Combination of pridopidine and HTT lowering agent for treating huntington disease and symptoms thereof

Abstract

Provided herein a method of treating Huntington disease and / or symptoms thereof, by administering to the patient a pharmaceutically effective amount of pridopidine or its pharmaceutically acceptable salt; and a composition comprising at least one HTT (huntingtin gene) lowering agent.

Description

P-601817-PCCOMBINATION OF PRIDOPIDINE AND HTT LOWERING AGENT FOR TREATING HUNTINGTON DISEASE AND SYMPTOMS THEREOFSEQUENCE LISTING

[0001] A Sequence Listing conforming to the rules of WIPO Standard ST.26 is hereby incorporated by reference. Said Sequence Listing has been filed as an electronic document via Patent Center encoded as XML in UTF-8 text. The electronic document, created on August 25, 2024, is entitled “P-601817-USPl_ST26.xml”, and is 18,362 bytes in size.FIELD OF THE INVENTION

[0002] Provided herein is a method of treatment, prevention, alleviation, delaying symptom onset, or slowing progression of Huntington disease and / or symptoms thereof in a subject in need thereof comprising administering a pharmaceutically effective amount of a composition comprising of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising at least one HTT lowering agent.BACKGROUND OF THE INVENTIONHuntington disease

[0003] Huntington disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is associated with motor, behavioral, functional, and cognitive symptoms. Motor disturbances are the defining feature of the disease, with chorea the most evident motor symptom. Although useful for diagnosis, chorea is a poor marker of disease severity. Rather, functional disability and disease severity best correlate with negative motor features such as impairment in fine motor skills, bradykinesia, and gross motor coordination skills, including speech difficulties, gait, and postural dysfunction as well as cognitive impairments [1],

[0004] Disease progression in HD is defined by clinical rating scales, i.e. The Unified Huntington’s Disease Rating Scale Total Functional Capacity (UHDRS-TFC) and the HD Integrated Scoring System (HD-ISS).

[0005] The UHDRS-Total Functional Capacity (TFC) scale is a validated and accepted tool used by clinicians to assess HD disease stage and the level of patient’s functionality. A decline in UHDRS-TFC is associated with other aspects of disease progression including brain atrophy, motor, cognitive and behavioral functions [2,3],P-601817-PCThe HD includes five stages:

[0006] HD1 (TFC 11-13), 0-8 years after onset. Early stage. Fully functional at home and at work, maintains typical pre-disease levels of independence when it comes to everyday activities.

[0007] HD2 (TFC 7-10), 3-13 years after onset. Early intermediate stage. Patient is still functional at work, but at a lower capacity.

[0008] HD3 (TFC 3-6) 5-16 years after onset. Late intermediate stage. Patients can no longer conduct work or manage household responsibilities.

[0009] HD4 (TFC 1-2) 9-21 years after onset. Early advanced stage. Patients are not independent at this stage, but still can reside in their home with help from either family or professionals, although their needs may be better met at an extended care facility.

[0010] HD5 (TFC 0) 11-26 years after onset, advanced stage. Patients need total support in daily activities from professional nursing care.A new Integrated Staging System (HD-ISS) defines 4 stages of HD:

[0011] The HD-ISS is an evidence-based staging system that addresses all stages of HD. The ISS defines landmark assessments and cut-off values to identify critical transitions in disease stages. HD-ISS has 4 distinct stages.

[0012] ISS Stage 0 (pre-symptomatic) includes all HD gene carriers for whom there is no detectable change in pathological markers, signs or symptoms related to HD.

[0013] In ISS stage 1, pathological changes indicating neurodegeneration, and an onset of specific signs can be detected, specifically changes to the volume of the caudate and putamen brain substructures.

[0014] ISS Stage 2 is defined by the presence of definite clinical signs and symptoms, both cognitive and motor, without any decline in function.

[0015] ISS Stage 3 is accompanied by a decline in functional capacity or independent.

[0016] ISS Stage 4 is characterized by a severe decline in both cognitive and motor functions, leading to a substantial loss of independence.

[0017] Genetically, HD belongs to the group of trinucleotides repeat expansion disorders. While individuals with a CAG repeat length of less than 35 located on exon 1 of HTT remain asymptomatic, alleles with 40 or more repeats show full penetrance. Intermediate alleles (36- 39 CAG repetitions) bear an increased risk to develop HD. Huntington’s disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant huntingtin (mHTT ) protein. [4], Only threeP-601817-PC drugs, tetrabenazine, deutetrabenazine and valbenazine (all act as VMAT2 inhibitors) are approved to treat chorea in HD patients, but no therapy has yet proved able to modify the progressive and inexorable functional decline of the disease [5,6], As such, there is a significant unmet medical need to develop medications to ameliorate symptoms of HD, and to delay disease progression.Pridopidine

[0018] Pridopidine (4-[3-(methylsulfonyl)phenyl]-l-propyl-piperidine) is a highly selective Sigma- 1 receptor (SIR) ligand with Ki=57 nM and low affinity for the Sigma-2 receptor (S2R Ki of 5450 nM) [7], Thus, pridopidine has 95-fold higher affinity for the SIR vs the S2R and is a highly selective SIR ligand.

[0019] The SIR is an endoplasmic reticulum (ER) protein located mainly at the mitochondria- associated membrane (MAM), modulating diverse cellular processes including calcium signaling, ion-channel activity, and the ER stress response [18,9], Pridopidine exerts neuroprotective effects, exquisitely mediated via activation of the SIR, as demonstrated in non- clinical models of HD and other neurodegenerative diseases [10-16], Specifically, pridopidine improves key pathophysiological pathways implicated in HD including rescue of mitochondrial-associated membrane (MAM) disruption

[0013] , enhancement of brain-derived neurotrophic factor secretion and signaling [10, 15], restoration of aberrant calcium signaling, rescue of synaptic plasticity and neuronal spine abnormalities

[0017] , enhancement of autophagy, upregulation of mitochondrial function

[0013] , reduction of ER and oxidative stress

[0014] , and rescue of mutant HTT -induced cell death

[0018] ,HTT lowering agents

[0020] Several huntingtin-lowering agents are currently under pre-clinical and clinical investigation in HD. These HTT lowering strategies span the whole spectrum of potential targets from genome editing via RNA interference to promoting protein degradation.

[0021] Recent studies revealed the importance of mutant huntingtin (mHTT) RNA in the pathogenesis of the disease. Therefore, mutant huntingtin - lowering by means of RNA interference appears to be a particularly promising strategy. Studies using antisense oligonucleotide (ASO) technology to lower HTT levels in Huntington’s disease (HD) subjects are currently ongoing. Antisense technologies for HTT lowering include tominersen and WVE- 003. Tominersen (SEQ ID 7) is a non-specific ASO that targets both wild-type and mutant huntingtin. WVE-003 is an ASO specific to mutant HTT. An additional technology inP-601817-PC development utilizing RNA interference is microRNA, which mimics endogenous microRNAs that serve to regulate gene expression. AMT-130 (SEQ ID 12) consists of an adenovirus- associated virus 5 (AAV5) vector containing a transgene encoding a microRNA targeted to both wild-type and mutant huntingtin. Thus, it is a non-selective HTT silencing agent.PTC518 (Votoplam, 2-[3-(2,2,6,6-Tetramethyl-4-piperidinyl)-3H-l,2,3-triazolo[4,5- c]pyridazin-6-yl]-5-(2H-l,2,3-triazol-2-yl)phenol) is a small molecule (splicing modifier that introduces a premature termination codon, leading to degradation of HTT mRNA. NanosiRNA developed by Medesis Pharma for treating HD, a therapeutic platform for delivering siRNA to treat Huntington’s disease. VO659 developed by Voyager Therapeutics is an antisense oligonucleotide (ASO) therapy designed to target the mutant huntingtin (mHTT) mRNA, which results from a CAG repeat expansion in the HTT gene.SUMMARY OF THE INVENTION

[0022] In some embodiments, this invention is directed to a method of treatment, prevention, or alleviation of Huntington disease in a subject in need thereof comprising administering a pharmaceutically effective amount of a composition comprising of pridopidine or pharmaceutically acceptable salt thereof, and a composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises at least one pridopidine’ s analog compound 1-7 represented by the following structures:P-601817-PC

[0023] In another embodiment, the HTT lowering agent comprises VO659, NanosiRNA, PTC518, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0025] Figures 1A and IB present the synergistic effect of lowering mHTT levels by 86% using pridopidine in combination with (CUG)?-ASO. Western blot analysis was performed for mHTT- 73Q-Exonl_EGFP overexpression.• Figure 1A: Blot showing detection of mHTT-73Q-Exonl_EGFP using anti-GFP antibody at the 60 kDa mark. Anti-GFP antibody produced in rabbit IgG, Cat# SAB4301138; Dilution - 1: 1000. Goat anti-Rabbit IgG Fc Secondary Antibody, HRP, Cat# A16116; Dilution - 1 :5000.• Figure IB: Quantification of band intensity analysis demonstrating the percentage reduction in mHTT levels following treatment.

[0026] Figure 2 demonstrates mitochondrial membrane potential (MMP) changes in mHTT- transfected cells compared to un-transfected control cells following tunicamycin-induced ER stress. Neuro2a cells were either left un-transfected or transfected with mHTT for 16 h, then exposed to tunicamycin (5 pM). MMP was assessed by TMRE staining and flow cytometry to evaluate mitochondrial function. Untreated un-transfected and mHTT-transfected cells both showed 100% MMP signal, indicating intact mitochondrial function. Following tunicamycin treatment, un-transfected cells retained 73% MMP -positive population, whereas mHTT- transfected cells exhibited a marked decrease, with only 23% MMP -positive cells. These findingsP-601817-PC highlight the increased vulnerability of mHTT-expressing cells to ER stress-induced mitochondrial dysfunction.

[0027] Figure 3 shows that pridopidine in combination with (CUG)7-ASO exerts a beneficial synergistic effect on mitochondrial function in HD cells. Mitochondrial membrane potential (MMP) assay was performed in Neuro2a cells following tunicamycin (5 pM) treatment. MMP levels were quantified and normalized to the untreated control group (set to 100%). Treatment with pridopidine alone or ASO alone resulted in partial rescue of mitochondrial function (28% and 10% improvement, respectively), whereas the combination treatment markedly improved mitochondrial function by 48% compared to the tunicamycin-treated group. Data are presented as mean ± SEM. Statistical significance: *p < 0.05, ***p < 0.001, ****p < 0.0001 vs. tunicamycin-treated group. Source: internal study.

[0027] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.DETAILED DESCRIPTION OF THE INVENTION

[0024] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.Method

[0025] In some embodiments, this invention is directed to treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease or any symptoms thereof, comprising administering a composition of this invention.

[0026] In some embodiments, this invention is directed to treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease or any symptoms thereof comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof, and a composition comprising at least one HTT lowering agent. In another embodiment, the symptoms of Huntington’s disease comprise impairment of physicalP-601817-PC symptom, mental symptom, emotional symptom, behavioral symptoms, impairment of functional capacity, motor function impairment, cognition impairment, memory impairment, anxiety and depression, speech impairment, lack of initiative, apathy, irritability, psychiatric symptoms, elevation in anti-inflammatory biomarkers, reduction in Brain-Derived Neurotrophic Factor (BDNF), increase of neurofilament light chain (NfL), deterioration of structural, functional, and metabolic measures in the brain, reduction in a patient’s quality of life, and reduced lifespan.

[0027] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises at least one pridopidine’ s analog compound 1-7 represented by the following structures:

[0028] In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof further comprises compound 1 or pharmaceutically acceptable salt thereof.

[0029] In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof further comprises compound 4 or pharmaceutically acceptable salt thereof.

[0030] In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof further comprises compound 1 and compound 4 or pharmaceutically acceptable salt thereof.P-601817-PC

[0031] In another embodiment, the HTT lowering agent is selected from PTC518, VO659, NanosiRNA, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof. Each represents a separate embodiment of this invention.

[0032] In another embodiment, the HTT lowering agent is selected from PTC518, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), or any combination thereof.

[0033] In another embodiment, the HTT lowering agent is selected from tominersen, WVE- 003, AMT-130, or any combination thereof.

[0034] In another embodiment, the method comprises administering a composition comprising at least two HTT lowering agents.

[0035] In some embodiments, this invention is directed to treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease or any symptoms thereof comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof, and at least one composition comprising at least one HTT lowering agent. In another embodiment, the symptoms of Huntington’s disease comprise impairment of physical symptom, mental symptom, emotional symptom, behavioral symptoms, impairment of functional capacity, motor function impairment, cognition impairment, memory impairment, anxiety and depression, speech impairment, lack of initiative, apathy, irritability, psychiatric symptoms, elevation in anti-inflammatory biomarkers, reduction in Brain-Derived Neurotrophic Factor (BDNF), increase of neurofilament light chain (NfL), deterioration of structural, functional, and metabolic measures in the brain, reduction in a patient’s quality of life, and reduced lifespan. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof, further comprises at least one pridopidine’ s analog compound 1-7.

[0036] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subjectP-601817-PC with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of maintaining, lessening the increase or reducing levels of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech in a subject with Huntington Disease; wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the HTT lowering agent comprises PTC518, VO659, NanosiRNA, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), or any combination thereof. In another embodiment, the HTT lowering agent is selected from PTC518, VO659, NanosiRNA, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof. In another embodiment, the HTT lowering agent is selected from tominersen, WVE-003, AMT-130 or any combination thereof.

[0037] In another embodiment, the HTT lowering agent is PTC518. In another embodiment, the HTT lowering agent is antisense oligonucleotide (ASO). In another embodiment, the HTT lowering agent is microRNA (miRNA). In another embodiment, the HTT lowering agent isP-601817-PCVO659. In another embodiment, the HTT lowering agent is NanosiRNA. In another embodiment, the HTT lowering agent is small interfering RNA (siRNA). In another embodiment, the antisense oligonucleotide (ASO) comprises tominersen, WVE-003, or any combination thereof. In another embodiment, the HTT lowering agent is tominersen. In another embodiment, the HTT lowering agent is WVE-003. In another embodiment, the HTT lowering agent is AMT-130.

[0038] In another embodiment, the method comprises administering a composition comprising at least two HTT lowering agents.

[0039] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject withP-601817-PCHuntington’s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof, optionally at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent.

[0040] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; wherein theP-601817-PC method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof, optionally at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof; and at least one composition comprising at least one HTT lowering agent.

[0041] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of maintaining or lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one pridopidine’ s analog compound 1-7 or pharmaceuticallyP-601817-PC acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the method comprises administering a composition comprising at least two HTT lowering agents.

[0042] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset; or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subj ect with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of maintaining or lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment or improving of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’ s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subj ect with Huntington’ s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one HTT lowering agent. In another embodiment, the composition further comprises at least one pridopidine’ s analogP-601817-PC compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the HTT lowering agent comprises PTC518, antisense oligonucleotide (ASO), microRNA (miRNA), VO659, NanosiRNA, small interfering RNA (siRNA), or any combination thereof. In another embodiment, the HTT lowering agent is selected from PTC518, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), tominersen, VO659, NanosiRNA, WVE- 003, AMT-130 or any combination thereof.

[0043] In some embodiments, this invention is directed to a method for treatment, prevention, alleviation, or slowing of progression of Huntington disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 1 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 1 or compound 4 or pharmaceutically acceptable salt thereof.

[0044] In some embodiments, this invention is directed to a method for maintaining, improving, or reducing impairment of functional capacity in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0045] In some embodiments, this invention is directed to a method of improving, maintaining, or reducing impairment of motor function in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0046] In some embodiments, this invention is directed to a method of improving, maintaining, or reducing the impairment of cognition in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable saltP-601817-PC thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0047] In some embodiments, this invention is directed to a method for slowing worsening or reducing anxiety and depression in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0048] In some embodiments, this invention is directed to a method for slowing the increase or reducing impairment of anti-inflammatory biomarkers in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0049] In some embodiments, this invention is directed to a method for slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF). in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0050] In some embodiments, this invention is directed to a method for maintaining, or reducing levels of neurofilament light chain (NfL) in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0051] In some embodiments, this invention is directed to a method for improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.P-601817-PC

[0052] In some embodiments, this invention is directed to a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0053] In some embodiments, this invention is directed to a method a method of delaying the onset, stopping or slowing down the decline of disease progression of Huntington Disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0054] In some embodiments, this invention is directed to a method of improving, maintaining, or slowing the decline of quality of life in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0055] In some embodiments, this invention is directed to a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0056] In some embodiments, this invention is directed to a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.P-601817-PC

[0057] In some embodiments, this invention is directed to a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0058] In some embodiments, this invention is directed to a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0059] In some embodiments, this invention is directed to a method of maintaining or reducing lack of initiative, apathy, or irritability in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0060] In some embodiments, this invention is directed to a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0061] a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0062] In some embodiments, provided herein is a method of reducing or maintaining a human patient’s involuntary movements comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the compositionP-601817-PC comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0063] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of slowing worsening or reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of maintaining or lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent; wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the additional composition comprising at least one HTT lowering agent are administeredP-601817-PC sequentially or concomitantly in either order. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the additional composition comprising at least one HTT lowering agent are administered sequentially. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the additional composition comprising at least one HTT lowering agent are administered concomitantly in either order. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0064] In another embodiment, the HTT lowering agent comprises PTC518, antisense oligonucleotide (ASO), VO659, NanosiRNA, microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof. In another embodiment, the HTT lowering agent is PTC518. In another embodiment, the HTT lowering agent is an antisense oligonucleotide (ASO). In another embodiment, the HTT lowering agent is VO659. In another embodiment, the HTT lowering agent is aNanosiRNA. In another embodiment, the HTT lowering agent is microRNA. In another embodiment, the HTT lowering agent is selected from tominersen, WVE-003, AMT-130 or any combination thereof.

[0065] In another embodiment, the method provided herein comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising one, two, three, four, five, six, seven, eight, nine, or ten HTT lowering agent. Each represents a separate embodiment of this invention. In another embodiment, the method provided herein comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising at least two HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the method provided herein comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and a at least one, two, three, four, five, six, seven, eight, nine, or ten compositions comprising at least one HTT lowering agent.

[0067] In another embodiment, the additional composition comprising at least one HTT lowering agent refers to at least one additional composition comprising at least one HTT lowering agent.

[0068] In some embodiments, the method of this invention comprises administering to a subject with Huntington’s Disease, a composition comprising pridopidine or pharmaceuticallyP-601817-PC acceptable salt thereof, and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the additional composition comprising at least one HTT lowering agent are each independently administered once a day. In another embodiment, the compositions are each independently administered twice per day. In another embodiment, the compositions are each independently administered three times per day. In another embodiment, the compositions are each independently administered once a week, twice weekly, three, four times a week, or every other day. In another embodiment, the compositions are each independently administered once daily, twice daily, three times daily, four times daily, or less than once a day.

[0069] In another embodiment, the pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof is administered once a day. In another embodiment, the composition is administered twice per day. In another embodiment, the composition is administered three times per day. In another embodiment, the composition is administered once a week, twice weekly, three times a week, or every other day. In another embodiment, the composition is administered once daily, twice daily, three times daily, four times daily, or less than once a day. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition is administered orally.

[0070] In another embodiment, the pharmaceutical composition comprising at least one HTT lowering agent is administered once a day. In another embodiment, the composition is administered twice per day. In another embodiment, the composition is administered three times per day. In another embodiment, the composition is administered once a week, twice weekly, three times a week, or every other day. In another embodiment, the composition is administered once daily, twice daily, three times daily, four times daily, or less than once a day. In another embodiment, the composition is administered every two weeks, every three weeks, or every 4 weeks. In another embodiment, the composition is administered every 6, 8 or 10 weeks. In another embodiment, the composition is administered orally or intravenously.

[0071] In some embodiments, the composition comprising pridopidine and the composition comprising at least one HTT lowering agent are each independently administered daily (once a day or twice a day), weekly, bi-weekly, every two weeks, every month, every 2 months, once in 3 months, once in 6 months, once a year.

[0072] In some embodiments, the compositions provided herein are administered at different intervals.P-601817-PC

[0073] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the additional composition comprising at least one HTT lowering agenflused in the methods of this invention are each administered for at least 12 weeks. In another embodiment, for at least 26 weeks. In another embodiment, for at least 52 weeks. In another embodiment, for at least 65 weeks. In another embodiment, for at least 78 weeks. In another embodiment, the compositions are each administered for at least 1, 2, 3, 4, 5 years. In another embodiment, the compositions are each administered chronically, or for a lifetime. In another embodiment, the compositions are administered for over 5 years, over 6 years, over 7 years, over 8 years, over 9 years, or over 10 years.

[0074] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof is administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, intracranial, or intradermal route. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition is administered orally.

[0075] In some embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the additional composition comprising at least one HTT lowering agent are each independently administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, intracranial, or intradermal route. Each represents a separate embodiment of this invention.

[0076] In another embodiment, the composition comprising at least one|HTT lowering agent is administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, intracranial, or intradermal route. In another embodiment, the composition is administered intravenously.

[0077] In another embodiment, the composition is administered intrathecal.

[0078] In another embodiment, the compositions provided herein are each independently administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, intracranial, or intradermal route. Each represents a separate embodiment of this invention. In another embodiment, the compositions provided herein are administered in combination via oneP-601817-PC or more of these routes. In some embodiments, the compositions are administered sequentially or concomitantly.

[0079] In another embodiment, an equal amount of the composition is administered at each administration.

[0080] In some embodiments the methods provided herein comprise pretreatment with a composition comprising pridopidine followed by administering a composition comprising at least one HTT lowering agent, wherein, administering the composition comprising at least one HTT lowering agent is administered following 2 weeks, 3 weeks, 4 weeks pretreatment of the composition comprising pridopidine. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt thereof; and the additional composition comprising at least one HTT lowering agent are each administered orally or intrathecally. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one pridopidine’ s analog compound 1 -7 or pharmaceutically acceptable salt thereof; and the additional composition comprising at least one HTT lowering agent are each administered orally or intrathecally.

[0083] In some embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt used for the methods of this invention, comprises pridopidine as the only active material. In other embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 1 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 2 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 3 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 5 or pharmaceutically acceptable salt thereof. In another embodiment, theP-601817-PC composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 6 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof, compound 1 or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof.

[0084] In some embodiments, this invention is directed to a method for treating, preventing, alleviating, delaying symptom onset, or slowing of progression of Huntington disease or one or more symptoms thereof, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0085] In other embodiments, the one or more symptoms of Huntington Disease comprise impairment of functional capacity, impairment of motor function, impairment of cognition, anxiety and depression, elevation in anti-inflammatory biomarkers, reduction in Brain-Derived Neurotrophic Factor (BDNF), increase of neurofilament light chain (NfL), memory impairment, deterioration of structural, functional, and metabolic measures, impairment of quality of life, impairment of a physical symptom, impairment of a mental symptom, disease progression, emotional symptom, behavioral symptoms, lack of initiative, apathy, or irritability, psychiatric symptoms and / or reduced lifespan.

[0086] In another embodiment, the one or more symptoms are measured by Total Functional Capacity (TFC), Unified Huntington's Disease Rating Scale (UHDRS), UHDRS Independence Score (UHDRS-IS), composite UHDRS (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, UHDRS modified Motor Score (mMS), UHDRS-Chorea score, UHDRS-TMS-Dysarthria, UHDRS-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, Huntington Disease Health Index (HD-HI), and Digitomotography (finger tapping) assessment, UHDRS TMS score, UHDRS TMS score minus chorea, UHDRS TMS score minus dystonia, HD-Quality of Life scale (HD- QoL), Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), Problem Behaviors Assessment (PBA) total score, PBA for depressed mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessive-compulsiveness, PBA for disorientedP-601817-PC behavior, Apathy Evaluation Scale (AES), PBA for disoriented behavior, Problem Behaviors Assessment-Short form (PB A-S), PBA short form total score, PBA short form apathy sub-item, Interview-based Impression of Change plus Caregiver Input (CIBIC-Plus), Physical Disability Score (PDS), Functional Assessment (FA), Clinical Global Impression of Change (CGI-C), Clinician Global Impression of Severity (CGI-S), Patient Global Impression of Change (PGI- C), Patient Global Impression of Severity (PGI-S), , abbreviated Montreal Cognitive Assessment (MoCA) scale, Trail Making Test B assessment, EuroQol 5-Dimension 5-Level (EQ-5D-5L), Walk-12, Modified Physical Performance Test (mPPT), trail making test B (TMT-B), HD Cognitive Assessment Battery (HD-CAB), which includes 6 tests, trail Making Test B assessment, Hopkins Verbal Learning Test - Revised (HVLT-R), One Touch Stockings (OTS) of Cambridge (abbreviated), Emotion Recognition, Trail Making B, the Hopkins Verbal Learning test, The Leiter International Performance Scale, and the Peabody Picture Vocabulary Test, Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Patient Health Questionnaire, Center for Epidemiological Studies Depression Scale for Children (CES-DC), Clinically Useful Depression Outcome Scale, Diagnostic Inventory for Depression, Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology, Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, Cornell Scale for Depression in Dementia (CSDD), State-Trait Anxiety Inventory (STAI), Fear Survey Schedule, Beck Anxiety Inventory (BAI), Brief Fear of Negative Evaluation Scale - BFNE, Clinician Administered PTSD Scale (CAPS), Daily Assessment of Symptoms - Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self-Report Version, Social Phobia Inventory (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), or Zung Self- Rating Anxiety Scale, Volumetric magnetic resonance imaging (MRI) of the caudate and putamen, Functional MRI (fMRI), and Metabolic imaging using 18F-fluoro-2-deoxy-D- glucose (18FDG)-PET.

[0087] In some embodiments, this invention is directed to a method for treating, preventing, alleviating, delaying symptom onset, or slowing of progression of Huntington disease or one orP-601817-PC more symptoms thereof, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the disease progression is measured by moving from HD-ISS stage 2 to HD-ISS stage 3. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0088] In some embodiments, this invention is directed to a method for improving, maintaining or reducing impairment of functional capacity, impairment of motor function, cognition and impairment of quality of life in a subject with Huntington Disease comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the functional capacity, motor function, cognition and quality of life are measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

[0089] In some embodiments, this invention is directed to a method for improving, maintaining or reducing impairment of functional capacity, in a subject with Huntington Disease comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the functional capacity is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).

[0090] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of functional capacity in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the functional capacity is measured by evaluation of Total Functional Capacity (TFC) in accordance with the Unified Huntington’s Disease Rating Scale (UHDRS) subscale of Total Functional Capacity (TFC).

[0091] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by the composite Unified Huntington's Disease Ratings Scale (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, Unified Huntington's Disease Rating Scale (UHDRS), the Unified Huntington's Disease Rating ScaleP-601817-PC(UHDRS) modified Motor Score (mMS), the Unified Huntington's Disease Rating Scale (UHDRS)-Chorea score, the Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, The Huntington Disease Health Index (HD-HI), and / or Digitomotography (finger tapping) assessment. In another embodiment, the motor functional impairment is measured by digitomotography (speeded index finger tapping), dysdiadochomotography (pronation / supination hand tapping), manumotography and choreomotography (grip force and chorea analysis), and / or pedomotography (speeded foot tapping).

[0092] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function, wherein the motor function may comprise motor mobility, gait and balance, dystonia, finger tap impairments and / or chorea.

[0093] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function, wherein the motor function comprises gait and balance, bradykinesia, finger tapping, and / or pronation supination.

[0094] In some embodiments this invention is directed to a method of improving, maintaining or reducing impairment of motor mobility in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by UHDRS Total Motor Score (TMS) score, the UHDRS TMS score minus chorea, and / or UHDRS TMS score minus dystonia.

[0095] In some embodiments, this invention is directed to a method of maintaining or reducing the level of dystonia or slowing the worsening of dystonia in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by UHDRS TMS dystonia score.

[0096] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of gait and balance in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by UHDRS TMS gait and balance score.

[0097] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of chorea in a subject with Huntington’s disease, comprisingP-601817-PC administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by UHDRS TMS chorea score.

[0098] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of finger tap speed frequency, finger tap Inter-Onset-Interval, finger tap Inter-Tap-Interval, finger tap inter-peak interval, pronate / supinate hand tapping frequency, hand tapping inter-onset interval, grip force tongue force or any combination thereof in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the motor function impairment is measured by Q-Motor subscales for each mentioned impairment.

[0099] In another embodiment a subject has improved or maintained or lessens the decline in Q- Motor finger tap speed frequency, improved or maintained or lessens the decline in Q-Motor finger tap Inter-Onset-Interval, improved or maintained or lessens the decline in Q-Motor finger tap Inter-Tap-Interval, improved or maintained or lessens the decline in Q-Motor inter-peak interval, improved or maintained or lessens the decline in Q-Motor pronate / supinate hand tapping frequency, improved or maintained or lessens the decline in Q-Motor hand tapping inter-onset interval, improved or maintained or lessens the decline in grip force, decreased tongue force or any combination thereof compared to healthy controls.

[0100] Further provided is a method of improve or maintain or lessen the decline in motor ability as assessed by Q-Motor in a human patient comprising administering to the patient a pharmaceutical composition comprising pridopidine and / or its analog or a pharmaceutically acceptable salt thereof and at least one HTT lowering agent, so as to thereby improve or maintain or lessen the decline in Q-Motor ability in the human patient. In some embodiments, an improvement in motor ability constitutes improved Q-Motor finger tap Inter-Tap Interval, improved or maintained Q-motor inter-peak interval, improved or maintained Q-Motor pronate / supinate hand tapping frequency, improved or maintained Q-Motor hand-tapping interonset interval, improve or maintain or lessen the decline in Q-Motor hand-tapping inter-tapping interval, improve or maintain or lessen the decline in Q-Motor hand-tapping inter-peak interval improve or maintain or lessen the decline in grip force, improved or maintained tongue force or any combination thereof. In some embodiments, this invention is directed to a method of improving, maintaining or learning the decline in a human patient’s behavior and / or psychiatric state in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; andP-601817-PC additional composition at least one HTT lowering agent, wherein the behavior and / or psychiatric state is measured by one or any of the following scales; Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), Problem Behaviors Assessment-Short form (PBA-s), The Problem Behaviors Assessment (PBA) total score, The Problem Behaviors Assessment for depressed mood, The Problem Behaviors Assessment for irritability, The Problem Behaviors Assessment for lack of initiative or apathy, The Problem Behaviors Assessment for obsessive-compulsiveness, or by the Problem Behaviors Assessment for disoriented behavior.Quantitative-Motor (Q-Motor)

[0101] Q-Motor is an objective assessment of specific motor functions that utilizes precalibrated and temperature-independent force transducers and three-dimensional position sensors to provide standardized, unbiased measurements.

[0102] In another embodiment, a subject has improved or maintained or lessens the decline in Q-Motor finger tap speed frequency by a mean or SD of between 5%-50%, improved or maintained or lessens the decline in Q-Motor finger tap Inter-Onset-Interval, improved or maintained or lessens the decline in Q-Motor finger tap Inter-Tap-Interval, improved or maintained or lessens the decline in Q-Motor inter-peak interval, improved or maintained or lessens the decline in Q-Motor pronate / supinate hand tapping frequency, improved or maintained or lessens the decline in Q-Motor hand tapping inter-onset interval, improved or maintained or lessens the decline in grip force, decreased tongue force or any combination thereof compared to healthy controls.

[0103] Further provided is a method of improve or maintain or lessen the decline in motor ability as assessed by Q-Motor in a human patient comprising administering to the patient a pharmaceutical composition comprising pridopidine pridopidine or a pharmaceutically acceptable salt thereof and a composition comprising at least one Htt lowering agent, so as to thereby improve or maintain or lessen the decline in Q-Motor ability in the human patient. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0104] Further provided is a method of improve or maintain or lessen the decline in motor ability as assessed by Q-Motor in a human patient comprising administering to the patient a pharmaceutical composition comprising pridopidine and / or its analog or a pharmaceutically acceptable salt thereof and at least one Htt lowering agent, so as to thereby improve or maintainP-601817-PC or lessen the decline in Q-Motor ability in the human patient. In some embodiments, an improvement in motor ability constitutes improved Q-Motor finger tap Inter-Tap Interval, improved or maintained Q-motor inter-peak interval, improved or maintained Q-Motor pronate / supinate hand tapping frequency, improved or maintained Q-Motor hand-tapping interonset interval, improve or maintain or lessen the decline in Q-Motor hand-tapping inter-tapping interval, improve or maintain or lessen the decline in Q-Motor hand-tapping inter-peak interval improve or maintain or lessen the decline in grip force, improved or maintained tongue force or any combination thereof.

[0105] The invention additionally provides a method of achieving a reduced change from baseline in the Stroop Word test in a human HD patient, comprising administering to the patient a pharmaceutical composition comprising pridopidine and / or its analog or a pharmaceutically acceptable salt thereof and at least one HTT lowering agent, so as to thereby improve or maintain the human patient’s cognitive state

[0106] In some embodiments, this invention is directed to a method of improving, maintaining or learning the decline of cognitive impairments in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the cognitive impairment is measured by one or more of the following scales; The trail making test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), The Leiter International Performance Scale and the Peabody Picture Vocabulary Test, Hopkins Verbal Learning Test - Revised (HVLT-R), One Touch Stockings (OTS) of Cambridge (abbreviated), Emotion Recognition, Trail Making B, the Hopkins Verbal Learning test

[0107] In some embodiments, this invention is directed to a method of maintaining or reducing depression in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the depression is measured by Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Patient Health Questionnaire, Center for Epidemiological Studies Depression Scale for Children (CES-DC), Clinically Useful Depression Outcome Scale, Diagnostic Inventory for Depression, Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology, Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery -P-601817-PCAsberg Depression Rating Scale (MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, or Cornell Scale for Depression in Dementia (CSDD).

[0108] In some embodiments, this invention is directed to a method of maintaining or reducing anxiety in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the anxiety impairment is measured by one of the following anxiety rating scales: the State-Trait Anxiety Inventory (STAI), the problem Behaviors Assessment- Short (PBA-S) scale, the Fear Survey Schedule, Beck Anxiety Inventory (BAI), Brief Fear of Negative Evaluation Scale - BFNE, Clinician Administered PTSD Scale (CAPS), Daily Assessment of Symptoms - Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self-Report Version, Social Phobia Inventory (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), or the Zung Self-Rating Anxiety Scale.

[0109] In some embodiments, behavioral symptoms or psychiatric symptoms may include lack of initiative, apathy, or irritability.

[0110] In some embodiments, this invention is directed to a method of maintaining or reducing apathy in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the apathy impairment is measured by one of the following apathy rating scales: The Problem Behaviors Assessment (PBA) total score, the Problem Behaviors Assessment-short form (PBA-s), The Problem Behaviors Assessment for lack of initiative or apathy, The Problem Behaviors Assessment short form apathy sub-item, The Apathy Evaluation Scale (AES) and The Problem Behaviors Assessment for disoriented behavior.

[0111] In some embodiments, this invention is directed to a method of maintaining or reducing irritability in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein the irritability impairment is measured by one of the following irritability rating scales: The Problem Behaviors Assessment (PBA) total score, the Problem Behaviors Assessment-short form (PBA-s). The human patient'sP-601817-PC behavior and / or psychiatric state may also be measured by the Problem Behaviors Assessment for irritability.

[0112] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of reduction of metabolic measures in the brain in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein metabolic measures is measured by Volumetric magnetic resonance imaging (MRI) of the caudate and putamen, Functional MRI (fMRI), and Metabolic imaging using 18F-fluoro-2-deoxy -D-glucose (18FDG)-PET.

[0113] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of reduction of patient’s quality of life, and reduced lifespan, in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein quality of life is measured by the Resource Utilization in Dementia-Lite (RUD-Lite), EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D), including for example Proxy Version (EQ-5D Proxy).

[0114] In some embodiment, this invention is directed to a method of maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein speech symptom is is measured by UHDRS-TMS-Dysarthria.

[0115] In some embodiments, this invention is directed to a method of delaying the onset of disease progression, stop disease progression or slowing the decline of disease progression in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent, wherein disease progression is measured by Clinical Global Impression of Change (CGIC), Clinical Interview-Based Impression (CIBI), and the Global Deterioration Scale (GDS)In some embodiments of the methods of the invention, the subject has >36 CAG repeats in the Huntingtin gene. In some embodiments of the methods of this invention, the HD subject has been diagnosed as having at least 36 CAG repeats in the huntingtin gene.

[0116] The active compounds for use according to methods provided herein in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e.P-601817-PC physiologically) acceptable salts, deuterated, and pre- or prodrug forms of the compound of the invention.

[0117] In an embodiment, the term “treating Huntington disease” comprises reducing one or more symptoms of Huntington disease.

[0118] In some embodiment, provided herein a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent for use in treating, preventing, alleviating, or slowing of progression of Huntington disease and / or any symptoms thereof in a subject in need thereof. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0119] In some embodiment, provided herein a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and additional composition comprising at least one HTT lowering agent for use in: (i) treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) in improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) in improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) in improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) in maintaining or reducing anxiety and depression in a subject with Huntington Disease; (vi) in slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) in slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) in maintaining or lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) in improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) in delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) in delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) in improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) in maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) in maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) in improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) in slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improvingP-601817-PC lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) in maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; in a subject in need thereof. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0120] In another embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the additional composition comprising at least one HTT lowering agent are administered sequentially or concomitantly in either order.

[0121] In some embodiment, provided herein, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the at least one HTT lowering agent for use in: (i) treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease; (ii) in improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) in improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) in improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) in maintaining or reducing anxiety and depression in a subject with Huntington Disease; (vi) in slowing the increase or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) in slowing the decrease, or increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) in maintaining or lessening the increase of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) in improving, maintaining, or reducing worsening of memory impairment in a subject with Huntington Disease; (x) in delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) in delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) in improving, maintaining, or reducing impairment of quality of life in a subject with Huntington Disease; (xiii) in maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) in maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) in improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) in slowing the worsening or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of slowing the worsening or improving lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of improving or lesseningP-601817-PC the decline of reduced lifespan in a subject with Huntington’s Disease; (xviiii) in maintaining, improving, lessening the decline, or reducing impairment of a speech symptom in a subject with Huntington Disease; in a subject in need thereof.Composition

[0122] In some embodiments, provided herein is a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof for use in the methods of this invention.

[0123] In some embodiments, provided herein a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof for use in the methods of this invention.

[0124] In some embodiments, provided herein is a pharmaceutical composition comprising at least one HTT lowering agent for use in the methods of this invention. In another embodiment, the HTT lowering agent is selected from PTC518, VO659, NanosiRNA, antisense oligonucleotide (ASO), microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof. Each represents a separate embodiment of this invention.

[0125] In some embodiments, provided herein is a pharmaceutical composition comprising at least one HTT lowering agent for use in the methods of this invention.

[0126] In some embodiments, provided herein is a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof, and at least one HTT lowering agent. In another embodiment, the pharmaceutical composition further comprises at least one pridopidine’ s analog compound 1-7.

[0127] In some embodiments, provided herein is a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof, at least one pridopidine’ s analog compound or pharmaceutically acceptable salt thereof and at least one HTT lowering agent.

[0128] In some embodiments, the composition comprising at least one HTT lowering agent provided herein, comprises at least two HTT lowering agent. In some embodiments, the composition comprising at least one HTT lowering agent provided herein, comprises at least three HTT lowering agents.

[0129] In some embodiments, provided herein is a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof, and at least two HTT lowering agents.P-601817-PCIn another embodiment, the pharmaceutical composition further comprises at least one pridopidine’s analog compound 1-7.

[0130] In some embodiments, the methods of this invention comprise administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and administering a composition comprising at least one HTT lowering agent.

[0131] In some embodiment, the methods of this invention comprise administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising at least one HTT lowering agent. In another embodiment, the pharmaceutical composition further comprises at least one pridopidine’s analog compound 1- 7.

[0132] In some embodiment, the methods of this invention comprise administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising HTT lowering agent.

[0133] In some embodiments, the HTT lowering agent provided herein comprises PTC518, antisense oligonucleotide (ASO), VO659, NanosiRNA, microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof.

[0134] In another embodiment, the HTT lowering agent is PTC518.

[0135] In another embodiment, the HTT lowering agent is an antisense oligonucleotide. In another embodiment, the HTT lowering agent is a microRNA. In another embodiment, the HTT lowering agent is a NanosiRNA. In another embodiment, the HTT lowering agent targets mutant HTT . In another embodiment, the HTT lowering agent targets HTT and mHTT . In another embodiment, the HTT lowering agent is selected from tominersen, WVE-003, AMT- 130, VO759, or any combination thereof. In another embodiment, the HTT lowering agent is tominersen. In another embodiment, the HTT lowering agent is WVE-003. In another embodiment, the HTT lowering agent is AMT-130. In another embodiment, the HTT lowering agent is VO659.

[0136] In some embodiments, the HTT lowering agent is any molecule known in the art to target sequences in HTT or mHTT. In some embodiments, the HTT lowering agent specifically targets the following sequences in the HTT mRNA transcript:Target RNA Sequences:P-601817-PC

[0137] In some embodiments, the HTT lowering agent is any ASO known in the art to target sequences in HTT or mHTT. In some embodiments, the HTT lowering agent is an ASO with the following sequence:ASO Sequences

[0138] In some embodiments, the HTT lowering agent is any microRNA known in the art to target sequences in HTT or mHTT . In some embodiments, the HTT lowering agent is any microRNA known in the art to target RNA sequences regulating HTT or mHTT . In some embodiments, the HTT lowering agent is a microRNA with the following sequence: miR SequencesP-601817-PC

[0139] As used herein, an “HTT lowering agent” refers to any molecule, compound, construct, or modality that directly or indirectly reduces the expression, stability, or translation of huntingtin (HTT) or mutant huntingtin (mHTT) transcripts or proteins. Such agents may act at the level of DNA, RNA, or protein.

[0140] Categories of HTT-lowering agents include, but are not limited to:

[0141] Nucleic acid-based agents• Antisense oligonucleotides (ASOs): synthetic single-stranded oligonucleotides that bind complementary HTT or mHTT RNA sequences and reduce expression through RNase H-mediated cleavage, splicing modulation, or translational inhibition.• siRNA / shRNA / RNAi molecules: double-stranded RNA or hairpin constructs that trigger RISC-mediated cleavage of HTT or mHTT transcripts.• microRNAs: endogenous or engineered miRNAs that target HTT or mHTT mRNA or regulatory elements thereof.• CRISPR-based agents: guide RNAs and associated nucleases (e.g., Cas9, Casl3) engineered to degrade or edit HTT / mHTT DNA or RNA.• Other nucleic acid analogs: including but not limited to morpholinos, locked nucleic acids (LNA), peptide nucleic acids (PNA), and gapmers.

[0142] Small-molecule agentsCompounds known to reduce HTT / mHTT expression or aggregation by modulating transcription, splicing, translation, or degradation pathways (e.g., splicing modulators such as PTC518, branaplam).

[0143] Biologic agents• RNA-binding proteins, engineered nucleases, or zinc finger repressors designed to bind HTT transcripts and reduce their expression.• Antibodies or antibody-like molecules that facilitate degradation of HTT or mHTT protein via proteasome or lysosome pathways.• Other modalities Any gene therapy, viral vector, or delivery platform (AAV, lipid nanoparticles, etc.) that delivers one or more of the above agents.P-601817-PC• Any agent that indirectly lowers HTT / mHTT levels by destabilizing its mRNA or enhancing its protein degradation.•

[0144] Specific Sequences:The invention further encompasses the specific RNA target sequences (SEQ ID NO: 1-6), ASOs (SEQ ID NO:7-11), and microRNA (SEQ ID NO: 12) as exemplary embodiments of HTT-lowering agents.

[0145] In another embodiment, the composition comprising at least one HTT lowering agent comprises between 0.05-99.95% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-10% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-20% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-30% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.5-2% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.5-5% w / w of HTT lowering agent. In another embodiment, the composition comprises between 1-5% w / w of HTT lowering agent. In another embodiment, the composition comprises between 1-10% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05- 2, 0.05-5, 0.05-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-99.95% w / w of HTT lowering agent or any ranges thereof. Each represents a separate embodiment of this invention.

[0146] In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and at least one HTT lowering agent, comprises between 0.05-99.95% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05- 10% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-20% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-30% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.5-2% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.5-5% w / w of HTT lowering agent. In another embodiment, the composition comprises between 1-5% w / w of HTT lowering agent. In another embodiment, the composition comprises between 1-10% w / w of HTT lowering agent. In another embodiment, the composition comprises between 0.05-2, 0.05-5, 0.05-10, 10-20, 20-30, 30- 40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-99.95% w / w of HTT lowering agent or any rangesP-601817-PC thereof. Each represents a separate embodiment of this invention. In another embodiment, the composition further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0147] In another embodiment, the composition comprising a HTT loweing agent comprises about 0.05, 0.2, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98% w / w or any ranges thereof of HTT lowering agent.

[0148] In another embodiment, the composition comprising pridopidine of pharmaceutically acceptable salt thereof, optionally further comprises at least one of pridopidine’s analog compound 1-7 as represented by the following structures:

[0149] In another embodiment, the composition for use in the methods of this invention comprises pridopidine or pharmaceutically acceptable salt thereof.

[0150] In another embodiment, the composition for use in the methods of this invention comprises pridopidine or pharmaceutically acceptable salt thereof and at least one of pridopidine’s analog compounds 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 1 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof, compound 1 and compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, theP-601817-PC composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 2 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 3 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 5 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 6 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 1, 2, 3, 4, 5, 6, 7 or a pharmaceutically acceptable salt thereof or any combination thereof.

[0151] In another embodiment, the pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt and at least one of pridopidine’ s analog compounds 1-7 or pharmaceutically acceptable salt thereof for use in the methods of this invention, comprises between 0%-10% w / w of each of the pridopidine’ s analog compound relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.005%-5% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.001%-l% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.05%-3% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.005%-0.1% w / w, 0.05%-0.1% w / w, 0.05%-0.15% w / w, 0.05%-0.2% w / w, 0.05%-0.5% w / w, 0.05%-2% w / w, 0.05%-3% w / w, 0.05%-4% w / w, 0.05%- 5% w / w, 0.1%-0.4% w / w, 0.15%-0.3% w / w, 0.15%-0.5 % w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. Each represents a separate embodiment of this invention.

[0152] In another embodiment, the pharmaceutical composition comprising pridopidine of pharmaceutically acceptable salt thereof comprises between 0.05 - 90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 10-90% w / w pridopidine or pharmaceutical acceptable saltP-601817-PC thereof. In another embodiment, the pharmaceutical composition comprises between 20-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 30-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 40-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 50-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 60-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 70-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 80-90% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition provided herein comprises between 0.05 - 99.95% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises between 0.05 - 99.95% w / w, 1-20% w / w, 5-20% w / w, 5-30% w / w, 10-99.95% w / w, 20-99.95% w / w, 30- 99.95% w / w, 40-99.95% w / w, 50-99.95% w / w, 60-99.95% w / w, 70-99.95% w / w, 80-99.95% w / w, 90-99.95% w / w pridopidine or pharmaceutical acceptable salt thereof. Each represents a separate embodiment of this invention. In another embodiment, the pharmaceutical composition comprises about 10, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98% w / w pridopidine or pharmaceutical acceptable salt thereof. Each represents a separate embodiment of this invention. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0153] In another embodiment, the pharmaceutical composition comprises about 70% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises about 80% w / w pridopidine or pharmaceutical acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises about 90% w / w pridopidine or pharmaceutical acceptable salt thereof.

[0154] In some embodiments, the composition comprising pridopidine or pharmaceutically acceptable salt thereof comprises between 10 mg to 300 mg pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition of this invention comprises between 10 mg to 150 mg pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition of this invention comprises between 10 mg to 90 mg pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition of thisP-601817-PC invention comprises between 10 mg to 45 mg pridopidine or pharmaceutically acceptable salt thereof. In some embodiments, the composition of this invention comprises between 10 mg to 22.5 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises between 10-22.5, 10-45, 10-50, 10-67.5, 10-90, 10-100, 10-125, 10-150, 10-250, 50-300, 50-100, 50-150, 50-250, 100-300, 100-200, 150-300 mg of pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition of this invention comprises about 10, 20, 22.5, 25, 30, 40, 45, 50, 60, 67.5 70, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300 mg of pridopidine or pharmaceutically acceptable salt thereof or any ranges thereof. Each represents a separate embodiment of this invention.

[0155] In some embodiments, the composition provided herein comprises pridopidine, and optionally at least one analog compound 1-7 in an amount of between 10 mg and 150 mg pridopidine or pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the composition provided herein comprises pridopidine and optionally at least one analog compound 1-7 in an amount of between 10 mg and 100 mg pridopidine or pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the composition comprising at least one HTT lowering agent comprises between 1 mg and 100 mg PTC518. In another embodiment, the composition comprises between 1 mg and 30 mg PTC518. In another embodiment, the composition comprises between 1-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-100 mg PTC518. Each represents a separate embodiment of this invention.

[0158] In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent within the composition or methods of use thereof is from about 1 :99 to about 99:1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1 :70 to about 70:1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1 :60 to about 60: 1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1 :50 to about 50: 1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1 :20 to about 20: 1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1 :10 to about 10: 1. In another embodiment, the weight ratioP-601817-PC between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is from about 1:5 to about 5:1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more HTT lowering agent is 20:1, 19: 1, 18:1, 17: 1, 16: 1, 15:1, 14: 1, 13: 1, 12:1, 11: 1, 10: 1, 9: 1, 8:1, 7:1, 6: 1, 5: 1, 4:1, 3:1, 2:1, 1 :1, 1:2, 1:3, 1 :4, 1:5, 1 :6, 1 :7, 1:8, 1 :9, 1 :10, 1 :11, 1 :12, 1 :13, 1 :14, 1 :15, 1 :16, 1 :17, 1 :18, 1 :19, 1 :20. Each represent a separate embodiment of this invention.

[0159] In some embodiments, the combination treatment provided herein results in reduced doses of at least one of the active agents (drugs) when administered alone.

[0160] In some embodiments, the pridopidine and / or the pridopidine’ s analog compound (each compound 1-7) of pharmaceutical composition of this invention, are each in the form of a salt. In another embodiment, the salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid-phosphate, sulphate, bisulfate, formate, gluconate, glucaronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisinate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate, and toluene-p-sulfonate and pamoate (i.e., l,l'-methylene-bis- (2 -hydroxy-3 -naphthoate)) salt. Each represents a separate embodiment of this invention. In another embodiment, the pridopidine is in the form of HC1 salt. In another embodiment, the pridopidine’ s analog compound is in the form of HC1 salt.

[0161] In some embodiments, the pharmaceutical composition provided herein is formulated with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients known and used in the art. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[0162] In some embodiments, the pharmaceutical composition provided herein is formulated together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0163] In some embodiments, the pharmaceutical composition for use in the methods of this invention comprises one or more pharmaceutically acceptable carriers or excipients.

[0164] In some embodiments, the pharmaceutically acceptable carriers or excipients are selected from a group consisting of: binder, filler, plasticizer, glidant and lubricant and mixtures thereof.P-601817-PC

[0165] In some embodiments, the binder is selected from a group consisting of starch, pregeletinized starch, polyethylene oxide, cellulose polymers, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.

[0166] In some embodiments, the filler is selected from a group consisting of microcrystalline cellulose, sugar spheres, lactose, sorbitol, dextrose, sucrose, mannitol, dibasic or tribasic calcium phosphate, calcium sulfate, starch, retalac and mixtures thereof.

[0167] In some embodiments, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.

[0168] In some embodiments, the filler is lactose. In another embodiment, the filler is a mixture of microcrystalline cellulose and lactose, and wherein the microcrystalline cellulose and is a silicified microcrystalline cellulose. In an embodiment, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.

[0169] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose and magnesium stearate as excipients.

[0170] In some embodiments, the lubricant is selected from a group consisting of: sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.

[0171] In some embodiments, the lubricant is magnesium stearate.

[0172] In some embodiments, the glidant is selected from a group consisting of starch, pregelatinized starch, silicone dioxide, colloidal silicone dioxide, talc and mixtures thereof.

[0173] In some embodiments, the glidant is colloidal silicone dioxide.

[0174] The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of administration include oral administration, in tablet, in capsule, in beads, minitablets, multiparticulates, in powder, or in liquid form, and parenteral administration, cutaneous, ophthalmic, eye drops, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

[0175] In some embodiments, multiarticulate or multiple unit dosage forms are the discrete, small, repetitive units of drug particles which may or may not possess similar drug release pattern.P-601817-PC

[0176] The active compounds for use according to methods provided herein in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts, deuterated, and pre- or prodrug forms of the compound of the invention.

[0177] In one embodiment, the HD subject is a pre-symptomatic HD subject. In one embodiment, the HD subject is a prodromal HD subject. In one embodiment, the HD subject is a juvenile HD subject. In one embodiment, the HD subject is an earlier stage HD subject. In one embodiment, the HD subject is mild to moderate HD subjects (baseline TFC 7-13). In one embodiment, the HD subject is HD1 subject. In one embodiment, the HD subject is HD1 and HD2 subject. In one embodiment, the HD subject is the later stage HD subject. In one embodiment, the HD subject is HD3 (TFC 3-6) subject. In one embodiment, the HD subject is HD4 (TFC 0-2) subject.

[0178] In one embodiment, the HD subject is in HD-ISS stage 0. In one embodiment, the HD subject is in HD-ISS stage 1. In one embodiment, the HD subject is in HD-ISS stage stage 2, In one embodiment, the HD subject is in HD-ISS stage 4.

[0179] As used herein, an amount of pridopidine as measured in milligrams refers to the milligrams of pridopidine (4-[3-(methylsulfonyl) phenyl]-l-propyl-piperidine) present in a preparation, regardless of the form of the preparation. For example, a unit dose containing “90 mg pridopidine” means the amount of pridopidine base in a preparation is 90 mg, regardless of the form of the preparation. Thus, when in the form of a salt, e.g. pridopidine hydrochloride, the weight of the salt form necessary to provide a dose of 90 mg pridopidine would be greater than 90 mg due to the presence of the salt.

[0180] As used herein, “effective” as in an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of this disclosure. For example, an amount effective to treat a movement disorder. The specific effective amount varies with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

[0181] As used herein to “treat” or "treating" encompasses, e.g., reducing a symptom, inducing inhibition, regression, or stasis of the disorder and / or disease. As used herein, “inhibition” ofP-601817-PC disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[0182] The term “about” in reference to a numerical value stated herein is to be understood as the stated value + / - 10%.

[0183] The term “pharmaceutical acceptable salt” refers to a salt selected from the group comprising of hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid- phosphate, sulphate, bisulfate, formate, gluconate, glucaronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisinate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate, and toluene-p-sulfonate and pamoate (i.e., 1, l'-methylene-bis-(2 -hydroxy-3 -naphthoate)) salt.EXAMPLESExample 1. An in vitro study to assess HTT lowering and protective effects of pridopidine in combination with an anti HTT ASO.

[0184] Mutant HTT lowering and protective effects of pridopidine alone and in combination with a known HTT lowering strategy is assessed in a preclinical in vitro study. The study is conducted in two parts. Part I directly assesses protein levels of both wild-type HTT and mutant HTT after pridopidine treatment alone and in combination with an ASO specifically targeting the HTT mRNA transcript. Part II assesses the efficacy of pridopidine alone or in combination with a known HTT lowering ASO to promote cell survival in response to oxidative stress.

[0185] In part I, human embryonic stem cells (hESC) from HD donors carrying the mutant HTT gene with >36 CAG repeats are treated for 72 hours with either increasing concentrations of pridopidine, increasing concentrations of anti HTT ASO, or combinations of pridopidine and the ASO. After the 72-hour treatment, cells are lysed and protein levels of wild-type HTT and mutant HTT are assessed using antibodies specific for the respective Htt proteins.

[0186] Part II of the study assesses the protective effects of pridopidine in combination with an anti HTT ASO. HD hESC cells expressing mutant HTT are sensitive to oxidative stress and will undergo cell death in response to increased oxidative stress. Hydrogen peroxide (H2O2) is used to induce oxidative stress in HD hESCs. Stressed HD hESCs are treated with eitherP-601817-PC pridopidine, an anti HTT ASO, or a combination of pridopidine and the ASO. Cell viability is assessed after hydrogen peroxide-induced stress.Example 2. In vitro study assessing the effects of Pridopidine and an Htt-lowering agent, alone and in combination, on mutant Htt expression and mitochondrial function in an HD cell model

[0187] This study utilizes an HD cellular model of Neuro-2a mouse neuroblastoma cells overexpressing the pathogenic Exon 1 of the human huntingtin gene with 73 CAG repeats (mHTT). The model was used to evaluate the effect of pridopidine and an HTT-lowering agent alone, and in combination on mHtt protein levels (part I) and on Mitochondrial membrane potential (MMP) (Part II). The (CUG)? ASO is a short synthetic antisense oligonucleotide specifically designed to hybridize to the expanded CAG repeat region in mutant HTT mRNA. Preclinical models show that it can selectively reduce mHTT (

[0019] ,

[0020] ).

[0188] (CUG)? ASO -CAG-repeat targeting antisense oligonucleotide. The antisense oligonucleotide used in the experiments was the (CUG)7 oligoribonucleotide, with the sequence 5'-CUGCUGCUGCUGCUGCUGCUG-3'. This ASO was specifically designed to selectively bind to expanded CAG repeat tracts, such as those present in exon 1 of the human huntingtin (HTT) transcript carrying 73 CAG repeats, cloned in-frame with EGFP (mHTT- 73Q-Exonl-EGFP) under the control of the EFla promoter.Part I: The effect of pridopidine and HTT-lowering ASO [(CUG)?] alone, and in combination of mHtt protein levels

[0189] Neuro-2a mouse neuroblastoma cells overexpressing the truncated exon 1 of the huntingtin gene with 73 CAG repeats (mHTT-Exonl-73Q construct) were treated for 24 hours with varying concentrations of pridopidine, (CUG)? ASO, or their combination. mHtt protein levels were then quantified by Western blot analysis.

[0190] Western blot analysis (Figure 1A) demonstrates the expression of mHtt protein in Neuro-2a cells transfected with the mHTT-Exonl-73Q construct. Treatment with pridopidine (1 pM) for 24 hours resulted in a 28% reduction of mHtt protein levels while treatment with the (CUG)? ASO (5 ng / million cells) reduced mHtt levels by 52%, compared to untreated cells. Importantly, the combination treatment of pridopidine and the (CUG)? ASO showed a synergistic effect, leading to a robust 86% reduction in mHtt protein levels compared to untreated mHtt-expressing cells (Figures 1 A and IB).P-601817-PCPart II: Mitochondrial membrane potential (MMP) impairment by mHTT and rescue by combination therapy

[0191] To assess mitochondrial function, the same Neuro-2a mouse neuroblastoma cells were cultured under standard conditions and transfected with the mHTT construct containing 73 CAG repeats (mHTT-Exonl-73Q-EGFP).

[0192] Cells were treated with 1 pM Pridopidine, 5 ng / million cells of (CUG)? ASO, or their combination. Treatments were applied for 12 hours following 12-hour pre-treatment with 5 pM tunicamycin to induce ER stress. MMP assay was conducted at the end of the 24 hour experiment

[0193] As shown in Figure 2, Neuro-2a cells untransfected (WT, no mHTT overexpression) show 27% reduction (=73% MMP activity) in mitochondrial function as measured by MTT assay, after tunicamycin-induced ER stress. In contrast, neuro2a cells overexpressing mHTT show 77% reduction (=23% MMP activity) in mitochondrial function as measured by MMP assay, after tunicamycin-induced ER stress. This highlights the increased vulnerability of mHTT-expressing cells to ER stress, indicating that expression of mutant huntingtin significantly compromises mitochondrial integrity.

[0194] To determine whether therapeutic intervention can rescue mitochondrial function, mHTT-transfected cells were treated with pridopidine (1 pM), (CUG)? ASO (5 ng / million cells), or their combination following ER stress induction. As shown in Figure 3, pridopidine alone partially restored MMP by 28%, and (CUG)? ASO alone by 10%, while the combination treatment produced a synergistic effect, improving MMP by 48%.

[0195] Together, these results demonstrate that the combination of pridopidine and the (CUG)? ASO exerts a synergistic effect in reducing mHTT protein levels and restoring mitochondrial membrane potential under ER stress conditions in mHTT-expressing cells.Example 3. An in vitro study to assess the effects of pridopidine and an HTT-lowering agent alone and in combination on mutant HTT levels and cell viability in human HD iPSCs

[0196] This study utilizes HD iPSCs (>36 CAG repeats in the HTT gene) derived into neural progenitor cells (NPCs), to evaluate the effect of pridopidine and an HTT-lowering agent alone, and in combination on mHTT levels (part I) and on cell viability (Part II).P-601817-PCPart I

[0197] HD iPSCs are differentiated into NPCs, and treated with increasing concentrations of pridopidine alone, increasing concentrations of HTT-lowering agent alone, or in combinations for 18 hours. After treatment, the expression levels of HTT and mHTT are determined by quantitative PCR, Western blot analysis and FACS assay.Part II

[0198] HD iPSCs are differentiated into NPCs and treated with 1.25uM tunicamycin for 12 hours to induce oxidative stress and cell death. Stressed cells are treated with pridopidine alone, HTT-lowering agent alone, and in combination for 12 hours. Number of live cells (% cell viability) will be assessed using a quantitative FACS assay.Example 4: In vivo evaluation of pridopidine and an HTT lowering agent in HD mice

[0199] HD model mice are treated with pridopidine, a HTT lowering agent or a combination of pridopidine and HTT lowering agent. After completing treatment, mice are assessed for motor function (i.e. rotarod, open field test, gait analysis, climbing test), cognitive function (i.e. Morris Water Maze) and behavioral function (forced swim test, elevated maze, marble burying). The combination of pridopidine and HTT lowering agent demonstrates a beneficial effect vs. pridopidine or the HTT lowering agent alone. Tissues are collected from HD mice following treatment for assessment of aggregation of HTT and mHTT. Biofluids are collected for assessment of HTT and mHTT levels. The combination of pridopidine and an HTT lowering agent demonstrates a beneficial effect on HTT and mHTT reduction. The combination also demonstrates a beneficial effect on other fluid biomarkers (i.e., neurofilament light protein).Example 5: Clinical study evaluating the effect of pridopidine in combination with HTT lowering agent in subjects with HD

[0200] The safety and efficacy of pridopidine in combination with a HTT lowering agent is assessed in HD subjects (baseline TFC 7-13) or in subjects who are at HD-ISS stage 2 and 3. Subjects are treated with either pridopidine, the HTT lowering agent, or a combination of the two for a period of 12, 26, 52, 39, 65 or 78 Weeks. Efficacy and safety are evaluated at 12, 26, 39 52, 65 and 78 weeks. Efficacy is evaluated by time to decline from HD-ISS stage 2 to HD- ISS stage 3, the UHDRS-TFC scale, the UHDRS-TMS scale, cUHDRS scale, Cognition (SWR SDMT) scales, Quality of life scale, the PBA-S scale, Stroop Word Reading, Symbol Digits Modalities Test and Q-Motor tests. The effect of pridopidine and a HTT lowering agent is alsoP-601817-PC assessed on HTT and mHTT protein levels in biofluids (i.e blood, serum, plasma, or CSF), as well as their effect on biomarkers (for example. ,NfL, BDNF). The effect of pridopidine and a HTT lowering agent is also assessed on imaging biomarkers (i.e., striatal, putamen, cortical and ventricular volume in the brain).P-601817-PCREFERENCES CITED:1. Mahant N, McCusker EA, Byth K, Graham S. Huntington’s disease: Clinical correlates of disability and progression. Neurology. 2003.2. Tabrizi SJ, Reilmann R, Roos RAC, Durr A, Leavitt B, Owen G, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: Analysis of 24-month observational data. Lancet Neurol. 2012.3. Tabrizi SJ, Scahill RI, Owen G, Durr A, Leavitt BR, Roos RA, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: Analysis of 36-month observational data. Lancet Neurol. 2013.4. S. J. Tabrizi; R. Ghosh; B. R. Leavitt, Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease. Neuron, 2019, Vol 101 (5), 801-819.5. Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: A randomized clinical trial. JAMA - J Am Med Assoc. 2016.6. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington’s and Other Diseases. Tremor Other Hyperkinet Mov (N Y). 2013.7. Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savoia J-M, et al. Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques. Mov Disord [Internet], 2018 Dec 21 [cited 2019 Mar 11]; Available from: http: / / doi.wiley.com / 10.1002 / mds.275658. Hayashi T, Su T-. The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology. Curr Neuropharmacol. 2005; 3(4):267-80.9. Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends in Pharmacological Sciences. 2010.10. Geva M, Kusko R, Soares H, et al. Pridopidine activates neuroprotective pathways impaired in Huntington Disease. Hum Mol Genet 2016; 25: 3975-3987.11. Ryskamp D, Wu L, Wu J, et al. Pridopidine stabilizes mushroom spines in mouse models of Alzheimer’s disease by acting on the sigma- 1 receptor. Neurobiol Dis 2019; 124: 489-504.P-601817-PC12. Francardo V, Geva M, Bez F, et al. Pridopidine Induces Functional Neurorestoration Via the Sigma- 1 Receptor in a Mouse Model of Parkinson’s Disease. Neurother J Am Soc Exp Neurother 2019; 16: 465-479.13. Naia L, Ly P, Mota SI, et al. The Sigma- 1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models. Neurother J Ara Soc Exp Neurother 2021; 18: 1017-1038.14. Shenkman M, Geva M, Gershoni-Emek N, et al. Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma- 1 receptor. J Neurochem 2021; 158: 467-481.15. Lenoir S, Lahaye RA, Vitet H, et al. Pridopidine rescues BDNF / TrkB trafficking dynamics and synapse homeostasis in a Huntington disease brain-on-a-chip model. Neurobiol Dis 2022; 173: 105857.16. Wang S-M, Wu H-E, Yasui Y, et al. Nucleoporin P0M121 signals TFEB-mediated autophagy via activation of SIGMAR 1 / sigma- 1 receptor chaperone by pridopidine. Autophagy 2023; 19: 126-151.17. Smith-Dijak Al, Nassrallah WB, Zhang LYJ, Geva M, Hayden MR, Raymond LA. Impairment and restoration of homeostatic plasticity in cultured cortical neurons from a mouse model of huntington disease. Front Cell Neurosci. 2019.18. Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma- 1 receptor. Neurobiol Dis. 2019.19. Datson NA, Gonzalez -Barriga A, Kourkouta E, Weij R, van de Giessen J, Mulders S, Kontkanen O, Heikkinen T, Lehtimaki K, van Deutekom JC. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One. 2017 Feb 9;12(2):e0171127. doi:10.1371 / joumal. pone.0171127. PMID: 28182673; PMCID: PMC5300196.20. Ou K, Jia Q, Li D, Li S, Li XJ, Yin P. Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease. Transl Neurodegener. 2025 Jan 21;14(1):4. doi: 10.1186 / s40035-025-00466-9. PMID: 39838446; PMCID: PMC11748355.

Claims

P-601817-PCCLAIMSWhat is claimed is1. A method of treatment, prevention, alleviation, delaying symptom onset, or slowing progression of Huntington disease and / or symptoms thereof in a subject in need thereof comprising administering a pharmaceutically effective amount of a composition comprising of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising at least one HTT lowering agent.

2. The method of claim 1, wherein the method comprises administering a composition comprising at least two HTT lowering agents.

3. The method of claim 1 or claim 2, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises at least one pridopidine’ s analog compound 1-7 represented by the following structures:

4. The method of claim 3, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 1 or pharmaceutically acceptable salt thereof.

5. The method of claim 3, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 4 or pharmaceutically acceptable salt thereof.

6. The method of claim 3, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, further comprises compound 1 andP-601817-PC compound 4 or pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1-6, wherein the HTT lowering agent is selected from PTC518, antisense oligonucleotide (ASO), VO659, NanosiRNA, microRNA (miRNA), small interfering RNA (siRNA), tominersen, WVE-003, AMT-130 or any combination thereof.

8. The method of any one of claims 1-7, wherein the HTT lowering agent is PTC518.

9. The method of any one of claims 1-7, wherein the HTT lowering agent is an antisense oligonucleotide (ASO).

10. The method of any one of claims 1-7, wherein the HTT lowering agent is a microRNA.

11. The method of any one of claims 1-10, wherein the disease progression is measured by moving from HD-ISS stage 2 to HD-ISS stage 3.

12. The method of any one of claims 1-11, wherein the treatment comprises improving, maintaining or reducing impairment of one or more symptoms in a human patient afflicted with Huntington’s disease.

13. The method of claim 12, wherein the symptoms of Huntington’s disease comprise impairment of physical symptom, mental symptom, emotional symptom, behavioral symptoms, functional capacity, motor function impairment, cognition impairment, memory impairment, anxiety and depression, speech impairment, lack of initiative, apathy, irritability, psychiatric symptoms, elevation in anti-inflammatory biomarkers, reduction in Brain-Derived Neurotrophic Factor (BDNF), increase of neurofilament light chain (NfL). deterioration of structural, functional, and metabolic measures in the brain, reduction in a patient’s quality of life, and reduced lifespan.

14. The method of claim 12 or claim 13, wherein human patient's functional capacity is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).

15. The method of claim 12 or claim 13, wherein the functional capacity, motor function, cognition and quality of life is measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

16. The method of claim 12 or claim 13, wherein the motor function impairment is measured by the composite Unified Huntington's Disease Ratings Scale (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, the Unified Huntington's Disease Rating Scale (UHDRS) the Unified Huntington's Disease Rating Scale (UHDRS) modified Motor Score (mMS), the Unified Huntington's DiseaseP-601817-PCRating Scale (UHDRS)-Chorea score, the Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia score, the Unified Huntington's Disease Rating Scale (UHDRS)- gait and balance, , eye movement score, hand movement score, score, timed up and go (TUG) assessment, The Huntington Disease Health Index (HD-HI), Digitomotography (finger tapping) assessment.

17. The method of claim 12 or claim 13, wherein the motor functional impairment measured by digitomotography (speeded index finger tapping), dysdiadochomotography (pronation / supination hand tapping), manumotography and choreomotography (grip force and chorea analysis) and pedomotography (speeded foot tapping).

18. The method of claim 12 or claim 13, wherein the patient's mental symptom, emotional symptom, behavioral symptoms, cognition impairment is measured by one or more of the following scales; Problem Behaviors Assessment (PBA) total score, PBA for depressed mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessive-compulsiveness, or by PBA for disoriented behavior, the trail making test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), trail making test B assessment, Hopkins Verbal Learning Test - Revised (HVLT-R), One Touch Stockings (OTS) of Cambridge (abbreviated), Emotion Recognition, Trail Making B, the Hopkins Verbal Learning test, Hamilton Rating Scale for Depression (HAM-D), Problem Behaviors Assessment-Short (PBA-S) scale, PBA short form apathy sub-item, Apathy Evaluation Scale (AES). Hamilton Anxiety Scale (HAM- A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self-Report Version, Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), cognitive assessment battery (CAB).

19. The method of any one of claims 1-18, wherein the treatment comprises reducing, lessening the increase or maintaining the concentration of neurofilament light protein.

20. The method of any one of claims 1-6, wherein the pridopidine and optionally at least one analog compound of pridopidine is in the form of a salt thereof.

21. The method of claim 20, wherein the salt is selected from the group consisting from hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid- phosphate, sulphate, bi sulfate, formate, gluconate, glucaronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate,P-601817-PC citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisinate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2- sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate, and toluene-p-sulfonate, pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salt.

22. The method of claim 21, wherein the pridopidine salt is pridopidine hydrochloride.

23. The method of any one of claims 1-22, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the composition comprising at least one HTT lowering agent are each independently administered or through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.

24. The method of any one of claims 1-23, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the composition comprising at least one HTT lowering agent are each orally administered.

25. The method of any one of claims 1-24, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the composition comprising at least one HTT lowering agent are administered sequentially or concomitantly in either order.

26. The method of any one of claims 1-25, wherein the pridopidine is administered at a daily dose of between 10 mg / day to 300 mg / day.

27. The method of any one of claims 1-26, wherein the pridopidine is administered at a daily dose of between 10 mg / day to 150 mg / day.

28. The method of any one of claims 1-27, wherein the pridopidine is administered at a daily dose of between 10 mg / day to 90 mg / day.

29. The method of any one of claims 1-28, wherein the pridopidine is administered at a daily dose of about 22.5 mg / day, 22.5 mg bid, 45 mg / day, 45 mg bid, or 90 mg / day.

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