Pridopidine and sigma 2 antagonists for the treatment of huntington's disease and symptoms thereof

Abstract

Provided herein are methods for treating, preventing, alleviating, delaying the onset of symptoms of, or slowing the progression of Huntington's disease, comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one composition comprising a sigma 2 antagonist.

Description

[0001] Invention Field This invention relates to a method for treating, preventing, or alleviating Huntington's disease and / or its symptoms in a subject, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and a composition comprising a σ2 antagonist. Background of the Invention Huntington's disease Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant inheritance pattern. The disease is associated with motor symptoms, behavioral symptoms, functional symptoms and cognitive symptoms. Motor impairment is the defining feature of the disease, with chorea being the most prominent motor symptom. Although useful for diagnosis, chorea is an unfavorable marker of disease severity. In contrast, functional impairment and disease severity are most associated with unfavorable motor features such as impairment of fine motor skills, bradykinesia and gross motor coordination skills, including speech difficulties, gait and postural dysfunction and cognitive impairment [1]. The UHDRS-Total Functional Capacity (TFC) scale is a validated and accepted tool used by clinicians to assess the level of function in HD disease stages and patients. Decreases in UHDRS-TFC are associated with other aspects of disease progression, including brain atrophy, motor, cognitive and behavioral function [2,3].

[0003] HD includes five stages: HD1 (TFC 11-13), occurring 0-8 years after onset. Early stage. Fully functional at home and work, maintaining typical pre-illness level of independence when performing daily activities.

[0004] HD2 (TFC 7-10), occurring 3-13 years after onset. Early to mid-stage. Patients still have some function at work, but at a lower level.

[0005] HD3 (TFC 3-6) occurs 5-16 years after onset. This is the late to mid-stage. Patients are no longer able to work or manage family responsibilities.

[0006] HD4 (TFC 1-2), occurring 9-21 years after onset. Early to late stage. Patients at this stage are not independent but can still live at home with the help of family or professionals, although their needs can be better met in extended care facilities.

[0007] HD5 (TFC 0) occurs 11-26 years after onset, representing a late stage. Patients require comprehensive support from professional care in their daily activities.

[0008] Genetically, Huntington's disease (HD) belongs to the trinucleotide repeat amplification disorder group. While individuals with a CAG repeat length of less than 35 on exon 1 of the HTT remain asymptomatic, alleles with 40 or more repeats show complete penetrance. Intermediate alleles (36–39 CAG repeats) have an increased risk of developing HD. HTT This is caused by abnormally amplified CAG repeats in the gene, which confers major toxicity to the mutant huntingtin protein (mHTT). [4] Several drugs have been prescribed to improve motor and mood problems associated with HD. However, there is almost no scientific evidence for the usefulness of many drugs in HD [5,6]. Only three drugs, tetrabenazine, deutetrabenazine, and valbenazine, have been approved for the treatment of chorea in patients with HD, but no therapy has been shown to alter the progressive and unstoppable functional decline of the disease [7,8]. Therefore, there is a significant unmet medical need to develop drugs to improve the symptoms of HD and slow the progression of the disease.

[0009] Pridopidin Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) is a highly selective S1R ligand with Ki = 57 nM and S2R Ki = 5450 nM[9]. Therefore, pridopidine has a 95-fold higher affinity for S1R than S2R and is a highly selective S1R ligand.

[0010] S1R is an endoplasmic reticulum (ER) protein located primarily in the mitochondrial-associated membrane (MAM) that regulates a variety of cellular processes, including calcium signaling, ion channel activity, and ER stress response [10,11].

[0011] As demonstrated in nonclinical models of HD and other neurodegenerative diseases, pridopidine exerts its neuroprotective effects through sophisticated S1R activation [29–35]. Specifically, pridopidine improves key pathophysiological pathways involved in HD, including rescuing mitochondrial-associated membrane (MAM) disruption

[32] , enhancing brain-derived neurotrophic factor secretion and signal transduction [29,34], restoring abnormal calcium signaling, rescuing synaptic plasticity and neuronal spike abnormalities

[14] , enhancing autophagy, upregulating mitochondrial function

[32] , reducing ER and oxidative stress

[33] , and rescuing HTT-induced cell death

[12] . All of these effects are mediated by S1R, as genetic deletion of the S1R gene or pharmacological S1R inhibition completely eliminates the effects of pridopidine.

[0012] σ2 antagonists S2R (σ2 receptor) is a transmembrane receptor, also known as transmembrane protein 97 (TMEM97). In the brain, S2R is present in several regions, including the cerebellum, cortex, hippocampus and substantia nigra, and is enriched in neurons. Activation of S2R induces cell death through multiple signaling pathways: caspase 3 activation, cell cycle disruption and autophagy disruption, while inhibition (antagonism of S2R) exerts a neuroprotective effect

[17] . Invention Overview In some embodiments, the present invention relates to a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease in a subject with appropriate need, or slowing the progression of Huntington's disease in a subject with appropriate need, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one composition comprising a σ2 antagonist.

[0014] In another embodiment, the σ2 antagonist is selected from CT1812, JVW-1009, SM-21, CT01344, DKR-1677, SAS-0132,

[125] RHM-4 or a combination thereof.

[0015] In another embodiment, the composition comprising pridopidine or a pharmaceutically acceptable salt thereof further comprises at least one of the pridopidine analog compounds 1-7 as described below: (1) (2) (3) (4) (5) (6) or (7). Brief description of the attached diagram The subject matter considered to be the present invention is specifically pointed out and expressly claimed in the concluding section of the specification. However, when combined with the appendix... Figure 1 When reading this invention, both its organization and operation methods, along with its objects, features, and advantages, can be best understood together with the following detailed description, in conjunction with the accompanying drawings: Figure 1 The combination of pridopidine and FA10 provides enhanced neuroprotection.

[0017] Combining FA10 with low-dose pridopidine demonstrated enhanced protection against mHTT-induced cytotoxicity. Increasing doses of FA10 (0 nM, 0.1 nM, 1 nM, and 3 nM) were combined with increasing concentrations of pridopidine (0 μM, 0.001 μM, 0.01 μM, 0.1 μM, and 1 μM), and the combined effects were evaluated in primary neurons transfected with either control HTT (N586-22Q) or mHTT (N586-82Q) as mentioned above. Mediator-treated control HTT neurons served as controls. Cell death was assessed by nuclear condensation assays, and the cytotoxicity fold was normalized to mediator-treated control HTT neurons (N586-22Q, 0 nM FA10, 0 μM pridopidine). One-way ANOVA (F(20,96)=9.615; p<0.0001) and Dunnett's multiple comparisons were used for statistical analysis. ####p<0.0001, relative to the control HTT (N586-22Q) mediator group; p<0.05, relative to the mHTT(N586-82Q) media group; p<0.01, relative to the mHTT(N586-82Q) media group; p < 0.0001, relative to the mHTT(N586-82Q) media group. N = 3.

[0018] Figure 2 The optimal dose of the combination of pridopidine and FA10, which provides improved neuroprotection, was presented. The effect of the optimal dose of FA10 and pridopidine on mHTT-induced cytotoxicity was tested in an HD cell model. The optimal dose of FA10 (0.003 μM) was combined with the optimal dose of pridopidine (1 μM), and the combined effect was evaluated in primary neurons transfected with control HTT (N586-22Q) or mHTT (N586-82Q) as mentioned above. Wild-type neurons expressing control HTT (N586-22Q) treated with the vector were used as negative controls. Cell death was evaluated by nuclear condensation assays, and the fold change in toxicity was normalized to the control HTT neurons treated with the vector (N586-22Q, 0 nM FA10, 0 μM pridopidine). One-way ANOVA (F(20,96)=9.615; p<0.0001) and Dunnett's multiple comparisons were used for statistical analysis. N=3. ##p<0.01, relative to the control HTT (N586-22Q) mediator group; p < 0.0001, relative to the mHTT(N586-82Q) media group. Invention Details In the following detailed description, numerous specific details are set forth to provide a thorough understanding of the invention. However, those skilled in the art will understand that the invention can 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 invention.

[0020] method In some embodiments, the present invention relates to treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease or slowing the progression of Huntington's disease, including administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist.

[0021] In some embodiments, the present invention relates to (i) a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease; (ii) a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease; (iii) a method for improving, maintaining, or reducing motor function impairment in a subject with Huntington's disease; (iv) a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease; and (v) a method for maintaining or reducing cognitive impairment in a subject with Huntington's disease. (vi) A method for monitoring anxiety and depression in subjects with Huntington's disease; (vii) A method for maintaining or reducing anti-inflammatory biomarkers in subjects with Huntington's disease; (viii) A method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with Huntington's disease; (viii) A method for maintaining or reducing neurofilament light chain (NfL) levels in subjects with Huntington's disease; (ix) A method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease; (x) A method for delaying or reducing structural, functional, and metabolic changes in the brain of subjects with Huntington's disease. Methods for the deterioration of indicators; (xi) a method for delaying the onset of disease progression in Huntington's disease, stopping the progression of disease in Huntington's disease, or slowing the decline of disease progression in Huntington's disease; (xii) a method for improving, maintaining, or reducing the impairment of quality of life of a subject with Huntington's disease; (xiii) a method for maintaining or improving physical symptoms of a subject with Huntington's disease or reducing the decline of physical symptoms of the subject; (xiv) a method for maintaining, improving, or reducing mental symptoms of a subject with Huntington's disease; (xv) a method for improving mood symptoms of a subject with Huntington's disease, preventing the deterioration of mood symptoms of a subject with Huntington's disease, or reducing mood symptoms of a subject with Huntington's disease; (xvi) a method for maintaining or reducing behavioral symptoms of a subject with Huntington's disease; (xvii) a method for maintaining, improving, or reducing the decline of lifespan shortening of a subject with Huntington's disease, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist.

[0022] In some embodiments, the present invention relates to (i) a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease; (ii) a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease; (iii) a method for improving, maintaining, or reducing motor function impairment in a subject with Huntington's disease; (iv) a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease; and (v) a method for maintaining or reducing anxiety and... Methods for treating depression; (vi) a method for maintaining or reducing anti-inflammatory biomarkers in subjects with Huntington's disease; (vii) a method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with Huntington's disease; (viii) a method for maintaining or reducing neurofilament light chain (NfL) levels in subjects with Huntington's disease; (ix) a method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic indicators in the brain of subjects with Huntington's disease; (xi) a method for delaying... Methods for initiating, stopping, or slowing the decline of Huntington's disease progression; (xii) a method for improving, maintaining, or reducing impairment of the quality of life of a subject with Huntington's disease; (xiii) a method for maintaining or improving physical symptoms of a subject with Huntington's disease or reducing the decline of physical symptoms of the subject; (xiv) a method for maintaining, improving, or reducing mental symptoms of a subject with Huntington's disease or reducing the decline of mental symptoms of the subject; (xv) a method for improving the mood of a subject with Huntington's disease. (xvi) A method for maintaining or reducing the deterioration of the mood symptoms of a subject with Huntington's disease; (xvii) A method for maintaining or reducing the behavioral or psychotic symptoms of a subject with Huntington's disease; (xvii) A method for maintaining or improving the shortening of lifespan of a subject with Huntington's disease or for mitigating the decline of the shortening of lifespan of the subject, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the σ2 antagonist comprises CT1812, JVW-1009, SM-21, CT01344, CT1812, DKR-1677, SAS-0132,

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

[0023] In some embodiments, the present invention relates to a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the present invention relates to a method for maintaining, improving, or reducing functional impairment in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing motor function impairment in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the present invention relates to a method for maintaining or reducing anxiety and depression in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the present invention relates to a method for maintaining or reducing anti-inflammatory biomarkers in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the present invention relates to a method for increasing brain-derived neurotrophic factor (BDNF) levels in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the present invention relates to a method for maintaining or reducing neurofilament light chain (NfL) levels in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing memory impairment in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the present invention relates to a method for delaying or reducing the deterioration of structural, functional, and metabolic indicators in the brain of a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the present invention relates to a method for delaying the onset of disease progression, stopping the progression of disease progression, or slowing the decline of disease progression in Huntington's disease, said method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the present invention relates to a method for improving, maintaining, or slowing the decline in the quality of life of a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present invention relates to a method for maintaining or improving physical symptoms of a subject suffering from Huntington's disease or for alleviating the decline of physical symptoms in said subject, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present invention relates to a method for maintaining, improving, or alleviating the decline of mental symptoms in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present invention relates to a method for improving, preventing the worsening of, or reducing the mood symptoms of a subject with Huntington's disease, said method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present invention relates to a method for maintaining or reducing behavioral or psychotic symptoms in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the present invention relates to a method for maintaining, improving, or mitigating the decline in lifespan of a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the present invention relates to (i) a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease; (ii) a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease; (iii) a method for improving, maintaining, or reducing motor function impairment in a subject with Huntington's disease; (iv) a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease; and (v) a method for maintaining or reducing anxiety and depression in a subject with Huntington's disease. vi) A method for maintaining or reducing anti-inflammatory biomarkers in subjects with Huntington's disease; (vii) A method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with Huntington's disease; (viii) A method for maintaining or reducing neurofilament light chain (NfL) levels in subjects with Huntington's disease; (ix) A method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease; (x) A method for delaying or reducing the deterioration of structural, functional, and metabolic indicators in the brain of subjects with Huntington's disease; (xi) A method for delaying the onset of disease progression in Huntington's disease. (xii) A method for stopping the progression of Huntington's disease or slowing the decline of the progression of Huntington's disease; (xiii) A method for improving or maintaining the quality of life of a subject with Huntington's disease or reducing the impairment of the quality of life of said subject; (xiv) A method for maintaining or improving physical symptoms of a subject with Huntington's disease or reducing the decline of physical symptoms of said subject; (xiv) A method for maintaining or improving mental symptoms of a subject with Huntington's disease or reducing the decline of mental symptoms of said subject; (xv) A method for improving mood symptoms of a subject with Huntington's disease or preventing mood symptoms of a subject with Huntington's disease. A method for worsening or reducing mood symptoms in a subject with Huntington's disease; (xvi) a method for maintaining or reducing behavioral or psychotic symptoms in a subject with Huntington's disease; (xvii) a method for maintaining, improving, or mitigating the decline in lifespan of a subject with Huntington's disease, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist; wherein the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the composition comprising at least one σ2 antagonist are administered sequentially or simultaneously in any order. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the present invention relates to (i) a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease; (ii) a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease; (iii) a method for improving, maintaining, or reducing motor function impairment in a subject with Huntington's disease; (iv) a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease; (v) a method for maintaining or reducing anxiety and depression in a subject with Huntington's disease; and (vi) a method for maintaining... (vii) A method for maintaining or reducing anti-inflammatory biomarkers in subjects with Huntington's disease; (viii) A method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with Huntington's disease; (ix) A method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease; (x) A method for delaying or reducing the deterioration of structural, functional, and metabolic indicators in the brain of subjects with Huntington's disease; (xi) A method for delaying the onset, stopping, or reducing the progression of Huntington's disease. (xii) A method for slowing the decline of the progression of Huntington's disease; (xiii) A method for improving, maintaining, or reducing the impairment of the quality of life of a subject with Huntington's disease; (xiv) A method for maintaining or improving physical symptoms of a subject with Huntington's disease or reducing the decline of physical symptoms of the subject; (xiv) A method for maintaining, improving, or reducing the decline of mental symptoms of a subject with Huntington's disease; (xv) A method for improving the mood symptoms of a subject with Huntington's disease, preventing the worsening of the mood symptoms of a subject with Huntington's disease, or reducing the mood symptoms of a subject with Huntington's disease. (xvi) A method for maintaining or reducing behavioral or psychotic symptoms in a subject with Huntington's disease; (xvii) A method for maintaining, improving, or mitigating the decline in lifespan of a subject with Huntington's disease, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist; wherein the σ2 antagonist comprises CT1812, JVW-1009, SM-21, CT01344, DKR-1677, SAS-0132,

[125] RHM-4, FA-10, or any combination thereof. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof. In another embodiment, the method comprises administering one, two, or three compositions each comprising a σ2 antagonist.In another embodiment, at least one composition containing a σ2 antagonist means at least one composition containing at least one σ2 antagonist.

[0042] In some embodiments, the present invention relates to (i) a method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease, or slowing the progression of Huntington's disease; (ii) a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease; (iii) a method for improving, maintaining, or reducing motor function impairment in a subject with Huntington's disease; (iv) a method for improving, maintaining, or reducing cognitive impairment in a subject with Huntington's disease; (v) a method for maintaining or reducing anxiety and depression in a subject with Huntington's disease; and (vi) a method for maintaining or reducing cognitive impairment in a subject with Huntington's disease. (vii) A method for increasing brain-derived neurotrophic factor (BDNF) levels in subjects with Huntington's disease; (viii) A method for maintaining or reducing neurofilament light chain (NfL) levels in subjects with Huntington's disease; (ix) A method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease; (x) A method for delaying or reducing the deterioration of structural, functional, and metabolic indicators in the brain of subjects with Huntington's disease; (xi) A method for delaying the onset of disease progression, stopping disease progression, or slowing the decline of disease progression in Huntington's disease; (xii) A method for improving, maintaining, or reducing memory impairment in subjects with Huntington's disease. (xiii) A method for maintaining or reducing the impairment of the quality of life of a subject with Huntington's disease; (xiv) A method for maintaining or improving physical symptoms of a subject with Huntington's disease or reducing the decline of physical symptoms of the subject; (xv) A method for maintaining or improving mental symptoms of a subject with Huntington's disease or reducing the decline of mental symptoms of the subject; (xv) A method for improving emotional symptoms of a subject with Huntington's disease, preventing the deterioration of emotional symptoms of a subject with Huntington's disease, or reducing emotional symptoms of a subject with Huntington's disease; (xvi) A method for maintaining or reducing behavioral or psychotic symptoms of a subject with Huntington's disease; (xvii) A method for maintaining, improving, or mitigating the decline in lifespan of a subject suffering from Huntington's disease, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist; wherein the σ2 antagonist comprises CT1812, JVW-1009, SM-21, CT01344, DKR-1677, SAS-0132,

[125] RHM-4, FA-10, or any combination thereof; and the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the composition comprising at least one σ2 antagonist are administered sequentially or simultaneously in any order. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.In another embodiment, the method includes applying one, two, or three compositions, each containing a σ2 antagonist.

[0043] In some embodiments, the method of the present invention includes administering to a subject suffering from Huntington's disease a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the composition comprising at least one σ2 antagonist are each administered independently once daily. In another embodiment, the compositions are each administered independently twice daily. In another embodiment, the compositions are each administered independently three times daily. In another embodiment, the compositions are each administered independently once weekly, twice weekly, or three times weekly. In another embodiment, the compositions are each administered independently once daily, twice daily, three times daily, four times daily, or less than once daily.

[0044] In another embodiment, the pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof is administered once daily. In another embodiment, the composition is administered twice daily. In another embodiment, the composition is administered three times daily. In another embodiment, the composition is administered once weekly, twice weekly, or three times weekly. In another embodiment, the composition is administered once daily, twice daily, three times daily, four times daily, or less than once daily. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition is administered orally.

[0045] In another embodiment, the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the composition comprising at least one σ2 antagonist used in the method of the 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 year, 2 years, 3 years, 4 years, 5 years, long-term, or lifelong.

[0046] In another embodiment, the composition comprising pridopidine or a pharmaceutically acceptable salt thereof is administered via an oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, sublingual, vaginal, rectal, intraocular, intrathecal, local, intracranial, or intradermal route. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analogue compound 1-7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition is administered orally.

[0047] In another embodiment, the composition comprising a σ2 antagonist or a pharmaceutically acceptable salt thereof is administered via an oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, sublingual, vaginal, rectal, intraocular, intrathecal, local, intracranial, or intradermal route.

[0048] In some embodiments, the composition comprising pridopidine or a pharmaceutically acceptable salt for use in the method of the present invention comprises pridopidine as the sole active material. In other embodiments, the composition comprising pridopidine or a pharmaceutically acceptable salt further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 2 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 3 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 5 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 6 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof, and compound 4 or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present invention relates to a method for treating, preventing, or alleviating Huntington's disease or one or more of its symptoms, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist. In another embodiment, the composition comprising pridopidine further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0050] In other implementations, one or more symptoms of Huntington's disease include impaired functioning, impaired motor function, cognitive impairment, anxiety and depression, elevated anti-inflammatory biomarkers, reduced brain-derived neurotrophic factor (BDNF), increased neurofilament light chains (NfL), memory impairment, deterioration of structural, functional and metabolic indicators, impaired quality of life, decline in physical symptoms, decline in mental symptoms, disease progression, mood symptoms, behavioral symptoms, psychotic symptoms and / or shortened lifespan.

[0051] In another implementation, one or more symptoms are measured by the following: 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-Chorusness Score, UHDRS-Dystonia Score, Multiple Sclerosis Gait Scale (MSWS-12), Physical Function Test (PPT), Eye Movement Score, Hand Movement Score, Gait and Balance Score, Timed Stand and Walk (TUG) Assessment, Huntington's Disease Health Index (HD-HI) and Finger Typing Assessment, UHDRS TMS Score, UHDRS TMS Score without Chorea or UHDRS TMS Score without Dystonia. TMS score, HD-QoL scale, Stroop word reading test (SWR), Symbolic digit modality test (SDMT), Problem Behavior Assessment (PBA) total score, PBA for depressive mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessive-compulsive disorder, or PBA for lost behavior, Apathy Rating Scale (AES), PBA for lost behavior, Problem Behavior Assessment Short Form (PBA-S), PBA Short Form total score, PBA Short Form apathy sub-item, Problem Behavior Assessment Short Form (PBA-S), Interview-Based Impressions of Change plus Caregiver Input (CIBIC-Plus), Physical Disability Scale (PDS), Functional Assessment (FA), Clinical Global Impressions of Change (CGI-C), Clinician Total Score The assessment includes: Body Severity Impression (CGI-S), Patient Overall Change Impression (PGI-C), Patient Overall Severity Impression (PGI-S), Multiple Sclerosis Walk Scale (MSWS-12), Physical Function Test (PPT), Eye Movement Score, Hand Movement Score, Gait and Balance Score, Quantitative Motor Assessment (Q-Motor), Timed Stand and Walk (TUG) Assessment, Cognitive Assessment Kit (CAB), Mini-Monthly Cognitive Assessment (MoCA), Connecting Test B Assessment, Huntington's Disease Health Index (HD-HI), EQ-5D-5L, Walk-12 or Modified Physical Function Test (mPPT), Connecting Test B (TMT-B), HD Cognitive Assessment Kit (HD-CAB) (comprising 6 tests), Leiter International Performance Scale, and Peabody Picture Vocabulary.Tests include the Hamilton Depression Rating Scale (HAM-D), the Beck Depression Scale (BDI), the Beck Despair Scale, the Center for Epidemiological Studies-Depression Scale (CES-D), the Patient Health Questionnaire, the Center for Epidemiological Studies Childhood Depression Scale (CES-DC), the Clinically Useful Depression Outcome Scale, the Diagnostic Depression Scale, the Edinburgh Postnatal Depression Scale (EPDS), the Depression Symptom Scale, the Geriatric Depression Scale (GDS), the Hospital Anxiety and Depression Scale, the Kutcher Adolescent Depression Scale (KADS), the Major Depression Scale (MDI), the Montgomery-Asberg Depression Rating Scale (MADRS), the Mood and Feeling Questionnaire (MFQ), the Zung Self-Rating Depression Scale, or the Cornell Scale for Depression in... Dementia (CSDD), State-Trait Anxiety Scale (STAI), Problem Behavior Assessment Short Form (PBA-S), Fear Questionnaire, Beck Anxiety Scale (BAI), Brief Fear Negation Scale-BFNE, PTSD Scale for Clinicians (CAPS), Symptom-Based Daily Assessment of Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton Anxiety Rating 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 Scale (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive-Compulsive Disorder Scale (YARB). Obsessive-Compulsive Scale (Y-BOCS) or Zung's 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.

[0052] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing impairment of functional ability, motor function, cognition, and quality of life in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein functional ability, motor function, cognition, and quality of life are measured by the Composite Unified Huntington's Disease Rating Scale (cUHDRS).

[0053] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing functional impairment in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the functional ability is measured by assessing total functional ability (TFC) according to a Unified Huntington's Disease Rating Scale (UHDRS) subscale of total functional ability (TFC).

[0054] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing motor function impairment in a subject suffering from Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by: the Composite Unified Huntington's Disease Rating Scale (cUHDRS), Total Motor Score (TMS), Quantitative Motor Assessment (Q-Motor), Unified Huntington's Disease Rating Scale (UHDRS), Unified Huntington's Disease Rating Scale (UHDRS) Modified Motor Score (mMS), Unified Huntington's Disease Rating Scale (UHDRS)-Chorus Disease Score, Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia Score, Multiple Sclerosis Gait Scale (MSWS-12), Physical Function Test (PPT), Eye Movement Score, Hand Movement Score, Gait and Balance Score, Timed Stand and Walk (TUG) Assessment, Huntington's Disease Health Index (HD-HI), and / or Finger Typing Assessment. In other implementations, motor function impairment is measured by the following: finger kinesiography (rapid index finger tapping), alternating kinesiography (pronation / supination hand tapping), hand kinesiography and choreiform kinesiography (grip strength and chorea analysis), and foot kinesiography (rapid foot tapping).

[0055] In some embodiments, the present invention relates to a method for improving, maintaining or reducing motor function impairment, wherein the motor function may include motor mobility, gait and balance, dystonia, finger-tapping impairment and / or chorea.

[0056] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing motor mobility impairment in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by a UHDRS Total Motor Score (TMS), a UHDRS TMS score without chorea, or a UHDRS TMS score without dystonia.

[0057] In some embodiments, the present invention relates to a method for maintaining or reducing the level of dystonia in a subject with Huntington's disease or for slowing the worsening of dystonia in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by a UHDRS TMS dystonia score.

[0058] In some embodiments, the present invention relates to a method for reducing, maintaining, or slowing the deterioration of gait and balance in subjects with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by a UHDRS TMS gait and balance score.

[0059] In some embodiments, the present invention relates to a method for reducing, maintaining, or slowing the progression of chorea in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by a UHDRS TMS chorea score.

[0060] In some embodiments, the present invention relates to a method for reducing, maintaining, or slowing the deterioration of finger tapping speed frequency, finger tapping initiation interval, finger tapping interval, finger tapping peak interval, pronation / supination hand tapping frequency, hand tapping initiation interval, grip strength, tongue strength, or any combination thereof in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the motor function impairment is measured by a Q-Motor subscale for each mentioned impairment.

[0061] In some embodiments, the present invention relates to a method for improving, maintaining, or alleviating the decline in the behavior and / or psychotic state of a human patient with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the behavior and / or psychotic state is measured by one or more of the following scales: Stroop Word Reading Test (SWR), Symbolic Digit Modal Test (SDMT), Problem Behavior Assessment Short Form (PBA-s), Problem Behavior Assessment (PBA) total score, Problem Behavior Assessment of Depressive Mood, Problem Behavior Assessment of Irritability, Problem Behavior Assessment of Lack of Initiative or Apathy, Problem Behavior Assessment of Obsessive-Compulsive Disorder, or Problem Behavior Assessment of Disorientation.

[0062] In some embodiments, the present invention relates to a method for improving, maintaining, or mitigating cognitive impairment in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the cognitive impairment is measured by one or more of the following scales: the Connecting Test B (TMT-B), the HD Cognitive Assessment Kit (HD-CAB) (which comprises six tests), the Wright International Performance Scale, and the Peabody Picture Vocabulary Test.

[0063] In some embodiments, the present invention relates to a method for maintaining or reducing depression in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the depression is measured by the following: Hamilton Depression Rating Scale (HAM-D), Beck Depression Scale (BDI), Beck Despair Scale, Center for Epidemiological Studies-Depression Scale (CES-D), Patient Health Questionnaire, Center for Epidemiological Studies Childhood Depression Scale (CES-DC), Clinically Practical Depression Outcome Scale, Diagnostic Depression Scale, Edinburgh Postnatal Depression Scale (EPDS), Depressive Symptom Scale, Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Major Depression Scale (MDI), Montgomery-Asperger's Depression Rating Scale (MADRS), Mood and Feeling Questionnaire (MFQ), Zung's Self-Rating Depression Scale, or Cornell Dementia Depression Scale (CSDD).

[0064] In some embodiments, the present invention relates to a method for maintaining or reducing anxiety in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the anxiety impairment is measured by one of the following anxiety rating scales: State-Trait Anxiety Scale (STAI), Problem Behavior Assessment Short Form (PBA-S), Fear Questionnaire, Beck Anxiety Scale (BAI), Brief Fear Negative Appraisal Scale-BFNE, Physician's PTSD Scale (CAPS), Symptom-Anxiety Scale. The following are considered: daily assessment of anxiety, generalized anxiety disorder 7 (GAD-7), Hamilton Anxiety Rating Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibovitz 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 Scale (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive-Compulsive Disorder Scale (Y-BOCS), or Zung's Self-Rating Anxiety Scale.

[0065] In some implementations, behavioral or psychotic symptoms may include lack of initiative, apathy, or irritability.

[0066] In some embodiments, the present invention relates to a method for maintaining or reducing apathy in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein impairment of apathy is measured by one of the following apathy rating scales: Problem Behavior Assessment (PBA) total score, Problem Behavior Assessment Short Form (PBA-s), Problem Behavior Assessment of Lack of Initiative or Apathy, Problem Behavior Assessment Short Form Apathy Sub-item, Apathy Rating Scale (AES), and Problem Behavior Assessment of Dissociative Behavior.

[0067] In some embodiments, the present invention relates to a method for maintaining or reducing irritability in a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein irritability impairment is measured by one of the following irritability rating scales: Problem Behavior Assessment (PBA) total score, Problem Behavior Assessment Short Form (PBA-s). The behavior and / or psychotic status of human patients may also be measured by the Problem Behavior Assessment of Irritability.

[0068] In some embodiments, the present invention relates to a method for improving, maintaining, or reducing the impairment of reduced metabolic indicators in the brain of a subject with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein the metabolic indicators are measured by volumetric magnetic resonance imaging (MRI), functional MRI (fMRI), and metabolic imaging using 18F-fluoro-2-deoxy-D-glucose (18FDG)-PET of the caudate and putamen.

[0069] In some embodiments, the present invention relates to a method for improving, maintaining or reducing the impairment of the patient's quality of life and lifespan shortening in subjects with Huntington's disease, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein quality of life is measured by the Dementia Resource Utilization Simplified Version (RUD-Lite), the EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ-5D) (including, for example, the Proxy version (EQ-5D Proxy)).

[0070] In some embodiments, the present invention relates to a method for delaying the onset of disease progression in a subject with Huntington's disease, stopping disease progression in the subject, or slowing the decline of disease progression in the subject, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof; and at least one composition comprising a σ2 antagonist, wherein disease progression is measured by Clinical Global Change Impression (CGIC), Clinical Interview-Based Impression (CIBI), and Global Deterioration Scale (GDS). In some embodiments of the method of the present invention, the subject has ≥36 CAG repeats in the Huntington's gene. In some embodiments of the method of the present invention, the HD subject has been diagnosed with at least 36 CAG repeats in the Huntington's gene.

[0071] The active compound used according to the methods provided herein is in any form suitable for intended administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salt forms, deuterated forms, and prodrug or predrug forms of the compounds of the present invention.

[0072] In the implementation plan, the term "treatment of Huntington's disease" includes reducing one or more symptoms of Huntington's disease.

[0073] Composition In some embodiments, this document provides pharmaceutical compositions comprising pridopidine or a pharmaceutically acceptable salt thereof for use in the methods of the present invention.

[0074] In some embodiments, this document provides pharmaceutical compositions comprising pridopidine or a pharmaceutically acceptable salt thereof and pridopidine analog compounds 1-7 or a pharmaceutically acceptable salt thereof for use in the methods of the present invention.

[0075] In some embodiments, this document provides pharmaceutical compositions comprising at least one σ2 antagonist for use in the methods of the present invention.

[0076] In some embodiments, this document provides a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one σ2 antagonist. In another embodiment, the composition further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof.

[0077] In another embodiment, the σ2 antagonist includes CT1812, JVW-1009, SM-21, CT01344, CT1812, DKR-1677, SAS-0132,

[125] RHM-4, FA-10, or any combination thereof. In another embodiment, the σ2 antagonist is CT1812. In another embodiment, the σ2 antagonist is JVW-1009. In another embodiment, the σ2 antagonist is SM-21. In another embodiment, the σ2 antagonist is CT01344. In another embodiment, the σ2 antagonist is DKR-1677. In another embodiment, the σ2 antagonist is SAS-0132. In another embodiment, the σ2 antagonist is

[125] RHM-4. In another embodiment, the σ2 antagonist is FA-10.

[0078] σ2 antagonists CT1812, also known as Elayta, is represented by the following structure: It is a small molecule antagonist of the σ-2 receptor, which selectively binds to the receptor at the subunit of the progesterone receptor membrane component 1. CT1812 reduces the affinity of oligomeric Aβ to its receptor and interferes with Aβ-induced synaptic toxicity. CT1812 blocks the binding of different Aβ substances to neuronal receptors and displaces Aβ upon application after Aβ binding. It promotes brain clearance of Aβ oligomers and improves cognitive behavior in transgenic mouse models of Alzheimer's disease and displaces Aβ oligomers from human post-mortem AD brain tissue. Preclinical models have shown that CT1812 and related compounds in the CT family prevent downstream synaptic toxicity and restore memory in aged transgenic mouse models of Alzheimer's disease.

[20] CT1812 was well tolerated in healthy young and healthy elderly subjects at single doses up to 1120 mg and in multiple doses up to 840 mg and 560 mg, respectively. CT1812 is currently being investigated in an early phase 2 trial in patients with Alzheimer's disease.

[21]

[0079] JVW-1009 is represented by the following structure: Ki, a small molecule σ receptor ligand, has 96 nM and 70 nM for σ1 and σ2 respectively, reducing neurodegeneration in a model of amyloid precursor protein-mediated neurodegeneration in Caenorhabditis elegans

[22] .

[0080] The SM-21 is represented by the following structure: , It is a σ2 antagonist. Studies have shown that σ receptors, concentrated in brain structures that control movement such as the red nucleus and substantia nigra, are involved in the regulation of movement and posture

[23] .

[0081] CT01344 is represented by the following structure: As a selective antagonist of the σ-2 / progesterone receptor membrane component 1 (PGRMC1) receptor, it can cross the blood-brain barrier and displace the radioligand (3H-DTG) from the human B cell line (Ki=48 nM). It effectively blocks Aβ-mediated membrane transport (EC50=8.7 μM) and binding on cultured neurons (EC50=3.9 μM). It can reverse Aβ oligomer-mediated transport defects (EC50=7.3 μM), restore normal synaptic function, and improve cognitive function in a mouse model of Alzheimer's disease (10 mg / kg-30 mg / kg, po after 5.5 months). It is effective when added 1 hour before or after the Aβ oligomer preparation

[24] .

[0082] DKR-1677 is represented by the following structure: DKR-1677 targets σ2 receptor / TMEM97 (σ2R / TMEM97) with an affinity of 5.1 nM (Ki). The therapeutic application of DKR-1677 is neuroprotection in traumatic brain injury (TBI). DKR-1677 reduces axonal degeneration after burst-induced TBI, enhances the survival of cortical neurons and oligodendrocytes after CCI (controlled cortical shock) injury, and maintains cognition in the Morris water maze after burst-induced TBI

[25] .

[0083] SAS-0132, also known as AS-0132, is represented by the following structure: AS-0132 is an innovative and potent brain penetrant, a σ2 receptor / PGRMC1 ligand, exhibiting excellent selectivity and low off-target affinity for most CNS-related targets. With a Ki value of 90 nM and 9-fold selectivity relative to the σ1 receptor, SAS-0132 demonstrates significant binding affinity and subtype specificity. SAS-0132 regulates intracellular Ca2+ in human SK-N-SH neuroblastoma cells. 2+ The level of efficacy highlights its potential for treating neurological disorders. Furthermore, the neuroprotective properties of SAS-0132 in a *C. elegans* model of amyloid precursor protein-mediated neurodegeneration and its ability 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-penetrating σ2 receptor / PGRMC1 ligand with a Ki value of 90 nM and 9-fold selectivity relative to the σ1 receptor. SAS-0132's low off-target affinity for most CNS-related targets, neuroprotective properties, and potential for treating neurological disorders make it an exciting and valuable compound for future research and development in this field [25, 26].

[0084]

[125] RHM-4 is represented by the following structure: .

[0085] [125I]RHM-4 is a radioiodinated ligand with high affinity and selectivity for σ2R / TMEM97 relative to σ1R, making it a promising biomarker for tumor proliferation and a target for cancer therapy. [125I]RHM-4 was developed as an alternative to [3H]DTG, which has moderate binding affinity for both σ1R and σ2R / TMEM97 and can introduce bias in screening experiments when co-administered with σ1R masking compounds. A head-to-head comparison was performed between [3H]DTG and [125I]RHM-4, and the results indicated that [125I]RHM-4 is an improved radioligand for in vitro binding studies of σ2R / TMEM97. Furthermore, this study identified two binding regions in σ2R / TMEM97: a "DTG" binding site and a second binding site, responsible for the high affinity and selectivity for σ2R / TMEM97 relative to σ1R [28, 37].

[0086] FA-10, also known as a specific compound of 1,2,3,4-tetrahydroquinoline, is represented by the following structure: FA-10 exhibits low nanomolar S2R (σ2 receptor) affinity and an impressive 2807-fold S2R selectivity relative to S1R (σ1 receptor), significantly exceeding the biological profile of the best 3,4-dihydroisoquinoline compounds. It has no cytotoxic effects, exhibits moderate interaction with P-gp, possesses adequate lipophilicity, and is readily radiolabelable.

[0087] In some embodiments, the composition containing a σ2 antagonist comprises at least one σ2 antagonist. In some embodiments, the composition contains a σ2 antagonist, comprising at least two σ2 antagonists. In some embodiments, the composition containing a σ2 antagonist comprises at least three σ2 antagonists.

[0088] In another embodiment, the pridopidine analog compounds 1-7 are represented by the following structures: (1) (2) (3) (4) (5) (6) or (7).

[0089] In other embodiments, the composition used in the method of the present invention comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of pridopidine analog compounds 1-7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof, compound 1, and compound 4 or pharmaceutically acceptable salts thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 2 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 3 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 5 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 6 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 7 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or a pharmaceutically acceptable salt thereof and compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7 or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0090] In another embodiment, the pharmaceutical composition used in the method of the present invention, comprising at least one of pridopidine or a pharmaceutically acceptable salt and pridopidine analog compounds 1-7 or a pharmaceutically acceptable salt thereof, comprises each of the pridopidine analog compounds at a concentration between 0% w / w and 10% w / w relative to pridopidine. In another embodiment, the pharmaceutical composition comprises each of the analog compounds 1-7 at a concentration between 0.005% w / w and 5% w / w relative to pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises each of the analog compounds 1-7 at a concentration between 0.001% w / w and 1% w / w relative to pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises each of the analog compounds 1-7 at a concentration between 0.05% w / w and 3% w / w relative to pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises each of the analog compounds 1-7 of pridocipidine in the range of 0.005% w / w-0.1% w / w, 0.05% w / w-0.1% w / w, 0.05% w / w-0.15% w / w, 0.05% w / w-0.2% w / w, 0.05% w / w-0.5% w / w, 0.05% w / w-2% w / w, 0.05% w / w-3% w / w, 0.05% w / w-4% w / w, 0.05% w / w-5% w / w, 0.1% w / w-0.4% w / w, 0.15% w / w-0.3% w / w, and 0.15% w / w-0.5% w / w, or a pharmaceutically acceptable salt thereof.

[0091] In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 0.05% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 10% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 20% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 30% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 40% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 50% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 60% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 70% w / w and 90% w / w. In another embodiment, the pharmaceutical composition comprises pridopidine or a pharmaceutically acceptable salt thereof at a concentration between 80% w / w and 90% w / w. In yet another embodiment, the pharmaceutical composition comprises about 10% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, 55% w / w, 60% w / w, 65% w / w, 70% w / w, 75% w / w, 80% w / w, 85% w / w, 90% w / w, 95% w / w, or 98% w / w of pridopidine or a pharmaceutically acceptable salt thereof.

[0092] In another embodiment, the pharmaceutical composition comprises about 70% w / w pridopidine or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises about 80% w / w pridopidine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the pharmaceutical composition comprises about 90% w / w pridopidine or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compositions of the present invention comprise pridopidine or a pharmaceutically acceptable salt thereof in the range of 10 mg to 300 mg. In another embodiment, the compositions comprise pridopidine or a pharmaceutically acceptable salt thereof in the ranges of 10 mg-50 mg, 10 mg-100 mg, 10 mg-150 mg, 10 mg-250 mg, 50 mg-300 mg, 50 mg-100 mg, 50 mg-150 mg, 50 mg-250 mg, 100 mg-300 mg, 100 mg-200 mg, and 150 mg-300 mg. In another embodiment, the composition of the present invention comprises about 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg or any range thereof of pridopidine or a pharmaceutically acceptable salt thereof.

[0094] In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:10000 and 1:1. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:10000 and 1:500. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:10000 and 1:10. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:1000 and 1:1. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:1000 and 1:500. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:500 and 1:200. In another embodiment, the molar ratio between one or more σ2 antagonists and pridopidine or a pharmaceutically acceptable salt thereof is between 1:500 and 1:10.

[0095] In some embodiments, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to one or more σ2 antagonists is about 1:9999 to about 9999:1. In another embodiment, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to one or more σ2 antagonists is about 1:999 to about 999:1. In yet another embodiment, the weight ratio of pridopidine or a pharmaceutically acceptable salt thereof to one or more σ2 antagonists is about 1:99 to about 99:1.

[0096] In some embodiments, the pridopidine and / or pridopidine analog compounds (each compound 1-7) of the pharmaceutical compositions of the present 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, sulfate, hydrogen sulfate, formate, gluconate, glucuronide, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, gentianate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, hydrogen tartrate, and p-toluenesulfonate, as well as embonate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarbamate)). Each represents a separate embodiment of the invention. In another embodiment, pridopidine is in the form of an HCl salt. In another embodiment, the pridopidine analog compound is in the form of an HCl salt.

[0097] In some embodiments, the pharmaceutical compositions provided herein are formulated with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or preventative ingredients known and used in the art. The carrier must be "acceptable" in the sense of compatibility with other components of the formulation and harmless to the recipient.

[0098] In some embodiments, the pharmaceutical compositions provided herein are formulated together with one or more excipients, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical adjuvants.

[0099] Further details regarding the techniques used in formulation and application can be found in the latest version. Remington's Pharmaceutical Sciences Found in (Mack Publishing Co., Easton, PA).

[0100] In some embodiments, the pharmaceutical composition used in the methods of the present invention comprises one or more pharmaceutically acceptable carriers or excipients.

[0101] In some implementations, the pharmaceutically acceptable carrier or excipient is selected from the group consisting of: adhesives, fillers, plasticizers, flow aids, and lubricants, and mixtures thereof.

[0102] In some embodiments, the adhesive is selected from the group consisting of: starch, pregelatinized starch, polyethylene oxide, cellulose polymers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof.

[0103] In some embodiments, the filler is selected from the group consisting of: microcrystalline cellulose, glycospheres, lactose, sorbitol, dextrose, sucrose, mannitol, dicalcium phosphate or tricalcium phosphate, calcium sulfate, starch, retalac and mixtures thereof.

[0104] In some implementations, the filler is microcrystalline cellulose, and specifically silicified microcrystalline cellulose.

[0105] In some embodiments, the filler is lactose. In another embodiment, the filler is a mixture of microcrystalline cellulose and lactose, wherein the microcrystalline cellulose is silicified microcrystalline cellulose. In another embodiment, the filler is microcrystalline cellulose and is silicified microcrystalline cellulose.

[0106] In some embodiments, the pharmaceutical composition comprises silanized microcrystalline cellulose and magnesium stearate as excipients.

[0107] In some embodiments, the lubricant is selected from the group consisting of: sodium stearoyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.

[0108] In some implementations, the lubricant is magnesium stearate.

[0109] In some embodiments, the gliding agent is selected from the group consisting of: starch, pregelatinized starch, silica, colloidal silica, talc, and mixtures thereof.

[0110] In some implementations, the flow aid is colloidal silica.

[0111] The pharmaceutical compositions of the present invention can be administered via any convenient route suitable for the desired therapy. Preferred routes of administration include oral administration, in tablet, capsule, bead, small tablet, multigranule, powder, or liquid form; and parenteral administration, skin, eye, eye drops, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical compositions of the present invention can be manufactured by a person skilled in the art using standard methods and conventional techniques suitable for the desired formulation. When desired, compositions suitable for the sustained release of the active ingredient can be employed.

[0112] In some implementations, multiparticle or multiunit dosage forms are discrete, small, repeating drug particle units that may or may not have a similar drug release pattern.

[0113] As used herein, the amount of pridopidine measured in milligrams refers to the number of milligrams of pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) present in the product, regardless of the form of the product. For example, a unit dose containing "90 mg pridopidine" means that the amount of pridopidine base in the product is 90 mg, regardless of the form of the product. Therefore, when in salt form, such as pridopidine hydrochloride, the weight of the salt form required to provide a dose of 90 mg pridopidine will be greater than 90 mg due to the presence of the salt.

[0114] As used herein, “treat” or “treating” encompasses, for example, reducing symptoms of disorder and / or disease, inducing inhibition, extinction, or cessation of disorder and / or disease. As used herein, “inhibition” of disease progression or disease complications in a subject means prevention or reduction of disease progression and / or disease complications in the subject.

[0115] The term "pharmaceutically acceptable salt" refers to a salt selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid phosphate, sulfate, hydrogen sulfate, formate, gluconate, glucuronide, glycosylate, isonicotinate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, bis(hydroxynaphthyl)ate, heptate, fumarate, glutamate, glycolate, lactate, maleate, gentianate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, hydrogen tartrate, and p-toluenesulfonate, as well as bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate).

[0116] List of abbreviations and definitions of terms The following abbreviations are used throughout this application: CAB: Cognitive Assessment Kit; CAG: Cytosine-Adenosine-Guanine; CGI-C: Clinical Global Change Impression; CIBIC-Plus: Change Impression Based on Clinician Interviews plus Staff Input; CIBIS: Severity Impression Based on Clinician Interviews; FA: Functional Assessment; HD: Huntington's Disease; HD-QoL: Quality of Life with Huntington's Disease; Htt: Huntington's Gene; IS: Independence Scale; PDS: Physical Disability Scale; PPT: Physical Function Test; Q- Motor: Quantitative Motor Skills; QoL: Quality of Life; S2R: σ2 Receptor; SDMT: Symbolic Digit Modality Test; TFC: Total Functional Capacity; TMS: Total Motor Skills Score; TUG: Timed Stand-Up and Walk; UHDRS: Unified Huntington's Disease Rating Scale; CUHDRS: Composite Unified Huntington's Disease Rating Scale; MSWS-12: Multiple Sclerosis Walk Scale-12; PPT: Physical Function Test; TUG: Timed Stand-Up and Walk; HD-HI: Huntington's Disease Health Index; AES: Apathy Assessment Scale; S2R: σ2 Receptor; SWR: Stroop Word Reading Test; SDMT: Symbolic Digit Modality Test; CIBIC-Plus: Impression of Change Based on Clinician Interviews plus Staff Input; PDS: Physical Disability Score; FA: Functional Assessment; CGI-C: Clinical Global Impression of Change; CGI-S: Clinician Global Severity Impression; PGI-C: Patient Global Impression of Change; PGI-S: Patient Global Severity Impression; EQ-5D-5L: EuroQol 5 dimensions and 5 levels; Walk-12: Walk-12 scale; mPPT: Modified Physical Function Test.

[0117] Example Example 1: The combination of pridopidine and the S2R antagonist (FA-10) demonstrated unexpected and enhanced neuroprotection against mHTT-induced cell death.

[0118] This study investigated the effects of pridopidine and the S2R selective antagonist FA-10 on mHTT-induced cell death in a HD cell model.

[0119] Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) is a highly selective S1R ligand with Ki = 57 nM, an S2R Ki of 5450, and 95-fold higher selectivity for S1R relative to S2R. [9] (Table 1). FA-10 (1-(3-[6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-yl)propyl]-5-methoxy-1,2,3,4-tetrahydroquinoline) is a highly selective S2R ligand with Ki = 1.42 nM, an S1R Ki of 3987 nM, and 2807-fold higher selectivity for S2R relative to S1R.

[36] (Table 1).

[0120] The HD model utilizes primary mouse cortical neurons transfected with either the mutant huntingtin gene (mHtt N586-82Q) or WT N586-22Q. N586-82Q contains the initial 586 amino acids of the huntingtin protein, including an uninterrupted polyglutamine sequence containing 82 consecutive glutamine residues (82 CAG repeats in the mHtt gene). N586-22Q contains 22 polyglutamine repeats, representing the normal Htt protein.

[0121] Following transfection, neurons were either untreated (control) or treated with pridopidine and FA-10 alone or in combination for 4 hours. Forty-eight hours post-transfection, neuronal cell death was measured by a nuclear aggregation assay (% cell death), a validated and commonly used method for detecting apoptosis by assessing changes in chromatin structure.

[0122] Table 1. Pridopidine is a highly selective S1R agonist and FA-10 is a highly selective S2R antagonist. (Johnston et al. 2018[9], Mauro et al. 2016

[36] ) Compared to each compound alone, the combination of pridopidine and the selective S2R antagonist FA-10 showed an unexpectedly enhanced neuroprotective effect.

[0123] Neurons transfected with the mHtt 82Q gene (hereinafter referred to as "HD cells") exhibited a robust increase in cytotoxicity compared to neurons transfected with the WT Htt 22Q gene (hereinafter referred to as "WT cells"). Treatment of HD cells with pridopidine and FA-10 alone demonstrated a significant reduction in toxicity. Both S1R activation and S2R inhibition resulted in neuroprotection against mHTT-induced toxicity. This article presents the combination of pridopidine and FA-10 in the mHTT-induced toxicity assay. The combination was evaluated at suboptimal and optimal doses of pridopidine (0.001 μM, 0.01 μM, 0.1 μM, and 1 μM) and FA-10 (0.0001 μM, 0.001 μM, and 0.003 μM). Analysis of variance revealed significant differences between treatment groups (F(20,96) = 9.615; p < 0.0001). Notably, a post-hoc Dunnett test showed that the lowest tested doses of pridopidine (0.001 μM) and FA10 (0.0001 μM), which had only moderate effects when tested alone, exhibited enhanced rescue effects against mHTT-induced neurotoxicity when administered in combination. Compared to either compound alone (pridopidine (0.001 μM), 33% reduction in neuronal death, p<0.05; FA10 (0.0001 μM), 32% reduction in neuronal death, p<0.01), the combination of pridopidine (0.001 μM) and FA10 (0.0001 μM) resulted in superior effects (54% reduction in neuronal death, p<0.0001). Figure 1 (See Table 1). In combination therapy, we found that pridopidine (1 μM) and FA10 (0.003 μM) provided the strongest neuroprotective effect (74% reduction in neuronal death, p<0.0001), which was greater than either treatment alone (pridopidine (1 μM), 51% reduction in neuronal death, p<0.0001; FA10 (0.003 μM), 46% reduction in neuronal death, p<0.0001). Figure 2 (See Table 1). The combination therapy of pridopidine and FA10 had minimal effect on control neurons (Table 2). These results support the hypothesis that simultaneous activation and inhibition of S1R and S2R provide enhanced neuroprotection compared to either activation or inhibition of S2R alone.

[0124] These results support the hypothesis that simultaneous activation of S1R and inhibition of S2R provide enhanced neuroprotection compared to either activation of S1R or inhibition of S2R alone.

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Claims

1. A method for treating, preventing, alleviating, delaying the onset of symptoms of Huntington's disease or slowing the progression of Huntington's disease in subjects with appropriate need, the method comprising administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and at least one composition comprising a σ2 antagonist.

2. The method of claim 1, wherein the composition comprising pridopidine or a pharmaceutically acceptable salt thereof further comprises at least one pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof, wherein the pridopidine analog compound 1-7 or a pharmaceutically acceptable salt thereof is represented by the following structure: (1)、 (2)、 (3) (4) (5) (6) or (7).

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

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

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

6. The method according to any one of claims 1-4, wherein the σ2 antagonist comprises CT1812, JVW-1009, SM-21, CT01344, DKR-1677, SAS-0132, [125]RHM-4 or a combination thereof.

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

8. The method of claim 7, wherein the symptoms of Huntington's disease include impaired functional capacity, impaired motor function, cognitive impairment, anxiety and depression, elevated anti-inflammatory biomarkers, decreased brain-derived neurotrophic factor (BDNF), increased neurofilament light chains (NfL), memory impairment, deterioration of structural, functional and metabolic indicators, impaired quality of life, decline in physical symptoms, decline in mental symptoms, disease progression, mood symptoms, behavioral symptoms, psychotic symptoms and / or shortened 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-Chorus Disease Score, UHDRS-Dystonia Score, Eye Movement Score, Hand Movement Score, Gait and Balance Score, Timed Stand and Walk (TUG) Assessment, Huntington's Disease Health Index (HD-HI) and Finger Typing Assessment, UHDRS TMS score, Problem Behavior Assessment (PBA) total score, PBA for depressive mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessive-compulsive disorder, or PBA for lost behavior, Connecting Test B (TMT-B), HD Cognitive Assessment Kit (HD-CAB), Hamilton Depression Rating Scale (HAM-D), Problem Behavior Assessment Short Form (PBA-S) scale, Hamilton Anxiety Rating Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibovitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and General Anxiety Rating Scale (GGRS). The following scales are included: Paraphobia 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 Sub-item, Apathy Rating Scale (AES), and PBA for Lost Behavior, HD-Quality of Life Scale (HD-QoL), Stroop Word Reading Test (SWR), Symbolic Digit Modal Test (SDMT), Quantitative Motor Assessment (Q-Motor), Timed Stand-Up and Walk (TUG) Assessment, Cognitive Assessment Kit (CAB), and Huntington's Disease Health Index (HD-HI).

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

11. The method or use according to any one of claims 7-9, wherein functional ability, motor function, cognition and quality of life are measured by the Composite Unified Huntington's Disease Rating Scale (cUHDRS).

12. The method according to any one of claims 7-9, wherein the motor function impairment is measured by the following: the Composite Unified Huntington's Disease Rating 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)-Chorus disease score, the Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia score, the Multiple Sclerosis Gait Scale (MSWS-12), Physical Function Test (PPT), eye movement score, hand movement score, gait and balance score, Timed Stand and Walk (TUG) assessment, Huntington's Disease Health Index (HD-HI), and finger tracing (finger tapping) assessment.

13. The method according to any one of claims 7-9, wherein the motor function impairment is measured by: finger kinematics (rapid index finger tapping), alternating kinematics (pronation / supination hand tapping), hand kinematics and choreiform kinematics (grip strength and chorea analysis) and foot kinematics (rapid foot tapping).

14. The method according to any one of claims 1-13, wherein the salt of pridopidine or the salt of a pridopidine analogue compound is selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid phosphate, sulfate, hydrogen sulfate, formate, gluconate, glucuronide, glycosylate, isonicotinate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, bis(hydroxynaphthyl)ate, heptate, fumarate, glutamate, glycolate, lactate, maleate, gentianate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, hydrogen tartrate, and p-toluenesulfonate, bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate).

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

16. The method according to any one of claims 1-15, wherein the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the at least one composition comprising a σ2 antagonist are each administered independently via an oral route, nasal route, inhalation route, intracranial route, subcutaneous route, intravenous route, intraperitoneal route, intramuscular route, intranasal route, sublingual route, vaginal route, rectal route, intraocular route, intrathecal route, local route, or intradermal route.

17. The method according to any one of claims 1-16, wherein the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the at least one composition comprising a σ2 antagonist are each administered orally.

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

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

20. The method according to any one of claims 1-19, wherein the composition comprising pridopidine or a pharmaceutically acceptable salt thereof and the at least one composition comprising a σ2 antagonist are administered sequentially or simultaneously in any order at a daily dose.

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