Treatment of neurodegenerative disorders with doxycycline alone or in combination with levodopa

Abstract

Provided herein are methods of treating a neurodegenerative disorder (e.g., Parkinson's disease) or symptoms thereof in a patient by administering to the patient doxycycline (or a pharmaceutically acceptable salt thereof), either alone or in combination with other therapeutic agents (e.g., levodopa).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 484,286, filed February 10, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Neurodegenerative disorders affect millions of people worldwide and are primarily characterized by neuronal loss. The most common neurodegenerative disorders are Alzheimer's disease and Parkinson's disease (PD). While several medications are currently approved to manage neurodegenerative disorders, most of them only address relevant symptoms. Furthermore, while surgical and other techniques have achieved some therapeutic success, the clinical acceptance of these approaches has been limited due to various concerns regarding their long-term benefits due to potential damage to the brain-brain barrier (see, for example, Lamptey RNL, et al., "A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics," Int. J. Mol. Sci. 2022 Feb 6;23(3):1851). The lack of etiologically targeted therapies is primarily due to the restrictive effect of the blood-brain barrier (BBB), which blocks nearly 99% of all "foreign substances" from the brain. The complex nature of the BBB, combined with its poor permeability for most, if not all, drugs, contributes to the lack of suitable treatment options for neurodegenerative disorders.

[0003] It is therefore an object of the present disclosure to provide improved methods for treating patients with neurodegenerative disorders, particularly PD. Summary of the Invention

[0004] Provided herein are methods for treating various neurodegenerative disorders or conditions by administering doxycycline (or a pharmaceutically acceptable salt thereof), either alone or in combination with other therapeutic agents (e.g., levodopa), to a patient in need of such treatment.

[0005] Exemplary neurodegenerative disorders include, but are not limited to, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease (PD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, frontotemporal neurocognitive disorder, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, ataxia, motor neuron disease, multiple system atrophy, hereditary ataxia, dementia, memory loss, mental retardation, Rett syndrome, progressive supranuclear palsy, Creutzfeldt-Jakob disease, neurofibromatosis, brain injury, stroke, multiple sclerosis, and α-synucleinopathy (e.g., Lewy body disease). In one embodiment, the neurodegenerative disorder is Alzheimer's disease. In another embodiment, the neurodegenerative disorder is PD.

[0006] Exemplary symptoms include, but are not limited to, abnormal mobility, abnormal balance, abnormal movements (e.g., tremors), abnormal swallowing, abnormal bladder and bowel function (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, abnormal sleep, abnormal breathing (e.g., shortness of breath), abnormal heart function (e.g., heart palpitations), abnormal memory, abnormal cognitive ability, abnormal mood, abnormal speech, anxiety, depression, stress, fatigue, feelings of panic, fear, worry, sleep problems, cold or sweaty hands and / or feet, mood lability, mania, decreased concentration or attention, cognitive problems, obsessions, impulsivity, repetitive behaviors, aggression, social phobia or disorder, stage fright, inability to settle and stay quiet, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, elation, disinhibition, irritability, wandering, and / or combinations thereof.

[0007] Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered to a patient by any suitable means. In one embodiment, the doxycycline is formulated as a powder for suspension. In another embodiment, the doxycycline is formulated as a capsule (e.g., sustained release). In another embodiment, the doxycycline is formulated as a tablet (e.g., delayed release). In another embodiment, the doxycycline is formulated as a syrup.

[0008] In some embodiments, doxycycline is administered to a patient in a therapeutically active amount. In some embodiments, doxycycline is administered to a patient at a dose of 50 mg to 200 mg (50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg) once daily. In one embodiment, doxycycline is administered at a dose of 50 mg once daily. In another embodiment, doxycycline is administered at a dose of 100 mg once daily. In another embodiment, the patient is an adult patient and doxycycline is administered at a dose of 100 mg every 12 hours on the first day, followed by 100 mg once daily, or 50-100 mg (e.g., 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg) every 12 hours. In another embodiment, doxycycline is administered to the patient at a subtherapeutic dose.

[0009] In some embodiments, the patient has previously been administered levodopa (or a pharmaceutically acceptable salt thereof). For example, in some embodiments, the patient has been treated with levodopa for 3 months, 6 months, 9 months, 1 year, 2 years, 3 years, 4 years, or more prior to being treated in accordance with the methods described herein.

[0010] Also provided herein is a method of treating a neurodegenerative disorder (e.g., PD) or condition (e.g., tremor) in a patient by administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof). In one embodiment, the doxycycline and levodopa are administered simultaneously. In another embodiment, the doxycycline and levodopa are administered sequentially in time. For example, in one embodiment, levodopa is administered before administration of doxycycline. In another embodiment, doxycycline is administered before administration of levodopa.

[0011] Levodopa (or a pharmaceutically acceptable salt thereof) can be administered to a patient by any suitable means. In one embodiment, levodopa is formulated as an oral tablet or capsule. In another embodiment, levodopa is formulated for oral inhalation. In another embodiment, levodopa is formulated for injection.

[0012] In some embodiments, levodopa (or a pharmaceutically acceptable salt thereof) is administered to a patient in a therapeutically active amount. In some embodiments, levodopa is administered in combination (e.g., separately or in a single formulation) with the drug carbidopa, which reduces or prevents nausea that levodopa alone can cause.

[0013] In one embodiment, levodopa is administered at a total dose of 100 to 1,000 mg of levodopa per day (e.g., administered as divided doses three to four times daily as immediate-release tablets). For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1,000 mg.

[0014] In another embodiment, levodopa is administered at a total daily dose of 100 to 1,600 mg (e.g., administered in divided doses as controlled-release tablets). For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg. In certain embodiments, levodopa is administered at a dose of 100 mg once daily.

[0015] In another embodiment, levodopa is administered in a total daily dose of 100 to 1,000 mg (eg, administered as an orally disintegrating tablet 3 to 4 times daily in divided doses).

[0016] In another embodiment, levodopa is administered at a dose of up to 2,000 mg over 16 hours (eg, as an enteral suspension). For example, levodopa can be administered in doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg. In certain embodiments, levodopa is administered at a dose of 100 mg once daily.

[0017] In another embodiment, levodopa is administered (eg, in divided doses as sustained release capsules) at a total daily dose of 855 to 2,340 mg of levodopa.

[0018] In another embodiment, levodopa is administered (e.g., administered as a tablet) at a total daily dose of 100 to 1,600 mg. For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg.

[0019] In another embodiment, levodopa is administered at a dose of 42 to 84 mg up to five times per day (e.g., as a capsule of inhaled powder). For example, levodopa can be administered at a dose of 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, or 84 mg. In one embodiment, levopoda is administered once daily, twice daily, three times daily, four times daily, or five times daily.

[0020] In another embodiment, levodopa is administered to the patient at a sub-therapeutic dose.

[0021] Also provided herein is a method of treating a neurodegenerative disorder (e.g., PD) or condition (e.g., tremor) in a patient by administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa results in a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0022] For administration of either doxycycline or levodopa alone.

[0023] Further provided is a method for treating a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor) in a patient by administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa, wherein subtherapeutic doses of doxycycline or levodopa alone are normally effective in combination. Thus, subtherapeutic doses of doxycycline and / or subtherapeutic doses of levodopa that would normally have no therapeutic effect in humans are found to have a therapeutic effect when administered in combination with doxycycline and levodopa. In other words, by administering a combination of doxycycline and levodopa, at least one or both of doxycycline and / or levodopa can be administered at subtherapeutic doses while still providing similar efficacy.

[0024] Thus, in aspects, methods are provided for treating a neurodegenerative disorder (e.g., PD) or condition (e.g., tremor) in a patient, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa (or a pharmaceutically acceptable salt thereof) to the patient, wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or levodopa required to achieve a therapeutic effect in the patient when administered alone.

[0025] The effectiveness of the treatment methods provided herein can be evaluated using any suitable means. In one embodiment, the neurodegenerative disorder is PD, and the treatment results in improvement according to a recognized clinical scale for assessing PD. For example, in one embodiment, the neurodegenerative disorder is PD, and the treatment results in improvement according to the Unified Parkinson's Disease Rating Scale (UPDRS). A score of 199 on the UPDRS scale represents the worst (complete disability), and a score of 0 represents (no disability). Thus, in one embodiment, treatment results in a reduction in score compared to baseline of, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 199 points. In another embodiment, treatment results in a reduction in score compared to baseline of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100%.

[0026] In another embodiment, the neurodegenerative disorder is PD and the treatment results in an improvement according to the Hoehn and Yahr staging scale. The Hoehn and Yahr staging scale includes seven different stages ranging from no disease (stage 1) to wheelchair or bedridden (stage 5): stage 0, stage 1, stage 1.5, stage 2, stage 2, stage 2.5, stage 3, stage 4, and stage 5. In one embodiment, the treatment results in a reduction of one or more stages in the score compared to baseline (e.g., a reduction of 1, 2, 3, 4, 5, 6, 7, or 8 stages).

[0027] In another embodiment, the neurodegenerative disorder is PD, and treatment results in an improvement according to the Schwab and England Activities of Daily Living Assessment, which ranges from 0 (completely independent) to 100% (vegetative functions) using 10% increments, with 11 possible ratings: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100%. In one embodiment, treatment results in a decrease of one or more ratings (e.g., a decrease of 1, 2, 3, 4, 5, 6, 7, 8, 1, or 10) compared to baseline.

[0028] In some embodiments, the neurodegenerative disorder is PD, and the treatment results in an improvement in tremor (e.g., a reduction in tremor), for example, by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Improvement can be assessed by any suitable means, including, but not limited to, electromyography (EMG), electromagnetic motion trackers, non-contact measurements obtained from devices (e.g., Kinect), laser Doppler vibrometers, accelerometers, gyroscopes, or smart wearable technology devices.

[0029] Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered according to the methods described herein: (1) alone; (2) in combination with levodopa (or a pharmaceutically acceptable salt thereof); (3) in combination with one or more other therapeutic agents; or (4) in combination with levodopa and one or more other therapeutic agents.

[0030] Any other suitable therapeutic agent may be administered. In one embodiment, the other therapeutic agent is a Kv7 channel activator (e.g., retigabine, flupirtine, or an endocannabinoid-like molecule).

[0031] In another embodiment, the other therapeutic agent is an antibody against alpha-synuclein (e.g., Abeam's "Syn204," Alexis's "15G 7," Becton Dickinson's "42," Chemicon's "7B 2,12," NovaCastra's "KM51," SantaCruz's "Syn211," or Zymed's "LB509").

[0032] In another embodiment, the other therapeutic agent is a decarboxylase inhibitor, such as carbidopa.

[0033] In another embodiment, the other therapeutic agent is a dopamine agonist (e.g., Parlodel (BROMOCRIPTINE®), cabergoline, Apokyn (APOMORPHINE®), Mirapex (PRAMIPEXOLE®), Requip (ROPINIROLE®), or Neupro (ROTIGOTINE®)).

[0034] In another embodiment, the other therapeutic agent is a monoamine oxidase (MAO) B inhibitor (e.g., isocarboxazid (MARPLAN®), phenelzine (NARDIL®), selegiline (EMSAM®), tranylcypromine (PARNATE®), selegiline hydrochloride (ELDEPRYL®), selegiline hydrochloride (ZELAPAR®), rasagiline (AZILECT®), or safinamide (XADAGO®).

[0035] In another embodiment, the other therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor (e.g., entacapone (COMTAN®, COMTESS®, STALEVO®), nebicapone, nitecapone, opicapone (ONGENTYS®), or tolcapone (TASMAR®).

[0036] In another embodiment, the other therapeutic agent is an anticholinergic (e.g., (1) an antimuscarinic agent, e.g., an antipsychotic (CLOZAPINE®, QUETIAPINE®), atropine, benztropine (COGENTIN®), biperiden, chlorpheniramine, certain SSRIs (PAROXETINE®), dicyclomine (DICYCLOVERINE®), dimenhydrinate, diphenhydramine, doxepin, doxylamine, flavoxazone, etc.). or (2) anti-nicotinic agents, e.g., bupropion, dextromethorphan, doxacurium, dexamethasone, mecamylamine, tubocurarine, cyclosporine, cyclopentasiloxane ...

[0037] In another embodiment, the other therapeutic agent is an adenosine receptor antagonist (A2A receptor antagonist) (e.g., caffeine, theophylline, or istradefylline (NOURIANZ®), or Nuplazid (PIMAVANSERIN®)).

[0038] In another embodiment, the other therapeutic agent is a TNF-alpha targeted agent or inhibitor (e.g., liximab (REMICADE®), adalimumab (HUMIRA®), certolizumab pegol (CIMZIA®), golimumab (SIMPONI®), and etanercept (ENBREL®).

[0039] In another embodiment, the other therapeutic agent is an IL17A targeting agent or inhibitor (e.g., secukinumab (COSENTYX®), ixekizumab (TALTZ®), bimekizumab (BIMZELX®), or brodalumab (SILIQ®).

[0040] In another embodiment, the other therapeutic agent is deep brain stimulation.

[0041] Further provided are kits comprising a dose of doxycycline adapted for use in a method described herein, e.g., for the effective treatment of a neurodegenerative disorder (e.g., PD) or condition (e.g., tremor). In one embodiment, the kit comprises (a) a dose of doxycycline and (b) instructions for using the doxycycline in a method described herein. In another embodiment, the kit comprises (a) a dose of doxycycline, (b) a dose of levodopa, and (c) instructions for using the doxycycline and levodopa in a method described herein. In one embodiment, the dose of doxycycline is a therapeutically effective amount. In one embodiment, the dose of levodopa is a therapeutically effective amount. In one embodiment, the doses of doxycycline and / or levodopa are subtherapeutic.

[0042] Also provided is the use of doxycycline for the treatment of a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein the doxycycline (or a pharmaceutically acceptable salt thereof) is administered to a patient in an amount and frequency sufficient to treat the neurodegenerative disorder or symptom. Further provided is the use of doxycycline in combination with levodopa (or a pharmaceutically acceptable salt thereof) for the treatment of a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein the doxycycline and levodopa are administered to a patient in an amount and frequency sufficient to treat the neurodegenerative disorder or symptom. In one embodiment, the combination of doxycycline and levodopa provides a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone. In another embodiment, the combination of doxycycline and levodopa allows for the administration of doxycycline and / or levodopa at subtherapeutic doses. DETAILED DESCRIPTION OF THE INVENTION

[0043] The following detailed description is provided to assist those skilled in the art in practicing the present invention. Exemplary embodiments are described in detail hereinafter. However, these embodiments are merely exemplary, and the disclosure is not limited thereto, but rather is defined by the scope of the appended claims. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the disclosure.

[0044] Accordingly, the embodiments are described below merely by reference to structures and schemes to illustrate aspects of the present specification.

[0045] I. Definition As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." When preceding a list of elements, phrases such as "at least one of" modify the entire list of elements, but not each individual element of the list.

[0046] When an element is referred to as being "on" another element, it should be understood that it may be in direct contact with the other element, or there may be intervening elements between them. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0047] Terms such as first, second, and third may be used herein to describe various elements, components, regions, layers, and / or sections, but it should be understood that these elements, components, regions, layers, and / or sections are not limited by these terms. These terms are used only to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below could be referred to as a second element, component, region, layer, or section without departing from the teachings of embodiments of the present invention.

[0048] As used herein, the terms "comprises" and / or "comprising" or "includes" and / or "including" specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but are to be understood as not excluding the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The terms used herein are only for describing specific embodiments and are not intended to be limiting. Terms, such as those defined in commonly used dictionaries, should be interpreted to have a meaning consistent with their meaning in the relevant technical field and in the context of this disclosure, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0050] As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application. If a term is not specifically defined herein, the term will be given the art-recognized meaning by those of ordinary skill in the art who apply the term in the context of its use in describing the present invention.

[0051] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0052] II. Neurodegenerative Disorders and Conditions Neurons are central to the proper functioning of the human brain because they play a key role in communication (see, e.g., Lamptey RNL, et al., 2022; and Van den Heuvel MP, et al., "Network hubs in the human brain," Trends Cogn. Sci. 2013;17:683-696). While most neurons originate in the brain, they are present throughout the body. During childhood, neural stem cells produce the majority of neurons, and their numbers decrease significantly in adulthood (see, e.g., Ganat YM, et al., "Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo," J. Neurosci. 2006;26:8609-862). Neurons are not immortal. However, the progressive loss of neurons, neuronal structures, and / or their functions (known as "neurodegeneration") is central to the pathophysiology of several brain disorders and is also a major health concern (see, for example, Przedborski S., et al., "Series Introduction: Neurodegeneration: What is it and where are we?", J. Clin. Investig. 2003; 111: 3-10). Neurodegeneration is associated with the dysfunction of synapses, neural networks, and the deposition of physiochemically altered variants of proteins in the brain. Diseases characterized by neurodegeneration are collectively referred to as NDs (see, for example, Lamptey RNL, et al., 2022).

[0053] Any neurodegenerative disorder or symptom can be treated according to the methods described herein.Exemplary neurodegenerative disorder includes but is not limited to amyotrophic lateral sclerosis (ALS), Huntington's disease, PD, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, ataxia, hereditary ataxia, dementia, memory loss, mental retardation and Rett syndrome.

[0054] The methods described herein can also be used to treat one or more symptoms of neurodegenerative disorders.Exemplary neurodegenerative disorders include but are not limited to: anxiety, depression, stress, fatigue, panic, fear, worry, sleep problems, cold or sweaty hands and / or feet, mood instability, mania, poor concentration or attention, cognitive problems, obsessive thoughts, impulses, repetitive behavior, aggression, social phobia or disorder, stage fright, shortness of breath, heart palpitations, inability to calm down and stay quiet, dry mouth, numbness or tingling in hands or feet, nausea, muscle tension, dizziness, apathy, elation, disinhibition, irritability, wandering, irritable bowel, abdominal pain, abdominal discomfort, diarrhea, change in bowel habits, abdominal distension, abdominal gas, abdominal distension and / or constipation.

[0055] A. Parkinson's disease PD is a neurodegenerative disease that typically begins around age 60 and causes slow movement (bradykinesia), muscle rigidity (rigidity), tremor, poor postural stability, low voice, shuffling gait, a sudden cessation of movement called freezing, and a lack of spontaneous movement (akinesia) (see, e.g., Fahn S., "Description of Parkinson's disease as a clinical syndrome," Ann. N.Y.Acad. Sci. 2003;991:1-14). Motor symptoms usually begin on one side of the body and later affect the other side (see, e.g., Rajput AH, et al., "Accuracy of clinical diagnosis in parkinsonism—A prospective study," Can. J. Neurol. Sci. 1991;18:275-278). The underlying degeneration of dopaminergic nigrostriatal neurons and subsequent striatal dopamine deficiency form the basis of pharmacotherapy (see, e.g., McColl CD, et al., “Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease,” Mov. Disord. 2002;17:1227-1234).

[0056] As used herein, the term "tremor" refers to involuntary vibrations and rhythmic movements caused by simultaneous or alternating contraction of agonist / antagonist muscles (see, e.g., Sigcha L, et al., "Automatic Resting Tremor Assessment in Parkinson's Disease Using Smartwatches and Multitask Convolutional Neural Networks", Sensors (Basel). 2021 Jan 4;21(1):291. Tremor can occur in the hands, head, trunk, or legs (see, e.g., Puschmann A., et al., "Diagnosis and Treatment of Common Forms of Tremor", Semin. Neurol. 2011;31:65-77). In PD, tremor can appear early in the disease and reduce quality of life by interfering with activities such as reading, writing, and eating (see, e.g., Hssayeni MD, et al., "Wearable Sensors for Estimation of Parkinsonian Tremor Severity during Free Body Movements,” Sensors. 2019;19:4215). Over 70% of all PD patients experience resting tremor during the course of their disease, and the effects of tremor tend to become more severe with age (see, e.g., Baumann CR, “Epidemiology, diagnosis and differential diagnosis in Parkinson's disease tremor,” Parkinsonism Relat. Disord. 2012;18:S90-S92).Tremor in PD can be divided into (1) resting tremor, which occurs when patients relax their muscles, and (2) action tremor (postural and kinetic), which occurs while the subject performs voluntary muscle movements (see, e.g., Bhidayasiri R., "Differential Diagnosis of Common Tremor Syndromes," Postgrad. Med. J. 2005;81:756-762).

[0057] Exemplary technologies for assessing PD tremor include sensor technologies, such as electromyography (EMG) (see, e.g., Mailankody P., et al., Re-emergent tremor in Parkinson's disease: A clinical and electromyographic study,” J. Neurol. Sci. 2016; 366:33-36; Palmes P., et al., “Pattern Mining of Multichannel sEMG for Tremor Classification,” IEEE Trans. Biomed. Eng. 2010; 57:2795-2805; and Kwon K., et al., “Comparison of motor and non-motor features between essential tremor and tremor dominant Parkinson's disease,” J. Neurol. Sci. 2016; 361:34-38), electromagnetic motion trackers (see, e.g., Perera T., et al., “Clinical validation of a precision electromagnetic tremor measurement system in participants receiving deep brain stimulation for essential tremor” [J. Neurol. Sci. 2016; 361:34-38]). tremor”, Physiol. Meas. 2016;37:1516-1527), non-contact measurements obtained from devices such as Kinect (see, for example, Sooklal S., et al., “Using the Kinect for detecting tremors: Challenges and opportunities; Proceedings of the IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI); Valencia, Spain. 1-4 June 2014; pp.768-771), laser Doppler vibrometers (see, for example, Sooklal S., et al.Examples of sensors that can be used include, but are not limited to, sensors such as Ossig AAC, et al., "Wearable sensor-based objective assessment of motor symptoms in Parkinson's disease," J. Neural Transm. 2016;123:57-64; and Rovini E., et al., "How Wearable Sensors Can Support Parkinson's Disease Diagnosis and Treatment: A Systematic Review," Front. Neurosci. 2017;11:555), and smart wearable technologies.

[0058] Several scales have been established as a means of assessing the severity of PD, for example, by measuring motor symptoms, assessing the ability to perform daily functional activities, and symptomatic response to medications. The most common scales are the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr staging scale, and the Schwab and England Activities of Daily Living Assessment (see, e.g., Perlmutter JS, "Assessment of Parkinson's disease manifestations," Curr. Protoc Neurosci. 2009 Oct; Chapter 10: Unit 10.1).

[0059] The Unified Parkinson's Disease Rating Scale (UPDRS) is the most accepted tool for assessing interventions and following up patients (see, e.g., Martinez-Martin P, et al., "The Cooperative Multicentric Group Unified Parkinson's Disease Rating Scale characteristics and structure," Mov. Disord. 1994;9:76-8). A detailed description of the UPDRS is provided by Perlmutter JS ("Assessment of Parkinson's disease manifestations," Curr Protoc Neurosci. 2009 Oct;Chapter 10:Unit10.1), the contents of which are expressly incorporated herein by reference.

[0060] The current UPDRS includes four subscales: Subscale 1 covers mental functioning, behavior, and mood; Subscale 2 assesses activities of daily living; Subscale 3 is a clinician assessment of the motor symptoms of PD; and Subscale 4 covers complications of therapy. Data for Subscales 1, 2, and 4 are elicited from patients and caregivers, while data for Subscale 3 is test-based. Training tapes are available for UPDRS subscales 2 and 3, and reviewing these can improve the reliability of measurements (see, e.g., Goetz CG, et al., "Standardized training tools for the UPDRS activities of daily living scale: Newly available teaching program," Mov. Disord. 2003;18:1455-1458; Goetz CG, et al., "Teaching tape for the motor section of the unified Parkinson's disease rating scale," Mov. Disord. 1995;10:263-266; and, e.g., Goetz CG et al., "Assuring interrater reliability for the UPDRS motor section: Utility of the UPDRS teaching tape," Mov. Disord. 2004;19:1453-1456). However, reliability of the other subscales depends on patient report as well as examiner skill, although training tapes are available for the Activities of Daily Living Component Subscale 2 activities (see, e.g., Louis ED, et al., "Reliability of patient completion of the historical section of the Unified Parkinson's Disease Rating Scale," Mov. Disord. 1996;11:185-192). The total UPDRS score and UPDRS subscale scores are not interval scales, meaning that there are no quantified equal distances between values ​​on these scales.For example, a score of 4, although greater than 2, does not necessarily indicate twice the severity. Each part of the rating is an ordinal measure, not a precise interval change; this must be taken into account when using these data for statistical analysis. Some sections of the UPDRS scale require the assignment of multiple grades to each limb, resulting in a maximum possible score of 199. A score of 199 on the UPDRS scale represents the worst (total disability), and a score of 0 represents (no disability).

[0061] The Hoehn and Yahr scale was the first rating scale to describe PD progression and describes five stages of PD progression. It is a simple staging system of PD motor symptoms from 0 to 5, intended to reflect the degree of progression, combining characteristics of motor impairment and disability. However, this scale may not be linear or even ordinal, and individuals ranked as stage 2 (significant bradykinesia but good stability on the pull test) may be more disabled than those ranked as stage 3 (falls on the pull test but relatively mild bradykinesia and rigidity). The scale was subsequently modified to include two 0.5-step scores, as described below in Table 1 (see, e.g., Goetz CG, et al., Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. Mov. Disord. 2004;19:1020-1028). [Table 1-1] [Table 1-2]

[0062] The Schwab and England scale is an "Activities of Daily Living" (ADL) scale frequently used to provide a single estimate of a patient's functional ability. The rating is made by the person interviewing the patient, often by a collateral source such as a spouse. The rating ranges from 0 to 100% using 5% increments and is listed in Table 2 below. [Table 2]

[0063] III. Doxycycline and its pharmaceutically acceptable salts As used herein, the term doxycycline (ADOXA®, ADOXA CK®, ADOXA PAK®, ADOXA TT®, DORYX®, MONODOX®, ORACEA®, PERIOSTAT®, VIBRAMYCIN CALCIUM®, VIBRAMYCIN HYCLATE®, and VIBRA-TABS®) includes doxycycline and its pharmaceutically acceptable salts. Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline is listed on the World Health Organization's List of Essential Medicines and is available as a generic drug.

[0064] Doxycycline belongs to a class of medicines known as tetracycline antibiotics. It is a second-generation tetracycline, first discovered in 1967. Second-generation tetracyclines are less toxic than first-generation tetracyclines. Doxycycline is used to treat a wide variety of gram-positive and gram-negative bacterial infections.

[0065] Doxycycline is a broad-spectrum tetracycline-class antibiotic used to treat infections caused by bacteria and certain parasites. According to the National Library of Medicine of the National Institutes of Health, doxycycline is also used to treat or prevent anthrax (a serious infection that could be intentionally spread as part of a bioterrorism attack) in people who may have been exposed to anthrax in the air, as well as to treat plague and tularemia (a serious infection that could be intentionally spread as part of a bioterrorism attack). Doxycycline is also used to prevent malaria. Along with other drugs, doxycycline is used to treat acne and rosacea (a skin condition that causes redness, flushing, and breakouts on the face).

[0066] Doxycycline is a highly lipophilic drug, allowing it to cross multiple membranes of target molecules. It exhibits favorable intracellular penetration, resulting in antibacterial activity against a wide range of bacteria. Doxycycline also exhibits antiparasitic and anti-inflammatory properties. Its anti-inflammatory effects have been investigated in various inflammatory skin conditions, such as bullous dermatoses and rosacea.

[0067] Protein synthesis is essential for the survival and function of cells, including bacteria. Doxycycline inhibits bacterial protein synthesis by allosterically binding to the 30S prokaryotic ribosomal subunit. The drug blocks the association of charged aminoacyl-tRNA (aa-tRNA) with the ribosomal A site, the acceptor site on the mRNA-ribosome complex. Doxycycline ultimately prevents the elongation phase of protein synthesis, halting the production of proteins essential for bacterial survival and function.

[0068] Doxycycline mediates its anti-inflammatory effects by preventing calcium-dependent microtubule assembly and lymphocyte proliferation, thereby inhibiting leukocyte migration during inflammation. It also inhibits nitric oxide synthase, an enzyme that produces the inflammatory signaling molecule nitric oxide.

[0069] Doxycycline can be in a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends in part on the intended mode of administration and therapeutic application. For example, doxycycline intended for systemic or local delivery can be in the form of an injectable or infusible solution. Thus, doxycycline can be formulated for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). As used herein, "parenteral administration," "parenterally administered," and other grammatically equivalent phrases refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intranasal, intraocular, pulmonary, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intrathecal, intrathecal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0070] In one embodiment, doxycycline is formulated as a powder for suspension. In another embodiment, doxycycline is formulated as a capsule (e.g., sustained release). In another embodiment, doxycycline is formulated as a tablet (e.g., delayed release). In another embodiment, doxycycline is formulated as a syrup.

[0071] IV. Levodopa As used herein, the term levodopa (DHIVY®, DUODOPA®, DUOPA®, INBRIJA®, PARCOPA®, PROLOPA®, RYTARY®, SINEMET®, STALEVO®, BIDOPAL®, DOPAR®, DOPARL®, DOPASOL®, and DOPASTON®) includes levodopa and its pharmaceutically acceptable salts. Levodopa is a dopamine precursor used in the management of PD, often in combination with carbidopa, and other related conditions. Because levodopa can be metabolized to dopamine on both sides of the blood-brain barrier, it is commonly administered with a dopa decarboxylase inhibitor (e.g., carbidopa) to prevent metabolism until it crosses the blood-brain barrier (see, e.g., Djamshidian A, Poewe W, Parkinsonism Relat Disord. 2016 Dec;33 Suppl 1:S9-S12). Once across the blood-brain barrier, levodopa is metabolized to dopamine, compensating for low endogenous dopamine levels to treat the symptoms of PD.

[0072] Levodopa is often considered the first-line medication for managing PD motor symptoms. Levodopa is most often given in combination with the drug carbidopa to reduce or prevent the nausea that levodopa alone can cause. Carbidopa-levodopa is delivered in many forms, including immediate-release, controlled-release, or time-release oral tablets or capsules. In addition to pills and capsules, it is also available as an enteral gel (DUOPA®) and an inhaler (INBRIJAC®).

[0073] Carbidopa-levodopa immediate-release tablets (SINEMET®) are available in doses of 10-100 mg, 25-100 mg, or 25-250 mg. A typical treatment regimen is a total of 100-1,000 mg of levodopa per day (divided into 3-4 doses). In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0074] In one embodiment, levodopa is administered at a total dose of 100 to 1,000 mg of levodopa per day (e.g., administered as divided doses three to four times daily as immediate-release tablets). For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, and 1,000 mg.

[0075] Carbidopa-levodopa controlled-release tablets (SINEMET CR*®) are available in doses of 25-100 mg or 50-200 mg. A typical treatment regimen is 400-1,600 mg of levodopa in divided doses, depending on daily need.

[0076] In one embodiment, levodopa is administered at a total daily dose of 100 to 1,600 mg (e.g., administered in divided doses as a controlled-release tablet). For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg. In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0077] Carbidopa-levodopa orally disintegrating tablets (PARCOPA®) are available in doses of 10-100 mg, 25-100 mg, or 25-250 mg. A typical treatment regimen is a total of 100-1,000 mg of levodopa per day (in 3-4 divided doses).

[0078] In one embodiment, levodopa is administered in a total daily dose of 100 to 1,000 mg (eg, administered as an orally disintegrating tablet 3 to 4 times daily in divided doses).

[0079] Carbidopa-levodopa enteral suspension (DUOPA®) is available as a 4.86 / 20 per mL dose. This form of carbidopa-levodopa is delivered to the small intestine via a surgically implanted tube rather than via a pill. After surgery, this delivery method increases "on" time (the time during which a patient's symptoms are well controlled and they are able to move and function well) without problematic involuntary dyskinetic movements. A typical treatment regimen is up to 2,000 mg of levodopa over 16 hours.

[0080] In one embodiment, levodopa is administered at a dose of up to 2,000 mg over 16 hours (eg, as an enteral suspension). For example, levodopa can be administered in doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, or 2000 mg. In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0081] Carbidopa-levodopa extended-release (ER) capsules (RYTARY®) are available in doses of 23.75-95 mg, 36.25-145 mg, 48.75-195 mg, or 61.25-245 mg. This form of carbidopa-levodopa contains beads of both drugs, which dissolve and are absorbed at different rates. This can improve "on" time while requiring a smaller dosage. The dosage of carbidopa-levodopa ER capsules is not interchangeable with that of other carbidopa-levodopa products. A typical treatment regimen is 855-2,340 mg of levodopa in divided doses, depending on daily need.

[0082] In one embodiment, levodopa is administered (eg, in divided doses as sustained release capsules) at a total daily dose of 855 to 2,340 mg of levodopa.

[0083] Carbidopa-levodopa entacapone tablets (STALEVO®) are available in doses of 12.5-50-200 mg, 18.75-75-200 mg, 25-100-200 mg, 31.25-125-200 mg, or 37.5-150-200 mg. It is a combination drug containing entacapone and carbidopa-levodopa in a single pill. It is more convenient than carbidopa-levodopa and entacapone, which are taken separately. A typical treatment regimen is a total daily dose of 150-1,600 mg of levodopa (maximum of eight tablets per day), depending on daily needs.

[0084] In one embodiment, levodopa is administered (e.g., administered as a tablet) at a total daily dose of 100 to 1,600 mg. For example, levodopa can be administered at doses of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, or 1600 mg. In one embodiment, levodopa is administered at a dose of 100 mg once daily.

[0085] Levodopa inhalation powder (INBRIJA®) is available in 42 mg or 84 mg doses. This is the inhaled form of levodopa most commonly used for early morning "off" periods or sudden "off" periods (e.g., when PD motor and / or non-motor symptoms occur between doses), providing a low but faster-acting boost of dopamine. It is often used in addition to a more stable regimen. An inhaled oral formulation of levodopa was approved by the US Food and Drug Administration in 2018 to treat PD as adjunctive therapy to levodopa / carbidopa. Inhaled levodopa avoids the intestinal absorption and hepatic metabolism of oral levodopa and is available in dry powder form (see, e.g., LeWitt PA, et al., Lancet Neurol. 2019 Feb;18(2):145-154). A typical treatment regimen is 42–84 mg (1–2 capsules) up to five times daily.

[0086] In one embodiment, levodopa is administered at a dose of 42 to 84 mg up to five times per day (e.g., as an inhalation powder capsule). For example, levodopa can be administered at a dose of 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, or 84 mg. In one embodiment, levopoda is administered once daily, twice daily, three times daily, four times daily, or five times daily.

[0087] In one embodiment, levodopa is administered to the patient at a sub-therapeutic dose.

[0088] V. Treatment method Provided herein are methods for treating a neurodegenerative disorder (e.g., PD) or a symptom thereof (e.g., tremor) by administering doxycycline (or a pharmaceutically acceptable salt thereof) either alone or in combination with other therapeutic agents (e.g., levodopa) to a patient in need of such treatment.

[0089] As used herein, the term "subject" or "patient" refers to a human patient (eg, a patient with a neurodegenerative disorder or condition).

[0090] As used herein, the term "pediatric" patient is a human patient classified by a physician or caregiver as belonging to a non-adult category and can include, for example, newborns (both preterm and term), infants, children, and adolescents. Typically, a pediatric patient is a patient under the age of 18 (<18 years old).

[0091] As used herein, the term "adult" patient is a human patient who has been classified as such by a physician or caregiver based on, e.g., age, developmental status, physiological characteristics, etc., e.g., a patient who is not a neonate, infant, child, or adolescent. Typically, an adult patient is a patient who is 18 years of age or older (≧18 years of age).

[0092] As used herein, the terms "treat," "treating," and "treatment" refer to any type of intervention or process performed on a subject, or the administration of an active agent or combination of active agents to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting or slowing down, or preventing the progression, onset, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease.

[0093] As used herein, " effective treatment " refers to treatment that produces beneficial effects, for example, improves at least one symptom of disease or disorder. Beneficial effects can take the form of improvement relative to baseline, for example, improvement relative to the measurement or observation made before the start of therapy according to the present method. Effective treatment can refer to the alleviation of at least one symptom of neurodegenerative disorder.

[0094] The term "effective amount" refers to an amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. The result can be a reduction, amelioration, alleviation, reduction, delay, and / or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In one example, an "effective amount" is an amount clinically proven to alleviate at least one symptom of a neurodegenerative disorder. An effective amount can be administered in one or more administrations.

[0095] As used herein, the phrase "optimal biological dose (OBD)" is defined as the minimum dose of a drug or drug combination that produces an optimal and sustained in vivo response without clinically unacceptable toxicity. Toxicity and therapeutic effects can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, for example, determining LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic effect and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50.

[0096] As used herein, the terms "synergy," "therapeutic synergy," and "synergistic effect" refer to the phenomenon in which treatment of a patient with a combination of therapeutic agents (e.g., doxycycline and levodopa) results in a therapeutically superior outcome compared to the outcome achieved by each individual component of the combination when used alone (see, e.g., T.H. Corbett et al., 1982, Cancer Treatment Reports, 66, 1187). In this context, a therapeutically superior outcome includes one or more of the following: (a) an increase in therapeutic effect greater than the sum of the individual effects of each agent alone at the same dose as the combination; (b) a reduction in the dose of one or more agents in the combination without a decrease in therapeutic efficacy; (c) a reduction in the incidence of adverse events while receiving a therapeutic effect equivalent to or greater than that of monotherapy with each agent at the same dose as the combination; (d) a reduction in dose-limiting toxicity while receiving a therapeutic effect greater than that of monotherapy with each agent; and (e) a delay or minimization of the onset of drug resistance. The synergy of drug combinations can be determined, for example, according to the combination index (CI) theorem of Chou-Talalay (Chou et al., Adv. Enzyme Regul. 1984; 22:27-55; Chou, Cancer Res. 2010; 70(2):440-446).

[0097] "Relapse" or "recurrence" or "resurgence" are used interchangeably herein and refer to the diagnosis of the return of signs and symptoms after a period of improvement or response.

[0098] As used herein, a "sub-therapeutic dose" of a therapeutic compound (e.g., doxycycline or levodopa) refers to a dose that is lower than the usual / typical dose of that compound required to achieve a therapeutic effect.

[0099] The term "subtherapeutic amount" of a compound refers to an amount below the acceptable therapeutically effective amount. A subtherapeutic amount may be defined as an amount below the FDA-approved dosage or dosage for a particular disease. Alternatively, given that many drugs are used outside of their approved indications, a subtherapeutic amount may be defined as an amount below the amount typically prescribed by physicians for a particular disease. A subtherapeutic amount may also take into account factors such as body weight, sex, age, renal or hepatic impairment, and other parameters that may affect the effectiveness of a given amount of a particular drug. In some embodiments, a subtherapeutic amount may be 85% of the therapeutically effective amount. In other embodiments, a subtherapeutic amount may be 70% of the therapeutically effective amount. In other embodiments, a subtherapeutic amount may be 60% of the therapeutically effective amount. In other embodiments, a subtherapeutic amount may be 50% of the therapeutically effective amount. In other embodiments, a subtherapeutic amount may be 40% of the therapeutically effective amount. In other embodiments, a subtherapeutic amount may be 30% of the therapeutically effective amount. In further embodiments, a subtherapeutic amount may be even less.

[0100] In other words, a sub-therapeutic dose is an amount of a therapeutic compound (e.g., doxycycline or levodopa) that, when administered to a patient, is not itself sufficiently effective to treat a claimed disease (e.g., a neurodegenerative disorder such as PD). However, the combination is surprisingly effective in treating a claimed disorder even when one or more of the therapeutic compounds (e.g., doxycycline or levodopa) is administered at a dose that is not sufficiently effective to treat the disorder.

[0101] In one embodiment, a method of treating a neurodegenerative disorder or symptom thereof in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof).

[0102] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof).

[0103] In one embodiment, a method of treating a neurodegenerative disorder or symptom thereof in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof).

[0104] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof).

[0105] In one embodiment, a method of treating a neurodegenerative disorder or symptom thereof in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa provides a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0106] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, comprising administering to the patient a therapeutically active amount of doxycycline (or a pharmaceutically acceptable salt thereof) in combination with a therapeutically active amount of levodopa (or a pharmaceutically acceptable salt thereof), wherein the combined administration of doxycycline and levodopa provides a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

[0107] In one embodiment, a method for treating a neurodegenerative disorder or its symptoms in a patient is provided, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa, wherein a subtherapeutic dose of doxycycline or levodopa alone is typically effective in combination. Thus, subtherapeutic doses of doxycycline and / or subtherapeutic doses of levodopa, which would typically have no therapeutic effect in humans, are found to have a therapeutic effect when administered in combination with doxycycline and levodopa. In other words, by administering a combination of doxycycline and levodopa, at least one or both of doxycycline and / or levodopa can be administered at subtherapeutic doses, yet still provide similar efficacy.

[0108] In one embodiment, a method for treating PD or its symptoms (e.g., tremor) in a patient is provided, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa, wherein subtherapeutic doses of doxycycline or levodopa alone are typically effective in combination. Thus, subtherapeutic doses of doxycycline and / or subtherapeutic doses of levodopa that would typically have no therapeutic effect in humans are found to have a therapeutic effect when administered in combination with doxycycline and levodopa. In other words, by administering a combination of doxycycline and levodopa, at least one or both of doxycycline and / or levodopa can be administered at subtherapeutic doses while still providing similar efficacy.

[0109] In one embodiment, a method of treating a neurodegenerative disorder or symptom thereof in a patient is provided, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa (or a pharmaceutically acceptable salt thereof) to the patient, wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose of doxycycline and / or levodopa that is lower than the dose of doxycycline and / or levodopa that is required to achieve a therapeutic effect in the patient when administered alone.

[0110] In one embodiment, a method of treating PD or a symptom thereof (e.g., tremor) in a patient is provided, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) in combination with levodopa (or a pharmaceutically acceptable salt thereof) to the patient, wherein at least one of the doxycycline and / or levodopa is administered at a subtherapeutic dose. In some embodiments, the subtherapeutic dose of doxycycline and / or the subtherapeutic dose of levodopa is a dose of doxycycline and / or levodopa that is lower than the dose of doxycycline and / or levodopa required to achieve a therapeutic effect in the patient when administered alone.

[0111] VI. Other Combination Therapies Doxycycline (or a pharmaceutically acceptable salt thereof) can be administered according to the methods described herein (1) alone, (2) in combination with levodopa (or a pharmaceutically acceptable salt thereof), (3) in combination with one or more other therapeutic agents, or (4) in combination with levodopa and one or more other therapeutic agents. Any other suitable therapeutic agent can be administered.

[0112] In one embodiment, the other therapeutic agent is a Kv7 channel activator (eg, retigabine, flupirtine, or an endocannabinoid-like molecule).

[0113] In another embodiment, the other therapeutic agent is an antibody against alpha-synuclein (e.g., Abeam's "Syn204," Alexis's "15G 7," Becton Dickinson's "42," Chemicon's "7B 2,12," NovaCastra's "KM51," SantaCruz's "Syn211," or Zymed's "LB509").

[0114] In another embodiment, the other therapeutic agent is a decarboxylase inhibitor, such as carbidopa.

[0115] In another embodiment, the other therapeutic agent is a dopamine agonist (e.g., Parlodel (BROMOCRIPTINE®), cabergoline, Apokyn (APOMORPHINE®), Mirapex (PRAMIPEXOLE®), Requip (ROPINIROLE®), or Neupro (ROTIGOTINE®)).

[0116] In another embodiment, the other therapeutic agent is a monoamine oxidase (MAO) B inhibitor (e.g., isocarboxazid (MARPLAN®), phenelzine (NARDIL®), selegiline (EMSAM®), tranylcypromine (PARNATE®), selegiline hydrochloride (ELDEPRYL®), selegiline hydrochloride (ZELAPAR®), rasagiline (AZILECT®), or safinamide (XADAGO®).

[0117] In another embodiment, the other therapeutic agent is a catechol O-methyltransferase (COMT) inhibitor (e.g., entacapone (COMTAN®, COMTESS®, STALEVO®), nebicapone, nitecapone, opicapone (ONGENTYS®), or tolcapone (TASMAR®).

[0118] In another embodiment, the other therapeutic agent is an anticholinergic (e.g., (1) an antimuscarinic agent, e.g., an antipsychotic (CLOZAPINE®, QUETIAPINE®), atropine, benztropine (COGENTIN®), biperiden, chlorpheniramine, certain SSRIs (PAROXETINE®), dicyclomine (DICYCLOVERINE®), dimenhydrinate, diphenhydramine, doxepin, doxylamine, flavoxazone, etc.). or (2) anti-nicotinic agents, e.g., bupropion, dextromethorphan, doxacurium, dexamethasone, mecamylamine, tubocurarine, cyclosporine, cyclopentasiloxane ...

[0119] In another embodiment, the other therapeutic agent is an adenosine receptor antagonist (A2A receptor antagonist) (e.g., caffeine, theophylline, or istradefylline (NOURIANZ®), or Nuplazid (PIMAVANSERIN®)).

[0120] In another embodiment, the other therapeutic agent is a TNF-alpha targeted agent or inhibitor (e.g., liximab (REMICADE®), adalimumab (HUMIRA®), certolizumab pegol (CIMZIA®), golimumab (SIMPONI®), and etanercept (ENBREL®).

[0121] In another embodiment, the other therapeutic agent is an IL17A targeting agent or inhibitor (e.g., secukinumab (COSENTYX®), ixekizumab (TALTZ®), bimekizumab (BIMZELX®), or brodalumab (SILIQ®).

[0122] In another embodiment, the other therapeutic agent is deep brain stimulation.

[0123] VII. Results Provided herein are methods for treating a neurodegenerative disorder (e.g., PD) or symptom in a patient, comprising administering doxycycline (or a pharmaceutically acceptable salt thereof) to the patient, either alone or in combination with another therapeutic agent (e.g., levodopa). Patients treated according to the methods disclosed herein experience improvement in at least one symptom of the neurodegenerative disorder.

[0124] Exemplary symptoms of neurodegenerative disorders include, but are not limited to, abnormal mobility, abnormal balance, abnormal movements (e.g., tremors), abnormal swallowing, abnormal bladder and bowel function (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, abnormal sleep, abnormal breathing (e.g., shortness of breath), abnormal heart function (e.g., heart palpitations), abnormal memory, abnormal cognitive ability, abnormal mood, abnormal speech, anxiety, depression, stress, fatigue, feelings of panic, fear, worry, sleep problems, cold or sweaty hands and / or feet, mood lability, mania, decreased concentration or attention, cognitive problems, obsessions, impulsivity, repetitive behaviors, aggression, social phobia or disorder, stage fright, inability to settle down and stay quiet, dry mouth, numbness or tingling in the hands or feet, nausea, muscle tension, dizziness, apathy, elation, disinhibition, irritability, wandering, and / or combinations thereof.

[0125] In one embodiment, the patient is a PD patient.The exemplary symptoms of PD include but are not limited to tremor, slow movement (bradykinesia), rigid muscles, impaired posture and balance, loss of motility, change in speech and change in writing.Therefore, in some embodiments, the PD patient treated according to the methods described herein will experience the improvement of one or more of these symptoms.

[0126] In another embodiment, the patient is a PD patient, and the treatment results in an improvement according to a recognized clinical scale for assessing PD. For example, in one embodiment, the treatment results in an improvement according to the Unified Parkinson's Disease Rating Scale (UPDRS). A score of 199 on the UPDRS scale represents the worst (complete disability), and a score of 0 represents no disability. Thus, in one embodiment, the treatment results in a reduction in score of, for example, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 199 points compared to baseline. In another embodiment, treatment results in a 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% reduction in score compared to baseline.

[0127] In another embodiment, the patient is a PD patient and the treatment is PD, and the treatment results in an improvement according to the Hoehn and Yahr staging scale. The Hoehn and Yahr staging scale includes seven different stages ranging from no disease (stage 1) to wheelchair or bedridden (stage 5): stage 0, stage 1, stage 1.5, stage 2, stage 2, stage 2.5, stage 3, stage 4, and stage 5. In one embodiment, the treatment results in a reduction of one or more stages in the score compared to baseline (e.g., a reduction of 1, 2, 3, 4, 5, 6, 7, or 8 stages).

[0128] In another embodiment, the patient is a PD patient and treatment results in an improvement according to the Schwab and England Activities of Daily Living Assessment, which ranges from 0 (completely independent) to 100% (vegetative state) using 10% increments, with 11 possible ratings: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100%. In one embodiment, treatment results in a decrease in one or more ratings (e.g., a decrease of 1, 2, 3, 4, 5, 6, 7, 8, 1, or 10) compared to baseline.

[0129] In some embodiments, the patient is a PD patient and the treatment results in an improvement in tremor (e.g., a reduction in tremor), for example, by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Improvement can be assessed by any suitable means, including, but not limited to, electromyography (EMG), electromagnetic motion trackers, non-contact measurements obtained from devices (e.g., Kinect), laser Doppler vibrometers, accelerometers, gyroscopes, or smart wearable technology devices.

[0130] VIII. Kits and Unit Dosage Forms Also provided herein is a kit comprising a dose of doxycycline adapted for use in the preceding methods. In some embodiments, the kit further comprises a dose of levodopa. The kit can optionally also comprise instructions, including an administration schedule, for example, to enable a practitioner (e.g., a doctor, nurse, or patient) to administer the composition contained therein to a patient with a neurodegenerative disorder such as PD. The kit can also comprise a syringe.

[0131] In one embodiment, the kit comprises (a) a dose of doxycycline and (b) instructions for using the doxycycline in the methods described herein.

[0132] In another embodiment, the kit includes (a) a dose of doxycycline, (b) a dose of levodopa, and (c) instructions for using doxycycline and levodopa in the methods described herein. In one embodiment, the dose of doxycycline is a therapeutically effective amount. In one embodiment, the dose of levodopa is a therapeutically effective amount. In one embodiment, the doses of doxycycline and / or levodopa are subtherapeutic doses.

[0133] IX.Use Provided herein is a use of doxycycline for the treatment of a neurodegenerative disorder (e.g., PD) or symptom (e.g., tremor), wherein the doxycycline (or a pharmaceutically acceptable salt thereof) is administered to a patient in an amount and frequency to treat the neurodegenerative disorder or symptom.

[0134] Further provided is a use of doxycycline in combination with levodopa (or a pharmaceutically acceptable salt thereof) for the treatment of a neurodegenerative disorder (e.g., PD) or condition (e.g., tremor), wherein the doxycycline and levodopa are administered to a patient in amounts and at a frequency to treat the neurodegenerative disorder or condition. In one embodiment, the combination of doxycycline and levodopa provides a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone. In another embodiment, the combination of doxycycline and levodopa allows for the administration of doxycycline and / or levodopa at subtherapeutic doses.

[0135] Since numerous variations and equivalents will become apparent to those skilled in the art upon reading this disclosure, the following examples are merely illustrative and should not be construed as limiting the scope of the disclosure in any way. The contents of all references, Genbank entries, patents, and published patent applications cited throughout this application are hereby incorporated by reference. [Example]

[0136] Patient A, a 59-year-old man, was diagnosed with Parkinson's disease (PD) approximately 1.5 years ago and treated with levodopa. In addition to the typical symptoms of tremor, the patient also exhibited seborrheic dermatitis, an inflammatory skin condition known to be associated with a higher incidence of Parkinson's disease. The patient also experienced intermittent symptoms of irritable bowel disease. Prior to initiating doxycycline, the patient required increased levodopa doses approximately every three months as his PD, most notably his tremor, worsened. The patient began doxycycline 100 mg tablets once daily for his skin symptoms, and within three weeks, his seborrheic dermatitis resolved. Quite surprisingly and unexpectedly, the patient also demonstrated a clinically significant reduction in tremor after initiating doxycycline. Approximately eight weeks later, the patient discontinued doxycycline, and the seborrheic dermatitis recurred within two weeks, resulting in a clinical worsening of the tremor. The patient resumed doxycycline and again experienced remission of the seborrheic dermatitis and improvement in his tremor. The patient's inflammatory skin condition again remitted, and her Parkinson's disease tremor improved clinically. The patient continued doxycycline for an additional two months but discontinued it due to nausea. Upon de-challenge, the seborrheic dermatitis recurred within one month, and the tremor clinically worsened. The patient resumed doxycycline at 50 mg and experienced partial improvement of her skin symptoms and PD. When the dose was again increased to 100 mg, the seborrheic dermatitis remitted and the tremor improved. The patient continued taking doxycycline 100 mg tablets once daily for approximately two years and experienced complete remission of the seborrheic dermatitis, absence of irritable bowel symptoms, and clinically significant improvement of the tremor. In addition to improvement in PD tremor, the patient did not require an increase in Parkinson's disease medication for the first time, and his levodopa dose remained stable for approximately 2 years after initiating treatment with doxycycline 100 mg.

Claims

1. 1. A method for treating a neurodegenerative disorder or condition, comprising administering to a patient in need thereof a therapeutically active amount of doxycycline.

2. 2. The method of claim 1, wherein the neurodegenerative disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease (PD), supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, frontotemporal neurocognitive disorder, Alzheimer's disease, mild cognitive impairment, mild cognitive impairment due to Alzheimer's disease, ataxia, motor neuron disease, multiple system atrophy, hereditary ataxia, dementia, memory loss, mental retardation, Rett syndrome, progressive supranuclear palsy, Creutzfeldt-Jakob disease, neurofibromatosis, brain injury, stroke, multiple sclerosis, and a-synucleinopathy (e.g., Lewy body disease).

3. 3. The method of claim 1 or 2, wherein the neurodegenerative disorder is PD.

4. 2. The method of claim 1, wherein the symptom is selected from the group consisting of abnormal mobility, abnormal balance, abnormal movements, abnormal swallowing, abnormal bladder and bowel function (e.g., irritable bowel, abdominal pain, abdominal discomfort, diarrhea, bloating, abdominal gas, abdominal distension, and / or constipation), blood pressure fluctuations, abnormal sleep, abnormal breathing (e.g., shortness of breath), abnormal heart function (e.g., heart palpitations), abnormal memory, abnormal cognitive ability, abnormal mood, abnormal speech, anxiety, depression, stress, fatigue, feelings of panic, fear, worry, sleep problems, cold or sweaty hands and / or feet, mood lability, mania, decreased concentration or attention, cognitive problems, obsessive-compulsive thoughts, impulsivity, repetitive behaviors, aggression, social phobia or disorder, stage fright, inability to calm and quiet down, dry mouth, numbness or tingling in hands or feet, nausea, muscle tension, dizziness or apathy, elation, disinhibition, irritability, wandering, or a combination thereof.

5. 10. The method of any one of the preceding claims, wherein the therapeutically active amount of doxycycline is from 50 mg to 200 mg once daily.

6. 5. The method of any one of claims 1-4, wherein the therapeutically active amount of doxycycline is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg once daily.

7. 7. The method of claim 6, wherein the therapeutically active amount of doxycycline is 50 mg once daily.

8. 7. The method of claim 6, wherein the therapeutically active amount of doxycycline is 100 mg once daily.

9. 10. The method of any one of the preceding claims, wherein the patient was previously administered levodopa.

10. 10. The method of any one of the preceding claims, wherein the method further comprises administering levodopa to the patient.

11. 11. The method of claim 10, wherein the doxycycline and the levodopa are administered either simultaneously or sequentially in time.

12. 12. The method of claim 10 or 11, wherein the levodopa is administered prior to the administration of the doxycycline.

13. 12. The method of claim 10 or 11, wherein the doxycycline is administered prior to the administration of the levodopa.

14. The method of any one of claims 10 to 13, wherein levodopa is administered as an oral tablet or capsule, oral inhalation, or injection.

15. 15. The method of any one of claims 10 to 14, wherein levodopa is administered at a dose of about 100 mg to 2,340 mg once daily.

16. 15. The method of any one of claims 10 to 14, wherein levodopa is administered at a dose of about 100 mg once daily.

17. 17. The method of any one of claims 11 to 16, wherein administration of doxycycline and levodopa results in a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

18. 18. The method of any one of claims 11 to 17, wherein doxycycline and levodopa are administered in combination, and at least one of doxycycline and / or levodopa is administered at a sub-therapeutic dose.

19. 19. The method of claim 18, wherein the sub-therapeutic dose of doxycycline and / or the sub-therapeutic dose of levodopa is a dose that is lower than the dose of doxycycline and / or levodopa required to achieve a therapeutic effect in the patient when administered alone.

20. 10. The method of any one of the preceding claims, wherein the neurodegenerative disorder is PD and the treatment results in improvement according to the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr staging scale, and / or the Schwab and England Activities of Daily Living Assessment.

21. 10. The method of any one of the preceding claims, wherein the neurodegenerative disorder is PD and the treatment results in improvement of tremor.

22. 22. The method of claim 21, wherein the tremor improvement is assessed by electromyogram (EMG), an electromagnetic motion tracker, non-contact measurements obtained from a device (e.g., Kinect), a laser Doppler vibrometer, an accelerometer, a gyroscope, or a smart wearable technology device.

23. 10. The method of any one of the preceding claims, wherein doxycycline is administered in combination with an additional therapeutic agent.

24. 24. The method of claim 23, wherein the additional therapeutic agent is a Kv7 channel activator, an antibody against alpha-synuclein, carbidopa, a dopamine agonist, a monoamine oxidase (MAO) B inhibitor, a catechol O-methyltransferase (COMT) inhibitor, an anticholinergic agent, and an adenosine receptor antagonist (A2A receptor antagonist), or a combination thereof.

25. 24. The method of claim 23, wherein the additional therapeutic agent is a TNF-alpha targeting agent, an IL17A targeting agent, or a combination thereof.

26. 10. The method of any one of the preceding claims, wherein doxycycline is administered in combination with deep brain stimulation.

27. 27. A kit comprising: (a) a dose of doxycycline; and (b) instructions for using said doxycycline in the method of any one of claims 1 to 26.

28. 27. A kit comprising: (a) a dose of doxycycline; (b) a dose of levodopa; and (c) instructions for using doxycycline and levodopa in the method of any one of claims 1-26.

29. 1. Use of doxycycline for the treatment of a neurodegenerative disorder or condition, wherein the doxycycline is administered to a patient in an amount and frequency to treat said neurodegenerative disorder or condition.

30. 1. Use of doxycycline in combination with levodopa for the treatment of a neurodegenerative disorder or condition, wherein the doxycycline and levodopa are administered to a patient in amounts and with a frequency to treat said neurodegenerative disorder or condition.

31. 30. The use according to claim 28 or 29, wherein the neurodegenerative disorder is PD.

32. 31. The use of any one of claims 28 to 30, wherein the combination of doxycycline and levodopa provides a synergistic therapeutic effect compared to administration of either doxycycline or levodopa alone.

31. 31. The use of claim 29 or 30, wherein doxycycline and levodopa are administered in sub-therapeutic doses.

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