embodiment 17: A pharmaceutical composition comprising a tau propagation antagonist, and a permeation enhancer.

[0123] Embodiment 18: An embodiment of embodiment 17, wherein the tau propagation antagonist comprises cetrorelix, sincalide, or a combination thereof.

[0124] Embodiment 19: An embodiment of embodiment 17 or 18, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

[0125] Embodiment 20: An embodiment of any one of embodiments 17-19, wherein the permeation enhancer has a concentration in the pharmaceutical composition that is between 0.02 wt% and 2 wt%.

[0126] Embodiment 21: A nasal drug delivery system comprising a pharmaceutical composition, the pharmaceutical composition comprising a tau propagation antagonist.

[0127] Embodiment 22: An embodiment of embodiment 21, wherein the tau propagation antagonist comprises cetrorelix, sincalide (CCK-8), or a combination thereof. KILPATRICK TOWNSEND 794102311

[0128] Embodiment 23: An embodiment of embodiment 21 or 22, wherein the pharmaceutical composition further comprises a permeation enhancer.

[0129] Embodiment 24: An embodiment of embodiment 23, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

[0130] Embodiment 25: An embodiment of embodiment 23 or 24, wherein the permeation enhancer has a concentration in the pharmaceutical solution that is between 0.02 wt% and 2 wt%. EXAMPLES

[0131] The present disclosure will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes only, and are not intended to limit the disclosure in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. Example 1. Observations of tau propagation features in cells

[0132] Initial studies were performed using GFP staining of tau protein to discern characteristic differences between functional and abnormal forms of tau. FIGS.1 and 2 present exemplary immunostaining images from these studies. As seen in the image of FIG. 1, internally expressed wild-type tau protein binds to microtubules of the cell. In contrast, and as shown in the image of FIG. 2, when tau is propagated into cultured cells, the propagated tau can no longer bind to microtubules, but instead forms aggregates inside the cells. FIG.2 further shows that the abnormal tau spreads from initially affected neurons to neighboring healthy neurons. The observed inability of propagated tau to bind to microtubules lead to a hypothesis that tau propagation is very closely related to structural changes in tau.

[0133] Additional biochemical and cellular assays further elucidated mechanisms connecting structural changes of the tau protein to the different behaviors of functional and abnormal tau forms. FIG.3 shows results from a native polyacrylamide gel electrophoresis (PAGE) analysis with wild-type tau (e.g., the tau of FIG. 1) loaded into the left lane of the gel, and propagated tau (e.g., the tau of FIG. 2), loaded into the middle lane of the gel. The smaller size of the prominent lower band in the left lane of the FIG.3 gel indicates that the wild-type tau is present27 KILPATRICK TOWNSEND 794102311in a monomeric form. The larger size of the prominent upper band in the middle lane of the FIG.3 gel indicates that the propagated tau is instead present in a dimeric or oligomeric form.

[0134] Further evidence of the multimeric form of propagating tau was provided by a bimolecular fluorescence complementation assay, with results shown in the images of FIGS. 4A-C. The FIG.4A and FIG.4C images correspond to cell lines with individual monomers of tau, with each showing no observable propagation of tau. The FIG.4B image corresponds to a cell line with dimer tau formation, and shows abnormal tau spreading from one cell to another.

[0135] Together, the results from these various studies and assays demonstrated that propagated tau proteins are present in dimer or oligomer configurations. This provided a therapeutic target of not necessarily binding to tau monomers, but instead preventing tau monomers from forming dimers or oligomers. In this way, the normal functioning of tau can be unaffected, while the possibility of tau toxicity and propagation can be addressed. Example 2. Structural characteristics of propagating tau

[0136] Computational molecular dynamic simulations of tau dimerizations and oligomerizations were performed using quantum biological field theory to predict energy changes associated with the formation of multimers and their interactions with cell membranes. These simulations identified areas of the core tau protein structure that are integral to promoting the assemblies of tau dimers and oligomers and associated fibrils. Next, mutagenesis studies targeting these identified areas were carried out to determine key amino acid regions of the tau protein that can influence assembly of these structures. FIG. 5 schematically illustrates the chemical structures of tau proteins forming a dimer through attractive interactions between identified structural areas and amino acid regions of the proteins. The figure also schematically illustrates the structures of two mutagenized proteins (Mutagenesis 1 and Mutagenesis 2) that do not form dimers. In these cases, the mutagenized amino acid regions exhibit repulsive (as in Mutagenesis 1) or unattractive (as in Mutagenesis 2) interactions in the place of the attractive interactions exhibited by the corresponding non-mutagenized tau proteins.

[0137] FIG. 5 additionally includes fluorescence staining images for the dimerizing tau protein (top) and for the non-dimerizing mutagenized tau (bottom). The images reveal that the repulsive and unattractive interactions present in the mutagenized proteins prevent tau aggregation and propagation, whereas aggregation and propagation of the dimerizing tau can be clearly observed.28 KILPATRICK TOWNSEND 794102311Example 3. In vitro screening validation of drugs targeting tau propagation and fibrils in cultured cells

[0138] Based on results from the mutagenesis study of Example 2, an initial in silico compound screen was performed using docking simulations. These simulations were used to select for candidate peptide and drug compounds satisfying selection criteria related to the amino acid regions of tau shown to influence the assemblies of tau dimers and oligomers and associated fibrils. The objective of these screening simulations was the identification of compounds docking with particular targeted regions of tau, rather than with the entire tau protein. This is because a compound binding with tau as a whole is more likely to remove or interfere with the essential functions of normal healthy tau. As a result, such a compound will be more prone to being toxic to cells.

[0139] Once candidate molecules had been determined with the initial screen, in vitro studies with cultured cells were used to test the effects of the drugs on propagating tau. Exemplary results from these preliminary in vitro tests are shown in the immunostaining images of FIGS. 6-9. FIGS.6 and 7 depict cultured COS-7 cells, and FIGS.8 and 9 depict cultured neurons. In each of the tests shown in FIGS.6-9, the cells were cultured in the presence of tau, while in the tests of FIGS.7 and 9, a candidate drug was also added to the cell culture. The images of FIGS. 6 and 8 show that, when COS-7 cells or neurons are cultured with tau, the tau easily propagates into the cells. In contrast, and as shown in the images of FIGS.7 and 9, addition of drug to the tau-containing cell-culture results in a buildup of tau along the membranes of the cells, indicating that the tau is effectively blocked from entering within the cells, thereby blocking tau propagation.

[0140] FIG. 10 illustrates one aspect of the general screening procedure for visualizing tau and determining if a drug is effective in blocking or inhibiting the protein. As shown in the illustration, the procedure includes transfecting populations of cells, e.g., COS-7 cells, with control or target plasmids. The control plasmids include a reporter, e.g., eGFP. The target plasmids include the reporter linked to tau.

[0141] In further stages of screening the candidate peptides or drugs, those molecules exhibiting toxicity towards the tested cells, or a poorer ability to block tau from entering the tested cells, were eliminated. Following these selection steps, the molecules cetrorelix and sincalide (CCK-8) were among those chosen for further studies. FIG. 11 provides staining images showing the effects of 8 M cetrorelix and 8 M CCK-8 on the propagation of tau in the KILPATRICK TOWNSEND 794102311in vitro cultured cells. The results depicted in the images demonstrate that for control neural cell populations not administered either of these drugs, tau propagated and formed readily visible tangle-like aggregates. In contrast, in cell populations treated with either cetrorelix or CCK-8, these tangle-like aggregates were not visible, indicating that these drugs substantially reduced tau propagation.

[0142] In part because some amount of propagating tau is still able to enter cells even in the presence of the positive peptide or drug hits from the candidate screening, further tests were performed to determine whether this intracellular propagated tau can be degraded by the added peptide or drug. FIG.12 shows an image from an immunoblot assay in which the lanes 2 and 3 of the blot represent control experiments in which cells are cultured in the presence of propagating tau but in the absence of an added peptide or drug. Lanes 4-7 of the FIG. 12 immunoblot represent experiments in which increasing doses of added peptide or drug are added to cell cultures with propagating tau. The immunoblot image shows amounts of multimeric tau present in each case following 24 hours of incubation. Lanes 2 and 3 display bright bands corresponding to multimeric tau having a relatively large size and amount. Lane 4, representing the smallest tested positive dose of added peptide or drug, shows a brightness reduction in the multimeric tau band relative to that observed with the control cultures. Lanes 5-7, with increasing doses of added peptide or drug, display further reductions in brightness indicating reduced concentrations of multimeric tau, and therefore increased multimeric tau degradation.

[0143] FIG. 13 presents additional data supporting the conclusions drawn from the immunoblot assay of FIG.12. FIG.13 shows an image of a polyacrylamide electrophoresis gel with lanes corresponding to samples taken from a control cell culture with tau but no added peptide or drug (No), a cell culture with tau and added sincalide (K), and a cell culture with tau and added cetrorelix (D). The dark high-molecular-weight band in the left lane corresponding to the control sample indicates that the tau in this sample has formed dimers or oligomers. Notably, the intensity of this high-molecular-weight band is significantly reduced in both the center (K) and right (D) lanes, and additional lower-molecular-weight bands are present in these lanes with a greater intensity than in the left (No) lane. These results demonstrate that both cetrorelix and sincalide increase degradation of intracellular multimeric tau into smaller compounds. KILPATRICK TOWNSEND 794102311

[0144] FIG.14 shows transmission electron microscopy (TEM) images of samples with tau and no peptide or drug identified in the candidate screening ((a)-(d)), and images of samples with tau and either sincalide ((e)-(f)) or cetrorelix ((g)-(h)). The left TEM images of panels (a)- (d) show that the tau in these control samples form long fibrous structures. In contrast, the structures see in the right TEM images of panels (e)-(h) are significantly smaller, indicating no or minimal formation of long tau fibers. These results further demonstrate the ability of the tested peptides and drugs to mitigate harmful tau dimer, oligomer, and fiber assembly. Example 4. In vivo drug tests in PS-19 mouse model.

[0145] FIGS. 15 and 16 illustrate exemplary procedures for testing a drug, e.g. a drug identified using the screening protocol of Example 3, to determining the in vivo effects of the drug, e.g., effects of the drug on subject survival and / or weight. As shown in the illustration of FIG. 15, the procedure uses the PS-19 mouse model. These mice harbor the T34 isoform of microtubule-associated protein tau with one N-terminal insert and four microtubule binding repeats (1N4R) encoding the human P301S mutation, all driven by the mouse prion protein promoter. The PS-19 mice are therefore useful in studying neurofibrillary tangles, neurodegenerative tauopathy, and Alzheimer’s disease.

[0146] As show in FIG.16, the in vivo drug tests in the PS-19 mouse model further used an intranasal drug administration to allow the drugs to cross the blood brain barrier. This non- invasive technique is therefore particularly useful in allowing large molecules, such as cetrorelix and CCK-8, to access the central nervous system. In some instances, the drugs were dissolved in sterile water at a concentration of 1 mg / mL, and then diluted with phosphate- buffered saline (PBS). In other instances, the PBS was supplemented with 0.1% dodecyl maltoside (DDM) and 0.1% tetradecyl maltoside (TDM). DDM and TDM are permeabilization enhancers that are approved by the FDA for nasal usage. In particular cases, the diluted drug solution was administered intranasally at a dose of 1 μg / 25 g daily, for four days per week.

[0147] FIGS. 17 and 18 present graphs plotting survival probability data from in vivo tests of cetrorelix (identified in the graphs as drug D) in two separate cohorts each of PS-19 tau hemizygotes (FIG.17) and PS-19 tau homozygotes (FIG.18). The data demonstrate that mice administered cetrorelix exhibited significantly improved survival relative to those administered a vehicle control. The homozygous mice are generally known for rarely surviving longer than 10 weeks, while the hemizygous mice can survive longer. For both of these mice populations, the tested drug treatments were demonstrated to double, triple, or further elongate the lifespans KILPATRICK TOWNSEND 794102311beyond those observed with vehicle control groups. Additionally, data presented in the graphs of FIG.19 show that the mice that were administered cetrorelix also exhibited higher weights and reduced weight loss (i.e., improved weight retention) over the course of treatment relative to that seen with the control mice. Example 5. Cognitive function tests of treated mice.

[0148] As one behavioral study used to test the cognitive function of mice treated with the drugs and methods provided herein, the nest building activities of the treated mice were observed. FIG. 20 shows photographs of mice within enclosures containing nest building materials. The upper photographs of the figure relate to a PS-19 AD model mouse that had been treated with drug for 15 weeks, and the lower photographs relate to a PS-19 AD model mouse control provided no drug treatment. The right photographs in the figure show that the drug-treated mouse builds its own nest within 26 hours using the provided materials. In contrast, the control mouse was unable to similarly construct a nest given the same period of time and the same material availability.

[0149] In another behavioral study, one or more PS-19 model mice that had been treated with a provided drug were placed in the same enclosure as one or more PS-19 model mice that had not received a drug treatment. FIG. 21 shows a photograph of an exemplary enclosure from this study, where the enclosure contains two drug-treated mice and one non-treated mouse. The photograph shows that the two mice that had been administered the drug generally actively engaged with each other. The untreated mouse, however, generally isolated itself at an edge or corner of the enclosure and showed little interest in interacting with the other mice or in participating in any activities, either alone or as part of a group.

[0150] Additionally, a T Maze Spontaneous Alternation experiment was used to measure the spatial working memory in the mice cohorts of Example 4. In this experiment, each arm of a T maze was assigned a designation of 0, 1, or 2 as shown in FIG. 22. The mice subjects were initially placed in the start arm (0) of the T maze and allowed to freely explore the apparatus for 5 minutes. The sequence of arm entries was recorded. An arm entry was scored when all four paws plus the tail tip were in the arm. Alternation behavior in the experiment is defined as consecutive entries into all three arms (e.g., 0-1-2, 2-1-0, or 1-2-0, but not 1-2-1). The percentage of spontaneous alternations was calculated as the ratio of actual alternations to maximum number of alternations possible (total number of arm entries minus 2), as in the example of FIG. 23. The percentage of spontaneous alternations serves as an indicator of KILPATRICK TOWNSEND 794102311working memory. All animals were habituated to the testing area for at least 1 h before testing. The apparatuses were cleaned with 70% ethanol solution between subjects.

[0151] FIGS. 24-26 present graphs plotting data from two cohorts of subjects tested using the T Maze Spontaneous Alternation experiment. The results shown in the graphs of FIG. 24 demonstrate that, by no later than week 18 of the test, mice administered cetrorelix exhibited improved working memory relative to that of the mice administered the vehicle control. FIG. 25 presents another graph comparing the behaviors of the treated and untreated mice in the T Maze experiment. The novel location discrimination index percentages plotted in this graph are calculated based on the amount of time that a subject spends exploring a new location compared to a familiar location. In this way, this index informs about the spatial memory of the tested subjects. The values of FIG.25 show that the mice treated with cetrorelix (Drug D) were more interested in novel locations than were the control mice treated with vehicle (PBS). The graph of FIG.26 relates to the novel object discrimination index percentages for the treated and untreated mice in the T Maze experiment, where these percentages are calculated based on the amount of time that a subject spends exploring a new object compared to a familiar object. In this way, this index informs about the non-spatial memory of the tested subjects. The values of FIG. 26 show that the mice treated with cetrorelix (Drug D) were more interested in novel objects than were the control mice treated with vehicle (PBS). Example 6. Pathology examinations of treated mice.

[0152] Additional experiments were conducted to examine the tau content and other physiological characteristics of the brains of mice treated using a provided drug and method. FIGS.27 and 28 show images of electrophoresis gels loaded with samples from wild-type mice (WT) not having a neurological disorder, from untreated PS-19 AD model mice (PS19), from PS-19 mice treated with a vehicle control (V-controls), or from PS-19 mice treated with a drug (Drugged). In FIG.27, the drug-treated mice were administered cetrorelix, and in FIG.28, the drug-treated mice were administered sincalide. The gel lanes corresponding to untreated mice and mice treated with vehicle control each display intense high-molecular-weight bands indicating significant concentrations of abnormal tau in the brains of these subjects. The gels lanes corresponding to the mice treated with cetrorelix (FIG.27) or sincalide (FIG.28) show a reduced intensity of these bands, indicating reduced levels of abnormal tau. While the degree of intensity reduction varied to some degree among the drug-treated samples, even the drug- treated samples exhibiting the greatest intensity in this assay still had a lower intensity than KILPATRICK TOWNSEND 794102311that of the least intense vehicle control sample. These results therefore quantitatively demonstrate reduction of propagating tau levels in vivo in the brains of treated mice.

[0153] Immunohistochemistry procedures were also used to perform a pathology examination of the mice cohorts of Example 4 and Example 5. In these procedures, both treated and untreated B6; C3-Tg (Prnp-MAPT*P301S) PS19Vle / J (Jackson; #008169) mouse brains were rapidly removed after perfusion. One brain hemisphere was fixed in 4% paraformaldehyde (PFA) for 18–24 h and then cryoprotected in 30% sucrose in tris-buffered saline (TBS). Brains were sectioned (30 μm, coronal) using a freezing microtome and stored in cryoprotectant at -20 °C. Free-floating sections were processed for immunohistochemical staining with anti-tau antibodies phosphorylated at Ser202 and Thr205 (AT8; 1:500, ThermoFisher, #MN1020 and / or Tau1, 1:500, Agilent, #A002401).

[0154] For immunofluorescent staining, sections were pre-incubated in 80% methanol in TBS (at -20 °C) and permeabilized with 0.4% Triton in 1X TBS. The sections were then blocked with goat serum (Sigma-Aldrich, #G9023) before adding the primary antibodies. After primary and subsequent wash with 1X Tris-buffered saline with 0.1% TWEEN® 20 Detergent (TBST), sections were then incubated with secondary antibodies AlexaFluor594 (red) goat anti-rabbit (1:1000, Jackson Immun. Res. #115-585-144) and AlexaFluo488 (green) goat anti- mouse (1:1000, Jackson Immun. Res. #115-545-146). Images were captured using a Nikon Eclipse Ti2 with an ORCA-Fusion BT Digital CMOS camera (#C15440-20UP).

[0155] As shown in the images of FIG. 29, using the described immunochemistry procedures, healthy neurons in the hippocampus of mouse subjects could be easily visualized. In the lower sets of images (Drug-D) in the figure, corresponding to samples from mice treated with cetrorelix, relatively thick layers of distinct and healthy neurons are seen in each of three analyzed areas for each sample section. In contrast, the upper sets of images (PBS) in the figure, corresponding to mice treated with a vehicle control, the layers of neurons are relatively thin and the individual neurons are indistinct, reflecting a poorer health. FIG. 30 provides a graph plotting quantitative data derived from the images of FIG. 29 and showing significant differences between neural cell counts observed with the drug-treated and vehicle-treated subjects. Together, the results from FIGS. 29 and 30 thus demonstrate the ability of the provided treatment method to sustain healthy neurons by protecting them from degradation.

[0156] Another experiment also measured the degree of microglia cell activation in the brains of mice treated with the provided method. FIG.31 shows immunostaining images using KILPATRICK TOWNSEND 794102311brain samples from normal wild-type control mice, from mice treated with only vehicle, from mice treated with cetrorelix (D), and from mice treated with sincalide (K). The images rely on IBA 1 antibody staining to visualize activated microglia in the brain, since IBA 1 expression often correlates with microglia activation state. Furthermore, active microglia are known to not only disrupt diseased neurons, but also to affect neighboring healthy neurons. The more intense staining visible in the vehicle-treated samples indicates microglia activity significantly beyond that seen with the wild-type control samples, and provides evidence of the diseased nature of these samples. Notably, the “D treatment” and “K treatment” images in the figure show that treatment with cetrorelix or sincalide results in a much lower staining level similar to that of the healthy wild-type control samples. These results demonstrate that the drug treatments substantially reduce AD-associated neuroinflammation, which is a key feature of AD pathology.

[0157] Other tests provided further evidence that intranasally delivered drug is successfully delivered to the brain. As shown in FIG. 32, a mouse was intranasally administered drug conjugated to magnetic beads, where the locations of the magnetic beads within the mouse could be detected and visualized as an overly in the figure. FIG. 32 shows that, in as little as 20 minutes after the intranasal administration was initiated, the drug was delivered to the brain of the mouse subject. The concentrations of drug localized in the brain increased during the next hour. Then, by a time 4 hours after the drug administration was begun, the drug had reached the bladder of the mouse.

[0158] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub- combination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub- combination was individually and explicitly disclosed herein.

[0159] Although the foregoing disclosure has been described in some detail by way of illustration and example for purpose of clarity of understanding, one of skill in the art will KILPATRICK TOWNSEND 794102311appreciate that certain changes and modifications within the spirit and scope of the disclosure may be practiced, e.g., within the scope of the appended claims. It should also be understood that aspects of the disclosure and portions of various recited embodiments and features can be combined or interchanged either in whole or in part. In the foregoing descriptions of the various embodiments, those embodiments which refer to another embodiment may be appropriately combined with other embodiments as will be appreciated by one of skill in the art. Furthermore, those of ordinary skill in the art will appreciate that the foregoing description is by way of example only, and is not intended to limit the disclosure. In addition, each reference provided herein is incorporated by reference in its entirety for all purposes to the same extent as if each reference was individually incorporated by reference. KILPATRICK TOWNSEND 794102311

Claims

WHAT IS CLAIMED IS:

1. A method for preventing or treating a neurodegenerative disorder in a subject, the neurodegenerative disorder characterized by a deposition of abnormal tau protein in the brain of the subject, the method comprising administering to the subject a therapeutically effective amount of a drug that is a tau propagation antagonist.

2. The method of claim 1, wherein the method further comprises arresting or regressing formation of fibrils within neurons in the brain of the subject.

3. The method of claim 1, wherein the method further comprises inhibiting assembly of dimers or oligomers of the abnormal tau protein in the brain of the subject.

4. The method of claim 1, wherein the method further comprises degrading dimers or oligomers of the abnormal tau protein in the brain of the subject.

5. The method of claim 1, wherein the method further comprises blocking transport of the abnormal tau protein into neurons in the brain of the subject.

6. The method of claim 1, wherein the drug has a binding energy to the abnormal tau protein that is at most -5 kcal / mol.

7. The method of claim 1, wherein the drug has a molecular weight that is at least 500 g / mol.

8. The method of claim 1, wherein the drug does not cross the blood brain barrier of the subject.

9. The method of claim 1, wherein the drug comprises cetrorelix, sincalide (CCK-8), or a combination thereof.

10. The method of claim 1, wherein the administering comprises intranasal administration.

11. The method of claim 1, wherein the administering comprises administration of a pharmaceutical composition comprising the drug and a permeation enhancer. KILPATRICK TOWNSEND 79410231112. The method of claim 11, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

13. The method of claim 10, wherein the permeation enhancer has a concentration in the pharmaceutical composition that is between 0.02 wt% and 2 wt%.

14. The method of claim 1, wherein the therapeutically effective amount of the drug comprises an average dose of the drug that is between 0.1 μg / kg / day and 10 mg / kg / day.

15. The method of claim 1, wherein the therapeutically effective amount of the drug is administered with a first dose and a last dose that are at least 1 week apart.

16. The method of claim 1, wherein the neurodegenerative disorder comprises Alzheimer’s disease.

17. A pharmaceutical composition comprising a tau propagation antagonist, and a permeation enhancer.

18. The pharmaceutical composition of claim 17, wherein the tau propagation antagonist comprises cetrorelix, sincalide, or a combination thereof.

19. The pharmaceutical composition of claim 17, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

20. The pharmaceutical composition of claim 17, wherein the permeation enhancer has a concentration in the pharmaceutical composition that is between 0.02 wt% and 2 wt%.

21. A nasal drug delivery system comprising a pharmaceutical composition, the pharmaceutical composition comprising a tau propagation antagonist.

22. The nasal drug delivery system of claim 21, wherein the tau propagation antagonist comprises cetrorelix, sincalide (CCK-8), or a combination thereof.

23. The nasal drug delivery system of claim 21, wherein the pharmaceutical composition further comprises a permeation enhancer. KILPATRICK TOWNSEND 79410231124. The nasal drug delivery system of claim 23, wherein the permeation enhancer comprises dodecyl maltoside, tetradecyl maltoside, or a combination thereof.

25. The nasal drug delivery system of claim 23, wherein the permeation enhancer has a concentration in the pharmaceutical solution that is between 0.02 wt% and 2 KILPATRICK TOWNSEND 794102311

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