Pridopidine and sigma 2 antagonist agent for treating huntington disease and symptoms thereof

Abstract

Provided herein a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one composition comprising sigma 2 antagonist agent.

Description

PRIDOPIDINE AND SIGMA 2 ANTAGONIST AGENT FOR TREATING HUNTINGTON DISEASE AND SYMPTOMS THEREOFFIELD OF THE INVENTION

[0001] This invention is directed to a method for the treatment, prevention, or alleviation Huntington disease and / or symptoms thereof in a subject, comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and a composition comprising sigma 2 antagonist agent.BACKGROUND OF THE INVENTIONHuntington disease

[0002] 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], 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],

[0003] The HD includes five stages:

[0004] 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.

[0005] HD2 (TFC 7-10), 3-13 years after onset. Early intermediate stage. Patient is still functional at work, but at a lower capacity.

[0006] HD3 (TFC 3-6) 5-16 years after onset. Late intermediate stage. Patient can no longer conduct work or manage household responsibilities.

[0007] 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.

[0008] HD5 (TFC 0) 11-26 years after onset, advanced stage. Patients need total support in daily activities from professional nursing care.

[0009] 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] Several medications are prescribed to ameliorate the motor and emotional problems associated with HD. However, there is little scientific evidence for the usefulness of various drugs in HD [5,6], Only three drugs, tetrabenazine, deutetrabenazine and valbenazine 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 [7,8], As such, there is a significant unmet medical need to develop medications to ameliorate symptoms of HD, and to delay disease progression.Pridopidine

[0010] Pridopidine (4-[3-(methylsulfonyl)phenyl]-l-propyl-piperidine) is a highly selective SIR ligand with Ki= 57 nM and S2R Ki of 5450 nM [9], Thus, pridopidine has 95-fold higher affinity for the SIR vs the S2R and is a highly selective SIR ligand.

[0011] 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 [10,11],

[0012] Pridopidine exerts neuroprotective effects, exquisitely mediated via activation of the SIR, as demonstrated in non-clinical models of HD and other neurodegenerative diseases [29- 35], Specifically, pridopidine improves key pathophysiological pathways implicated in HD including rescue of mitochondrial-associated membrane (MAM) disruption

[0032] , enhancement of brain-derived neurotrophic factor secretion and signaling [29,34], restoration of aberrant calcium signaling, rescue of synaptic plasticity and neuronal spine abnormalities

[0014] , enhancement of autophagy, upregulation of mitochondrial function

[0032] , reduction of ER and oxidative stress

[0033] , and rescue of mutant HTT-induced cell death

[0012] , All these effects are mediated by the SIR, as either genetic deletion of the SIR gene, or pharmacological SIR inhibition completely abolishes pridopidine’ s effect.Sigma 2 antagonist agents

[0013] The S2R (Sigma 2 receptor) is a transmembrane receptor, also known as transmembrane protein 97 (TMEM97). Within the brain, S2R is found in several areas, including the cerebellum, cortex, hippocampus, and substantia nigra, and is enriched in neurons. Activation of the S2R-induces cell death via multiple signaling pathways: caspase 3 activation, impaired cell cycle, and impaired autophagy while inhibition (antagonism of the S2R) exerts neuroprotection

[0017] ,SUMMARY OF THE INVENTION

[0014] In some embodiments, this invention is directed to a method of treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease in a subject in need thereof comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one composition comprising sigma 2 antagonist agent.

[0015] In another embodiment, the sigma 2 antagonist agent is selected from CT1812, JVW- 1009, SM-21, CT01344, DKR-1677, SAS-0132,

[0125] RHM-4, or combination thereof.

[0016] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof further comprises at least one of pridopidine’ s analog compounds 1-7, represented herein below:BRIEF DESCRIPTION OF THE DRAWINGS

[0017] 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:Figure 1 presents pridopidine in combination with FA10 provides enhanced neuroprotection.FA10 combined with low doses of pridopidine demonstrated enhanced protection against mHTT-induced cell toxicity. Escalating doses of FA10 (OnM, O. lnM, InM, and 3nM) were combined with increasing concentrations of pridopidine (OpM, 0.001 pM, 0.01 pM, 0.1 pM, and 1 pM) and the combination effect was evaluated in primary neurons transfected with either control HTT (N586-22Q) or mHTT (N586-82Q) as mentioned above. Vehicle-treated control HTT neurons were used as a control. Cell death was evaluated by nuclear condensation assay, and fold toxicity was normalized to vehicle-treated control HTT neurons (N586-22Q, OnM FA10, OpM pridopidine). One-way ANOVA (F(20,96) = 9.615; p<0.0001) with Dunnett’s multiple comparisons was used for statistical analysis. ####p<0.0001 vs control HTT (N586- 22Q) vehicle group; *p<0.05 vs mHTT (N586-82Q) vehicle group; **p<0.01 vs mHTT (N586- 82Q) vehicle group; ****p<0.0001 vs mHTT (N586-82Q) vehicle group. N=3.Figure 2 presents optimal doses of combination of pridopidine and FA10 providing improved neuroprotective effect. The effect of the combination of optimal doses of FA10 and pridopidine on mHTT-induced cell toxicity was tested in the HD cell model. The optimal dose of FA10 (0.003 pM) was combined with an optimal dose of pridopidine (IpM), and the combination effect was evaluated in primary neurons transfected with either control HTT (N586-22Q) or mHTT (N586-82Q) as mentioned above. Vehicle-treated wild-type neurons expressing control HTT (N586-22Q) were used as a negative control. Cell death wasevaluated by nuclear condensation assay and fold toxicity was normalized to vehicle-treated control HTT neurons (N586-22Q, OnM FA10, OpM pridopidine). One-way ANOVA (F(20,96) = 9.615; p<0.0001) with Dunnett’s multiple comparisons was used for statistical analysis. N=3. ##p<0.01 vs control HTT (N586-22Q) vehicle group; ****p<0.0001 vs mHTT (N586-82Q) vehicle group.DETAILED DESCRIPTION OF THE INVENTION

[0018] In the following detailed description, numerous specific details are set forth 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

[0019] In some embodiments, this invention is directed to treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent.

[0020] 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 having Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject having Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject having Huntington Disease; (v) a method of maintaining or reducing anxiety and depression in a subject having Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject having Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject having Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject having Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject having Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject having 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, orreducing impairment of quality of life in a subject having Huntington Disease; (xiii) a method of maintaining or improving or lessening the decline of a physical symptom in a subject having Huntington Disease; (xiv) a method of maintaining, improving, or lessening the decline 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 having Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease, wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent.

[0021] 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 having Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject having Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject having Huntington Disease; (v) a method of maintaining or reducing anxiety and depression in a subject having Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject having Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject having Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject having Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject having Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject having 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 having Huntington Disease; (xiii) a method of maintaining or improving or lessening the decline of a physical symptom in a subject having Huntington Disease; (xiv) a method of maintaining, improving, or lessening the decline 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 having Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining improving or lessening the decline of reduced lifespan in a subject with Huntington’s 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 pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the sigma 2 antagonist agent comprises CT1812, JVW-1009, SM-21, CT01344, CT1812, DKR-1677, SAS-0132,

[0125] RHM-4, FA-10, or any combination thereof.

[0022] In some embodiments, this invention is directed to a method for treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0023] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0024] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0025] 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 salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0026] In some embodiments, this invention is directed to a method for maintaining or reducing anxiety and depression in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the compositioncomprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0027] In some embodiments, this invention is directed to a method for maintaining 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0028] In some embodiments, this invention is directed to a method for 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0029] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0030] In some embodiments, this invention is directed to a method for improving, maintaining, or reducing of memory impairment in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0031] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0032] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0033] 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0034] In some embodiments, this invention is directed to a method of maintaining or improving or lessening the decline of a physical symptom in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0035] In some embodiments, this invention is directed to a method of maintaining, improving, or lessening the decline of a mental symptom in a subject with Huntington’s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0036] In some embodiments, this invention is directed toa 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0037] In some embodiments, this invention is directed to a method of maintaining 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 at least one composition comprising a sigma 2 antagonist agent. In anotherembodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0038] In some embodiments, this invention is directed to a method of maintaining 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 at least one composition comprising a sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[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 having Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject having Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject having Huntington Disease; (v) a method of maintaining or reducing anxiety and depression in a subject having Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject having Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject having Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject having Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject having Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject having 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 having Huntington Disease; (xiii) a method of maintaining or improving or lessening the decline of a physical symptom in a subject having Huntington Disease; (xiv) a method of maintaining, improving, or lessening the decline 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 having Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease, wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2antagonist agent; wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the at least one composition comprising a sigma 2 antagonist agent are administered sequentially or 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.

[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 having Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject having Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject having Huntington Disease; (v) a method of maintaining or reducing anxiety and depression in a subject having Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject having Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject having Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject having Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject having Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject having 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 having Huntington Disease; (xiii) a method of maintaining or improving or lessening the decline of a physical symptom in a subject having Huntington Disease; (xiv) a method of maintaining, improving, or lessening the decline 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 having Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining improving or lessening the decline of reduced lifespan in a subj ect with Huntington’ s Disease,, wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent; wherein the sigma 2 antagonist agent comprises CT1812, JVW-1009, SM- 21, CT01344, DKR-1677, SAS-0132,

[0125] RHM-4, FA-10 or any combination thereof. In another embodiment, the composition comprising pridopidine further comprises at least onepridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the method comprises administering one, two or three compositions comprising each a sigma 2 antagonist. In another embodiment, the at least one composition comprising a sigma 2 antagonist agent refers to at least one composition comprising at least one sigma 2 antagonist 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 having Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject having Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject having Huntington Disease; (v) a method of maintaining or reducing anxiety and depression in a subject having Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject having Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject having Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject having Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject having Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject having 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 having Huntington Disease; (xiii) a method of maintaining or improving or lessening the decline of a physical symptom in a subject having Huntington Disease; (xiv) a method of maintaining, improving, or lessening the decline 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 having Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining improving or lessening the decline of reduced lifespan in a subj ect with Huntington’ s Disease,, wherein the method comprises administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent; wherein the sigma 2 antagonist agent comprises CT1812, JVW-1009, SM- 21, CT01344, DKR-1677, SAS-0132,

[0125] RHM-4, FA-10 or any combination thereof; and wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof,and the at least one composition comprising a sigma 2 antagonist agent are administered sequentially or 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. In another embodiment, the method comprises administering one, two or three compositions comprising each a sigma 2 antagonist.

[0042] In some embodiments, the methods of this invention comprise administering to a subject with Huntington’s Disease, a composition comprising pridopidine or pharmaceutically acceptable salt thereof, and at least one composition comprising sigma 2 antagonist agent. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the at least one composition comprising sigma 2 antagonist 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 times a week. 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.

[0043] 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. 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.

[0044] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof, and the composition comprising at least one sigma 2 antagonist agent used 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 1, 2, 3, 4, 5 years, chronically, or for a lifetime.

[0045] 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.

[0046] In another embodiment, the composition comprising a sigma 2 antagonist 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.

[0047] 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, 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, compound 1 or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof.

[0048] In some embodiments, this invention is directed to a method for treating, preventing, or alleviating Huntington disease or one or more symptoms thereof, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent. In another embodiment, thecomposition comprising pridopidine further comprises at least one pridopidine’s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0049] 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, decline of a physical symptom, decline of a mental symptom, disease progression, emotional symptom, behavioral symptoms, psychiatric symptoms and / or reduced lifespan.

[0050] 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 (IS), composite UHDRS (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q- Motor) assessment, UHDRS modified Motor Score (mMS), UHDRS-Chorea score, 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 or 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, or by PBA for disoriented behavior, Apathy Evaluation Scale (AES), PBA for disoriented behavior, Problem Behaviors Assessment-Short form (PBA-S), PBA short form total score, PBA short form apathy sub-item, Problem Behaviors Assessment- Short form (PBA-S), Interview-based Impression of Change plus Caregiver Input (CIBIC- Plus), Physical Disability Score (PDS), Functional Assessment (FA), Clinical Global Impression of Change (CGLC), Clinician Global Impression of Severity (CGLS), Patient Global Impression of Change (PGLC), Patient Global Impression of Severity (PGLS), Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), eye movement score, hand movement score, gait and balance score, Quantitative motor (Q-Motor) assessment, timed up and go (TUG) assessment, cognitive assessment battery (CAB), abbreviated Montreal Cognitive Assessment (MoCA) scale, Trail Making Test B assessment, Huntington Disease Health Index (HD-HI), EQ-5D-5L, Walk-12, or Modified Physical Performance Test (mPPT). The trail making test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), whichincludes 6 tests, 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, or Cornell Scale for Depression in Dementia (CSDD), State-Trait Anxiety Inventory (STAI), Problem Behaviors Assessment-Short (PBA- S) scale, 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.

[0051] 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 having Huntington Disease comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent, wherein the functional capacity, motor function, cognition and quality of life is measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

[0052] 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 at least one composition comprising a sigma 2 antagonist 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).

[0053] 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 at least one composition comprising a sigma 2 antagonist 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, the Unified Huntington's Disease Rating Scale (UHDRS) the Unified Huntington's Disease Rating Scale (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 other embodiments, 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 pedomotography (speeded foot tapping).

[0054] 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.

[0055] 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 at least one composition comprising a sigma 2 antagonist agent, wherein the motor function impairment is measured by UHDRS Total Motor Score (TMS) score, the UHDRS TMS score minus chorea, or UHDRS TMS score minus dystonia.

[0056] 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 subj ect with Huntington’ s disease, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent, wherein the motor function impairment is measured by UHDRS TMS dystonia score.

[0057] In some embodiments, this invention is directed to a method of reducing or maintainingor 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 at least one composition comprising a sigma 2 antagonist agent, wherein the motor function impairment is measured by UHDRS TMS gait and balance score.

[0058] 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, comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof; and at least one composition comprising a sigma 2 antagonist agent, wherein the motor function impairment is measured by UHDRS TMS chorea score.

[0059] 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-In terval, 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 at least one composition comprising a sigma 2 antagonist agent, wherein the motor function impairment is measured by Q- Motor subscales for each mentioned impairment.

[0060] 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; and at least one composition comprising a sigma 2 antagonist 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.

[0061] 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 at least one composition comprising a sigma 2 antagonist agent, wherein the cognitive impairment is measured by one or any of the following scales; The trailmaking test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), which includes 6 tests, The Leiter International Performance Scale and the Peabody Picture Vocabulary Test.

[0062] 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 at least one composition comprising a sigma 2 antagonist 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- Asberg Depression Rating Scale (MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, or Cornell Scale for Depression in Dementia (CSDD).

[0063] 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 at least one composition comprising a sigma 2 antagonist 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.

[0064] In some embodiments, behavioral symptoms or psychiatric symptoms may include lack of initiative, apathy, or irritability.

[0065] 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 at least onecomposition comprising a sigma 2 antagonist 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.

[0066] 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 at least one composition comprising a sigma 2 antagonist 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's behavior and / or psychiatric state may also be measured by the Problem Behaviors Assessment for irritability.

[0067] 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 at least one composition comprising a sigma 2 antagonist agent, wherein quality of life 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.

[0068] 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 at least one composition comprising a sigma 2 antagonist 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).

[0069] 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 at least one composition comprising a sigma 2 antagonist agent, wherein disease progression is measured by Clinical Global Impression of Change (CGIC), Clinical Interview-Based Impression (CIBI), and theGlobal 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.

[0070] 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.

[0071] In an embodiment, the term “treating Huntington disease” comprises reducing one or more symptoms of Huntington disease.Composition

[0072] In some embodiments, provided herein a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof for use in the methods of this invention.

[0073] In some embodiments, provided herein a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof for use in the methods of this invention.

[0074] In some embodiments, provided herein a pharmaceutical composition comprising at least one sigma 2 antagonist for use in the methods of this invention.

[0075] In some embodiments, provided herein a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one sigma 2 antagonist agent. In another embodiment, the composition, further comprises at least one pridopidine’ s analog compound 1-7 or pharmaceutically acceptable salt thereof.

[0076] In another embodiment, the sigma 2 antagonist agent comprises CT1812, JVW-1009, SM-21, CT01344, CT1812, DKR-1677, SAS-0132,

[0125] RHM-4, FA-10, or any combination thereof. In another embodiment, the sigma 2 antagonist agent is CT1812. In another embodiment, the sigma 2 antagonist agent is JVW-1009. In another embodiment, the sigma 2 antagonist agent is SM-21. In another embodiment, the sigma 2 antagonist agent is CTO 1344. In another embodiment, the sigma 2 antagonist agent is DKR-1677. In another embodiment, the sigma 2 antagonist agent is SAS-0132. In another embodiment, the sigma 2 antagonist agent is

[0125] RHM-4. In another embodiment, the sigma 2 antagonist agent is FA-10.Sigma 2 antagonists

[0077] CT1812, also known as Elayta, represented by the following structure:is a small-molecule antagonist of the sigma-2 receptor that selectively binds to the receptor at the progesterone receptor membrane component 1 subunit. It reduces the affinity of oligomeric Ap for its receptor and interferes with AP-induced synaptic toxicity. CT1812 block binding of different Ap species to neuronal receptors and displace Ap when applied after it has bound. It facilitates brain clearance of Ap oligomers and improves cognitive behaviors in transgenic mouse models of Alzheimer's disease and displaces Ap oligomers from human postmortem AD brain tissue. Pre-clinical models have shown that CT 1812 and related compounds in the CT family prevent downstream synaptotoxicity and restore memory in aged transgenic mouse models of Alzheimer's disease.

[0020] CT1812 was well tolerated with single dose administration up to 1120 mg and with multiple dose administration up to 840 mg and 560 mg in healthy young and healthy elderly subjects, respectively. CT1812 is currently being studied in early phase 2 trials in patients with Alzheimer's disease.

[0021]

[0078] JVW-1009 represented by the following structure:, is a small molecule sigma receptor ligand with Ki of 96 and 70 nM for sigma 1 and sigma 2 reduces neurodegeneration in C. elegans model of amyloid precursor protein-mediated neurodegeneration.

[0022]

[0079] SM-21 is represented by the following structure:is a sigma 2 antagonist. Studies suggest that s receptors, which are concentrated in brain structures that control movement such as the red nucleus and substantia nigra, are involved in the regulation of movements and posture stems.

[0023]

[0080] CT01344 is represented by the following structure:, acts as a selective antagonist of Sigma-2 / progesterone receptor membrane component 1 (PGRMC1) receptor, can cross the blood-brain barrier and displace radioligand (3H-DTG) from human B cell lines (Ki = 48 nM). It effectively blocks Abeta-mediated membrane trafficking (EC50 = 8.7 pM) and binding on cultured neurons (EC50 = 3.9 pM). It can reverse Abeta oligomer-mediated deficits in trafficking (EC50 = 7.3 pM), restore normal synaptic function, and improve cognitive abilities in a murine model of Alzheimer's disease (10-30 mg / kg. p.o. over 5.5 months). It is effective when added 1 hour prior to or after Abeta oligomer preparations.

[0024]

[0081] DKR-1677 is represented by the following structure:DKR-1677 target Sigma 2 receptor / TMEM97(o2R / TMEM97) with an affinity (Ki) of 5.1 nM. The therapeutic application of DKR-1677 is neuroprotection in traumatic brain injury (TBI). DKR-1677 reduces axonal degeneration after blast-induced TBI, enhances survival of cortical neurons and oligodendrocytes after CCI (controlled cortical impact) injury, and preserves cognition in the Morris water maze following blast- TBI.

[0025]

[0082] SAS-0132, also known as AS-0132, is represented by the following structure:. AS-0132 is an innovative and powerful brain penetrant sigma 2 receptor / PGRMCl ligand, with excellent selectivity and low off-targetaffinity for most CNS-relevant targets. With a Ki value of 90 nM and a 9-fold selectivity over sigma 1 receptors, SAS-0132 demonstrates remarkable binding affinity and subtype specificity. SAS-0132's ability to modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells highlights its potential for treating neurological disorders. Furthermore, its neuroprotective properties in a C. elegans model of amyloid precursor protein-mediated neurodegeneration and its capacity to improve cognitive performance in a transgenic mouse model of Alzheimer's disease make it a promising candidate for further development. SAS- 0132 is a potent, subtype-selective, and brain penetrant sigma 2 receptor / PGRMC 1 ligand with a Ki value of 90 nM and a 9-fold selectivity over sigma 1 receptors. Its low off-target affinity for most CNS-relevant targets, neuroprotective properties, and potential for treating neurological disorders make it an exciting and valuable compound for future research and development in the field. [25,26]

[0083] [125JRHM-4 is represented by the following structure:

[1251] RHM-4 is a radioiodinated ligand that has high affinity and selectivity for o2R / TMEM97 versus olR, making it a promising biomarker of tumor proliferation and a target for cancer therapy. It was developed to replace [3H] DTG, which has moderate binding affinities to both c l R and o2R / TMEM97 and can cause bias in screening experiments when co-administered with olR masking compounds. A head-to-head comparison between [3H] DTG and

[1251] RHM-4 was performed, and the results indicate that

[1251] RHM-4 is an improved radioligand for in vitro binding studies of the c2R / TMEM97. Additionally, the study identified two binding regions in the c2R / TMEM97: the "DTG" binding site and the secondary binding site, which is responsible for high affinity and selectivity for the O2R / TMEM97 versus the olR. [28, 37],

[0084] FA-10 also known as a specific compound of the 1,2,3,4-Tetrahydroquinoline, represented by the following structure:FA- 10 has low nanomolar S2R (sigma 2 receptor) affinity and impressive 2807-fold S2R versus SIR (sigma 1 receptor) selectivity largely exceeded the biological profile of the best 3,4-dihydroisoquinolin compounds. Has no cytotoxic effect and modest interaction with the P-gp, appropriate lipophilicity and the presence of easily radiolabeling functions.

[0085] In some embodiments, the composition comprising sigma 2 antagonist agent, comprises at least one sigma 2 antagonist agent. In some embodiments, the composition comprises sigma 2 antagonist agent, comprises at least two sigma 2 antagonist agents. In some embodiments, the composition comprising sigma 2 antagonist agent, comprises at least three sigma 2 antagonist agents.

[0086] In another embodiment, the pridopidine’s analog compound 1-7 is represented by the following structures:

[0087] In other embodiments, 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, compound1 and compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound2 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.

[0088] 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%-!% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable saltthereof 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.

[0089] In another embodiment, the pharmaceutical composition 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 salt 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 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.

[0090] 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.

[0091] In some embodiments, the composition of this invention comprises between 10 mg to 300 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises between 10-50, 10-100, 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, 25, 30, 40,45, 50, 60, 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.

[0092] In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is between 1 :10000 to 1: 1. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is 1 : 10000 to 1 :500. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is 1 : 10000 to 1 : 10. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is between 1: 1000 to 1: 1. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is between 1: 1000 to 1:500. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is between 1 :500 to 1 :200. In another embodiment, the molar ratio between the one or more sigma 2 antagonist and pridopidine or pharmaceutically acceptable salt thereof is between 1 :500 to 1 : 10.

[0093] In some embodiments, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more sigma 2 antagonist is from about 1 :9999 to about 9999:1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more sigma 2 antagonist agent is from about 1 :999 to about 999: 1. In another embodiment, the weight ratio between the pridopidine or pharmaceutically acceptable salt thereof and the one or more sigma 2 antagonist agent is from about 1 :99 to about 99:1.

[0094] In some embodiments, the pridopidine or / and 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. Inanother 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.

[0095] 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.

[0096] 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.

[0097] Further details on techniques for formulation and administration may be found in the latest edition of Remington ’s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

[0098] In some embodiments, the pharmaceutical composition for use in the methods of this invention comprises one or more pharmaceutically acceptable carriers or excipients.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] In some embodiments, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.

[0103] 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.

[0104] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose and magnesium stearate as excipients.

[0105] 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.

[0106] In some embodiments, the lubricant is magnesium stearate.

[0107] In some embodiments, the glidant is selected from a group consisting of starch, pregelatinized starch, silicone dioxide, colloidal silicone dioxide, talc and mixtures thereof.

[0108] In some embodiments, the glidant is colloidal silicone dioxide.

[0109] 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.

[0110] In some embodiments, multi articulate or multiple unit dosage forms are the discrete, small, repetitive units of drug particles which may or may not possess similar drug release pattern.

[0111] 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.

[0112] 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” of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[0113] 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., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salt.Listing of Abbreviations and Definitions of Terms

[0114] The following abbreviations are used throughout this application:CAB: cognitive assessment battery; CAG: cytosine-adenosine-guanine; CGI-C: Clinical Global Impression of Change; CIBIC-Plus: Clinician’s Interview-based Impression of Change plus Caregiver Input; CIBIS: Clinician’s Interview-based Impression of Severity; FA: Functional Assessment; HD: Huntington disease; HD-QoL: Huntington’s disease Quality of Life; Htt: Huntingtin gene; IS: Independence Score; PDS: Physical disability scale: PPT: physical performance test; Q-Motor: Quantitative motor; QoL: Quality of life; S2R: Sigma 2 receptor; SDMT: symbol digit modalities test; TFC: Total functional capacity; TMS: Total Motor Score; TUG: timed up an go; UHDRS: Unified Huntington’s Disease Rating Scale; CUHDRS: composite Unified Huntington Disease; MSWS-12: Multiple Sclerosis Walking Scale-12; PPT: Physical Performance Test; TUG: Timed Up and Go; HD-HI: Huntington Disease Health Index; AES: Apathy Evaluation Scale; S2R: sigma 2 receptor; SWR: Stroop Word Reading Test; SDMT: Symbol Digit Modalities Test; CIBIC-Plus: Clinician’s Interviewbased Impression of Change plus Caregiver Input; PDS: Physical Disability Score; FA: Functional Assessment; CGI-C: Clinical Global Impression of Change; CGI-S: Clinician Global Impression of Severity; PGI-C: Patient Global Impression of Change; PGI-S: Patient Global Impression of Severity; EQ-5D-5L: EuroQol 5-Dimension 5-Level; Walk-12: Walk-12 Scale; mPPT: Modified Physical Performance Test.EXAMPLESExample 1:The combination of pridopidine and the S2R antagonist (FA-10) shows unexpected, enhanced neuroprotection against mHTT-induced cell death.

[0115] The study investigated the effect of pridopidine and the S2R selective antagonist FA- 10 on mHTT induced cell death in an HD cell model.

[0116] Pridopidine (4- [3 -(methyl sulfonyl) phenyl]- 1-propyl-piperi dine) is a highly selective SIR ligand with Ki=57 nM, S2R Ki of 5450 and 95-fold higher selectivity for the SIR vs the S2R. [9] (Table 1). FA-10 (l-(3-[6,7-Dimethoxy-3,4-dihydroisoquinolin-2(lH)-yl) propyl]-5- methoxy-l,2,3,4-Tetrahydroquinolineis) is a highly selective S2R ligand with Ki=1.42 nM, SIR Ki of 3987nM and 2807-fold higher selectivity for the S2R vs the SIR

[0036] , (Table 1).

[0117] The HD model utilized mouse primary cortical neurons transfected with a mutant huntingtin gene (mHtt N586 -82Q) or WT N586-22Q. N586 -82Q comprises the initial 586 amino acids of the huntingtin protein, including an uninterrupted polyglutamine tract containing 82 consecutive glutamine residues (82 CAG repeats in the mHtt gene). N586 -22Q includes 22 polyglutamine repeats which represent the normal Htt protein.Neurons were treated not treated (control) or treated with Pridopidine and FA-10 alone or in combinations, for 4 hours after transfection. 48 hours post transfection, neuronal cell death was measured by nuclear condensation assay which measures cell death (% cell death), a validated and commonly used method to detect apoptosis by assessing changes in chromatin structure.Table 1. Pridopidine is a highly selective SIR agonist and FA-10 is a highly selective S2R antagonist.(Johnston et al 2018[9], Mauro el al 2016

[0036] )The combination of Pridopidine and the selective S2R antagonist FA-10 show an unexpected enhanced neuroprotective effect compared to each compound alone.

[0118] Neurons transfect with the mHtt 82Q gene (called “HD cells”) exhibited a robust increase in cell toxicity when compared to neurons transfected with the WT Htt 22Q gene (called “WT cells”). Treatment of HD cells with pridopidine and FA-10 alone demonstrated a significant reduction in toxicity. SIR activation and S2R inhibition both result in neuroprotection against mHTT-induced toxicity. Provided herein combinations of pridopidine and FA10 in the mHTT-induced toxicity assay. Suboptimal and optimal doses of pridopidine (0.001 pM, 0.01 pM, 0.1 pM, and 1 pM) and FA10 (0.0001 pM, 0.001 pM and 0.003 pM) were assessed in combination. An ANOVA test revealed significant differences in treatment groups (F(20,96) = 9.615; p<0.0001). Remarkably, a post-hoc Dunnett’s test showed that the lowest doses of pridopidine (0.001 pM) and FA10 (0.0001 pM) tested, which had only modest effects when tested separately, showed enhanced rescue of the neurotoxic effect induced by mHTT when dosed in combination. The combination of pridopidine (0.001 pM) and FA10 (0.0001 pM) resulted in superior (54% reduction in neuronal death, p<0.0001) compared to either compound alone (pridopidine (0.001 pM) 33% reduction in neuronal death, p<0.05; FA10 (0.0001 pM) 32% reduction in neuronal death, p<0.01) (Figure 1 and Table 1). In the combination treatments, we found that pridopidine (1 pM) with FA10 (0.003 pM) provided the strongest neuroprotective effect (74% reduction in neuronal death, p<0.0001), greater than either individual treatment (pridopidine (1 pM) 51% reduction in neuronal death, p<0.0001; FA10 (0.003 pM) 46% reduction in neuronal death, p<0.0001) (Figure 2 and Table 1). Combination treatments of pridopidine and FA10 had minimal effects on control neurons (Table 2). These results support the hypothesis that simultaneous activation of the SIR and inhibition of S2R provides enhanced neuroprotection compared to either alone.These results support the hypothesis that simultaneous activation of the SIR and inhibition of S2R provides enhanced neuroprotection compared to either alone.Table 1. The neuroprotective effect of pridopidine and FA10 on neurons expressing mHTT.NS = not significantTable 2: Combinations of FA10 and pridopidine had minimal effect on neurons expressing control HTT.NS = Not SignificantREFERENCES 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. 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Claims

CLAIMSWhat is claimed is1. A method of treatment, prevention, alleviation, delaying symptom onset, or slowing of progression of Huntington disease in a subject in need thereof comprising administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one composition comprising sigma 2 antagonist agent.

2. The method of claim 1, wherein 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, represented by the following structures:

3. The method of claim 2, wherein the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 1 or pharmaceutically acceptable salt thereof.

4. The method of claim 2, wherein the composition comprises pridopidine or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof.

5. The method of claim 2, wherein the composition comprises pridopidine or pharmaceutically acceptable salt thereoi ', compound 1 and compound 4 or pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1-4, wherein the sigma 2 antagonist agent comprises CT1812, JVW-1009, SM-21, CT01344, DKR-1677, SAS-0132, [125] RHM-4 or combination thereof.

7. The method of any one of claims 1-6, wherein the treatment comprises improving, maintaining, or reducing impairment of one or more symptoms of Huntington disease.

8. The method of claim 7, wherein the symptoms of Huntington’s 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, decline of a physical symptom, decline of a mental symptom, disease progression, emotional symptom, behavioral symptoms, psychiatric symptoms and / or reduced lifespan.

9. The method of claim 7 or claim 8, wherein the one or more symptoms are measured by, Total Functional Capacity (TFC), Unified Huntington's Disease Rating Scale (UHDRS), UHDRS Independence Score (IS), composite UHDRS (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, UHDRS modified Motor Score (mMS), UHDRS-Chorea score, UHDRS -Dystonia score, 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, 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), Hamilton Rating Scale for Depression (HAM-D), Problem Behaviors Assessment- Short (PBA-S) scale, 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, PBA total score, PBA-S, PBA for lack of initiative or apathy, PBA short form apathy subitem, Apathy Evaluation Scale (AES), and PBA for disoriented behavior. HD-Quality of Life scale (HD-QoL), Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), Quantitative motor (Q-Motor) assessment, timed up and go (TUG)assessment, cognitive assessment battery (CAB), Huntington Disease Health Index (HD-HI).

10. The method of any one of claims 7-9, wherein human patient's functional capacity is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).

11. The method or use of any one of claims 7-9, wherein the functional capacity, motor function, cognition and quality of life is measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

12. The method of any one of claims 7-9, 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), and 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), Digitomotography (finger tapping) assessment.

13. The method of any one of claim 7-9, wherein 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 pedomotography (speeded foot tapping).

14. The method of any one of claims 1-13, wherein the salt of pridopidine or of pridopidine’s analog compound 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, 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.

15. The method of claim 14, wherein the salt is hydrochloride.

16. The method of any one of claims 1-15, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the at least one composition comprising sigma 2 antagonist agent, are each independently administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, or intradermal route.

17. The method of any one of claims 1-16, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the at least one composition comprising sigma 2 antagonist agent are each orally administered.

18. The method of any one of claims 1-17, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof is administered at a daily dose of between 10 mg / day to 300 mg / day.

19. The method of any one of claims 1-18, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof is administered at a daily dose 10 mg / day to 100 mg / day.

20. The method of any one of claims 1-19, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and the at least one composition comprising sigma 2 antagonist agent are administered at a daily dose sequentially or concomitantly in either order.

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