Biomarkers for neurodegenerative diseases

Abstract

A method for monitoring and treating a subject having ALS based on a biomarker. In some embodiments, the method comprises identifying that the subject has a ratio of LPS1EGF associated with ALS; and based on the identification that the subject has a ratio of LPS:EGF associated with ALS, determining that the subject is eligible for sodium chlorite treatment for ALS, determining whether to continue a treatment regimen of sodium chlorite based on the ratio of LPS:EGF; wherein the ratio of LPS:EGF in the subject is 50 or less, and the treatment regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day administered orally and / or parenterally.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 343,568, filed May 19, 2022; U.S. Provisional Patent Application No. 63 / 392,237, filed Jul. 26, 2022; U.S. Provisional Patent Application No. 63 / 410,724, filed Sep. 28, 2022; and U.S. Provisional Patent Application No. 63 / 484,678, filed Feb. 13, 2023, each of which is hereby incorporated by reference in its entirety.

Background Art

[0002] Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that destroys motor neurons in the brain and spinal cord. ALS ultimately leads to paralysis and death, often within 2 - 4 years of diagnosis.

[0003] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference as if each individual publication, patent, or patent application had been specifically and individually indicated to be incorporated by reference.

Summary of the Invention

Means for Solving the Problems

[0004] Abstract Described herein are methods for monitoring and treating a subject having ALS based on biomarkers.

[0005] In some embodiments, the method includes: (a) determining that a subject has an LPS:EGF ratio associated with ALS; and (b) based on the determination that the subject has an LPS:EGF ratio associated with ALS, determining that the subject is eligible for sodium chlorite treatment for ALS. In some embodiments, the method includes: (a) determining that a subject has a level of TGFB1 associated with ALS; and (b) based on the determination that the subject has a level of TGFB1 associated with ALS, determining that the subject is eligible for sodium chlorite treatment for ALS. In some embodiments, the method includes: (a) determining that a subject has a level of LBP associated with ALS; and (b) based on the determination that the subject has a level of LBP associated with ALS, determining that the subject is eligible for sodium chlorite treatment for ALS.

[0006] In some embodiments, the method includes treating ALS in a subject in need of treatment for ALS, the method including: (a) determining that a subject has an LPS:EGF ratio associated with ALS; and (b) based on the determination that the subject has an LPS:EGF ratio associated with ALS, administering to the subject a therapeutically effective amount of sodium chlorite for ALS. In some embodiments, the method includes a method of treating ALS in a subject in need of treatment for ALS, the method including: (a) determining that a subject has a level of TGFB1 associated with ALS; and (b) based on the determination that the subject has a level of TGFB1 associated with ALS, administering to the subject a therapeutically effective amount of sodium chlorite for ALS. In some embodiments, the method includes a method of treating ALS in a subject in need of treatment for ALS, the method including: (a) determining that a subject has a level of LBP associated with ALS; and (b) based on the determination that the subject has a level of LBP associated with ALS, administering to the subject a therapeutically effective amount of sodium chlorite for ALS.

[0007] In some embodiments, the method comprises: (a) determining the ratio of LPS:EGF in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a treatment regimen of sodium chlorite; and (b) determining whether to continue the treatment regimen of sodium chlorite based on the ratio of LPS:EGF. In some embodiments, the method comprises: (a) determining the level of TGFB1 in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a treatment regimen of sodium chlorite; and (b) determining whether to continue the treatment regimen of sodium chlorite based on the level of TGFB1. In some embodiments, the method comprises: (a) determining the level of LBP in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a treatment regimen of sodium chlorite; and (b) determining whether to continue the treatment regimen of sodium chlorite based on the level of LBP.

[0008] In some embodiments, the method comprises: (a) obtaining a first level of inflammatory macrophages in the intestinal epithelium of a subject having ALS, wherein the first level of inflammatory macrophages in the intestinal epithelium of the subject having ALS is based on a blood assay; (b) initiating the subject on a regimen of sodium chlorite administration for a period of about six months, based at least in part on the first level of inflammatory macrophages in the intestinal epithelium of the subject; (c) after the period, obtaining a second level of inflammatory macrophages in the intestinal epithelium of the subject; (d) determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject; and (e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject.

[0009] In some embodiments, the method comprises: (a) obtaining a first level of LBP of a subject having ALS, wherein the first level of LBP of the subject having ALS is based on a blood assay; (b) starting the subject on a regimen of sodium chlorite administration for a period of at least about six months, based at least in part on the first level of LBP of the subject; (c) obtaining a second level of LBP of the subject after the period; (d) determining that the second level of LBP is lower than the first level of LBP of the subject by a predetermined threshold amount; and (e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of LBP is lower than the first level of LBP of the subject by a predetermined threshold amount.

[0010] In some embodiments, the method comprises: (a) obtaining a first level of TGFB1 of a subject having ALS, wherein the first level of TGFB1 of the subject having ALS is based on a blood assay; (b) starting the subject on a regimen of sodium chlorite administration for a period of at least about six months, based at least in part on the first level of TGFB1 of the subject; (c) obtaining a second level of TGFB1 of the subject after the period; (d) determining that the second level of TGFB1 is higher than the first level of TGFB1 of the subject by a predetermined threshold amount; and (e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of TGFB1 is higher than the first level of TGFB1 of the subject by a predetermined threshold amount.

[0011] In some embodiments, the method comprises: (a) obtaining a first plasma neurofilament light chain level of a subject having ALS, wherein the first plasma neurofilament light chain level of the subject having ALS is based on a blood assay; (b) initiating the subject on a regimen of sodium chlorite administration over a period of about six months, at least partially based on the first plasma neurofilament light chain level of the subject; (c) obtaining a second plasma neurofilament light chain level of the subject after the period; (d) determining that the second plasma neurofilament light chain level of the subject is a decrease of at least a predetermined threshold amount compared to the first plasma neurofilament light chain level of the subject; and (e) recommending that the subject continue the regimen of sodium chlorite administration, at least partially based on determining that the second plasma neurofilament light chain level of the subject is a decrease of at least a predetermined threshold amount compared to the first plasma neurofilament light chain level of the subject.

[0012] In some embodiments, the method includes a method of treating ALS in a subject in need of treatment for ALS, the method comprising: (a) obtaining a first level of a first biomarker in the subject; (b) obtaining a first level of a second biomarker in the subject; (c) after obtaining the first level of the first biomarker in the subject and obtaining the first level of the second biomarker in the subject, initiating the subject on a regimen of sodium chlorite administration for a period of at least about six months; (d) after the period, obtaining a second level of the first biomarker in the subject; (e) after the period, obtaining a second level of the second biomarker in the subject; (f) determining that the first level of the first biomarker in the subject is greater than the second level of the first biomarker in the subject; (g) determining that the first level of the second biomarker in the subject is less than the second level of the second biomarker in the subject; and (h) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the first level of the first biomarker in the subject is greater than the second level of the first biomarker in the subject and determining that the first level of the second biomarker in the subject is less than the second level of the second biomarker in the subject.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0041] Detailed Description of the Invention Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal neurodegenerative disease associated with inappropriate immune system dysfunction, including NF - kB activation, production of pro - inflammatory factors, and progressive changes in motor neuron function. Factors produced by spinal cord microglia damage neurons damaged by the accumulation of misfolded proteins and inhibit their repair. Inflammation and immune system dysregulation are involved in the progression of ALS, including the presence of activated macrophages in ALS patients. Compounds that can probably reduce inflammation and immune system dysregulation by returning macrophages to their inactivated state may be effective in treating ALS or other disorders associated with immune system dysfunction.

[0042] Macrophages are white blood cells produced by the division of monocytes that play a role in innate immunity (non-specific immune defense) and assist in the initiation of adaptive immunity (specific defense mechanisms). The cells phagocytize (i.e., engulf and then digest) cell debris and pathogens as stationary or mobile cells. When activated by pathogens or other mechanisms, macrophages stimulate and mobilize lymphocytes and other immune cells to respond. Activated macrophages are involved in the progression of several diseases and disorders, including amyotrophic lateral sclerosis (ALS). Activated macrophages induce massive leukocyte infiltration and flood the surrounding tissue with inflammatory mediators, apoptosis-promoting factors, and matrix-degrading proteases. These actions can lead to inflammation that has the potential to damage tissues to the point of causing severe injury. Tissue destruction caused by macrophage-induced inflammation, a form of immune system dysregulation, may be associated with the progression of the degenerative disease ALS.

[0043] ALS patients can be defined by four generalized patient groups: slowly progressive, rapidly progressive, early disease onset, and late disease onset. Of the four categories, only the slowly progressive patient group includes inflammation as an important aspect of ALS disease pathology. The association of the slowly progressive subset with inflammation was inferred during ALS research in relation to C-reactive protein (CRP) levels over time from diagnosis. The longer the lifespan of ALS patients after diagnosis, the higher the plasma CRP. This is evidence that a large subgroup of ALS patients has ongoing inflammation associated with a slower rate of progression and potentially increasing inflammation. A method for identifying ALS patients with inflammation is needed to treat such ALS patients with targeted immunomodulatory therapy.

[0044] ALS can also be distinguished by ALS symptoms, genetic causes, lack of clear genetic associations, or combinations thereof. In some embodiments, a subject having ALS can be classified as sporadic ALS or hereditary ALS. Sporadic ALS pathology occurs in subjects without a genetic or family history of ALS, while hereditary ALS pathology occurs in subjects with a genetic or family history of ALS. 90% - 95% of ALS cases can be sporadic and occur in subjects without a genetic or family history of ALS.

[0045] Mutations to one or more genes can be associated with subjects experiencing either hereditary or sporadic ALS pathology. For example, 60% of individuals with familial ALS can have identified gene mutations to one or more genes associated with the symptoms. In some embodiments, a subject experiencing either form of hereditary ALS pathology has a hereditary mutation to one or more of the genes listed in Table 1. Mutations in the C9orf72 gene account for 30% - 40% of hereditary ALS in the United States and Europe; worldwide SOD1 gene mutations cause 15% - 20% of hereditary ALS; and TARDBP and FUS gene mutations each account for approximately 5% of cases of hereditary ALS.

[0046] In some embodiments, mutations to one or more of the genes listed in Table 1 can be important for the normal function of motor neurons and other cells, and mutations to one or more of these genes can contribute to the decreased function or death of motor neurons in ALS patients. In some embodiments, mutations to one or more of the genes in Table 1 can contribute to decreased motor neuron function or neuron death as a result of the accumulation of protein aggregates in motor neurons, the deceleration of the transport of materials necessary for the proper function of axons in motor neurons, the accumulation of toxic substances in motor neurons, or combinations thereof.

Table 1-1

Table 1-2

[0047] The first event in ALS pathogenesis occurs at the neuromuscular junction where the axonal processes of neurons interact with muscle outside the central nervous system. This reaction is inflammatory and is mediated by components of the innate immune system including acute-phase reactant proteins as well as blood-derived granulocytes and macrophages. The trigger event may be related to the presence of abnormally folded or aggregated proteins associated with ALS (such as TDP43 and SOD-1, etc.) that are recognized by the innate immune system within the neuromuscular junction. Normally, immediately after the acute-phase reaction, immune signals follow that turn off the reaction to maintain the balance of the immune system. Thus, the plasma-based or humoral innate immune system provides feedback against activated macrophages which are the cellular drivers of inflammation and balances inflammatory and anti-inflammatory immune signals. Proteins associated with the acute-phase innate immune response can be measured in the blood, and one C-reactive protein (CRP) enables a quantitative determination of the degree of inflammation associated with the disease.

[0048] Plasma CRP levels rise rapidly by more than 30 - fold in the acute - phase response but decline rapidly as the initiator of inflammation is controlled. Two categories of injury mainly cause the synthesis of CRP from the liver: infection and tissue damage. Infection can trigger both the innate and adaptive responses such that the blood levels of factors produced by both immune responses are present in the plasma. CRP appears rapidly after injury and is regarded as a marker of inflammation severity, but its general function is to facilitate phagocytic clearance of foreign materials. Furthermore, CRP down - regulates other pro - inflammatory components of the innate immune response, reducing the production of inflammatory by - products. Thus, when CRP levels are chronically elevated, an ongoing infectious or tissue - damage process may be driving the persistent CRP response. Continuous tissue damage without the persistence of the acute - phase process suggests that the innate immune response fails to bind to the signals that normally drive that response.

[0049] Other plasma factors involved in the innate immune response include serum amyloid A (SAA), whose levels increase in parallel with CRP. SAA binds to and removes bacterial by - products such as lipopolysaccharide (LPS). Alpha2 - macroglobulin (A2M) is activated when the acute - phase reaction is initiated and removes the by - products of damaged cells, particularly proteases. Further activated by hypochlorite, a by - product of the oxidative burst reaction initiated by phagocyte (granulocyte, macrophage) activation, A2M forms a dimer, releases pre - formed TGFB1, and binds to and removes misfolded proteins and aggregates.

[0050] The innate immune system responds rapidly to infection and / or tissue damage. Within minutes, the acute - phase reactants CRP and serum amyloid A (SAA) increase by more than 30 - fold in plasma. Once the inflammatory response is initiated, it is necessary to remove or neutralize the by - products of that response to avoid significant tissue damage. CRP facilitates the clearance of dead cells and protein aggregates. SAA binds to and removes the products of bacterial clearance mediated by activated phagocytes such as LPS.

[0051] TGFB1 is a potent regulator of inflammation and downregulates inflammation drive. Together, CRP, SAA, and A2M represent major humoral components of the innate immune system and cooperate to regulate the degree of inflammatory responses associated with activated cellular components (macrophages, granulocytes) of the response.

[0052] NP001 can enhance the innate immune activation cycle in ALS patients with elevated baseline plasma CRP. The innate immune activation cycle is a self-regulatory process that occurs after the immune system is exposed to infection or tissue damage. Initiators of immune system activation can be the presence of misfolded or aggregated proteins, including TDP43.

[0053] In response to activation of the immune system, blood-derived macrophages undergo an oxidative burst and release hypochlorous acid as a byproduct. The acute-phase response is accompanied by increases in CRP and SAA. CRP promotes the clearance of damaged cells and tissues. SAA binds to bacterial byproducts, including LPS, and removes it. A2M is activated to remove damaged cell products, including proteases. Hypochlorous acid stimulates the production of taurine chloramine (TauCl) and promotes the dimerization of A2M. The A2M dimer removes misfolded proteins, releases pre-synthesized TGFB1, provides feedback to pro-inflammatory cells, and turns off NFkB. NP001 is converted to HClO in vivo and stimulates the dimerization of A2M and subsequent release of pre-synthesized TGFB1.

[0054] Method Disclosed herein is a method of identifying a subject having ALS who may be responsive to immunomodulatory therapy. In some embodiments, disclosed herein is a method of treating a subject having slowly progressive ALS with a pharmaceutical composition comprising sodium chlorite. In some embodiments, pharmaceutical compositions for use in treating symptoms, such as ALS, Parkinson's disease, Alzheimer's disease, chronic obstructive pulmonary disease (COPD), or colitis, are disclosed herein.

[0055] Compositions and methods for treating neurodegenerative diseases are disclosed herein. Non-limiting examples of neurodegenerative diseases include amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), Alzheimer's disease, vascular dementia, Parkinson's disease, multiple sclerosis, and primary progressive multiple sclerosis. In some embodiments, the neurodegenerative disease is ALS. In some embodiments, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the neurodegenerative disease is Parkinson's disease. Treatment can include, for example, a formulation of sodium chlorite.

[0056] Identifying that a subject has a level or ratio of one or more biomarkers associated with ALS; and determining that the subject is eligible for treatment with sodium chlorite for ALS based on the identification that the subject has a level or ratio of one or more biomarkers associated with ALS are disclosed herein.

[0057] In some embodiments, the method includes (a) identifying that a subject has a ratio of LPS:EGF associated with ALS; and (b) determining that the subject is eligible for treatment with sodium chlorite for ALS based on the identification that the subject has a ratio of LPS:EGF associated with ALS.

[0058] In some embodiments, the method includes (a) identifying that a subject has a level of TGFB1 associated with ALS; and (b) determining that the subject is eligible for treatment with sodium chlorite for ALS based on the identification that the subject has a level of TGFB1 associated with ALS.

[0059] In some embodiments, the method includes (a) identifying that a subject has a level of LBP associated with ALS; and (b) determining that the subject is eligible for treatment with sodium chlorite for ALS based on the identification that the subject has a level of LBP associated with ALS.

[0060] In some embodiments, the method further comprises recommending that a subject receive sodium chlorite treatment for ALS based on determining that the subject is eligible for sodium chlorite treatment for ALS.

[0061] Disclosed herein is a method of treating ALS in a subject in need thereof, comprising identifying that the subject has a level or ratio of one or more biomarkers associated with ALS; and administering to the subject a therapeutically effective amount of sodium chlorite for ALS based on the identifying that the subject has a level or ratio of one or more biomarkers associated with ALS.

[0062] In some embodiments, the method comprises treating ALS in a subject in need thereof, the method comprising: (a) identifying that the subject has an LPS:EGF ratio associated with ALS; and (b) administering to the subject a therapeutically effective amount of sodium chlorite for ALS based on the identifying that the subject has an LPS:EGF ratio associated with ALS.

[0063] In some embodiments, the method comprises a method of treating ALS in a subject in need thereof, the method comprising: (a) identifying that the subject has a level of TGFB1 associated with ALS; and (b) administering to the subject a therapeutically effective amount of sodium chlorite for ALS based on the identifying that the subject has a level of TGFB1 associated with ALS.

[0064] In some embodiments, the method comprises a method of treating ALS in a subject in need thereof, the method comprising: (a) identifying that the subject has a level of LBP associated with ALS; and (b) administering to the subject a therapeutically effective amount of sodium chlorite for ALS based on the identifying that the subject has a level of LBP associated with ALS.

[0065] Determining the level or ratio of one or more biomarkers in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a therapeutic regimen of sodium chlorite; and determining whether to continue the therapeutic regimen of sodium chlorite based on the level or ratio of one or more biomarkers, are disclosed herein.

[0066] In some embodiments, the method comprises: (a) determining the ratio of LPS:EGF in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a therapeutic regimen of sodium chlorite; and (b) determining whether to continue the therapeutic regimen of sodium chlorite based on the ratio of LPS:EGF.

[0067] In some embodiments, the method comprises: (a) determining the level of TGFB1 in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a therapeutic regimen of sodium chlorite; and (b) determining whether to continue the therapeutic regimen of sodium chlorite based on the level of TGFB1.

[0068] In some embodiments, the method comprises: (a) determining the level of LBP in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a therapeutic regimen of sodium chlorite; and (b) determining whether to continue the therapeutic regimen of sodium chlorite based on the level of LBP.

[0069] In some embodiments, the method further comprises determining to discontinue the regimen of sodium chlorite. In some embodiments, the method further comprises determining to continue the regimen of sodium chlorite.

[0070] (a) Obtaining a first level of one or more biomarkers of a subject having ALS, wherein the first level of the one or more biomarkers of the subject having ALS is based on a blood assay; (b) Initiating the subject on a regimen of sodium chlorite administration over a period of about six months, at least in part based on the first level of the one or more biomarkers of the subject; (c) After the period, obtaining a second level of the one or more biomarkers of the subject; (d) Determining that the second level of the one or more biomarkers in the subject is lower by a predetermined threshold amount than the first level of the one or more biomarkers in the subject; and (e) Recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of the one or more biomarkers in the subject is lower by a predetermined threshold amount than the first level of the one or more biomarkers in the subject. A method including these steps is disclosed herein.

[0071] In some embodiments, the method includes: (a) Obtaining a first level of inflammatory macrophages in the intestinal epithelium of a subject having ALS, wherein the first level of inflammatory macrophages in the intestinal epithelium of the subject having ALS is based on a blood assay; (b) Initiating the subject on a regimen of sodium chlorite administration over a period of about six months, at least in part based on the first level of inflammatory macrophages in the intestinal epithelium of the subject; (c) After the period, obtaining a second level of inflammatory macrophages in the intestinal epithelium of the subject; (d) Determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject; and (e) Recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject.

[0072] In some embodiments, the method comprises: (a) obtaining a first level of LBP of a subject having ALS, wherein the first level of LBP of the subject having ALS is based on a blood assay; (b) starting the subject on a regimen of sodium chlorite administration for a period of at least about six months, at least in part based on the first level of LBP of the subject; (c) after the period, obtaining a second level of LBP of the subject; (d) determining that the second level of LBP is lower than the first level of LBP of the subject by a predetermined threshold amount; and (e) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of LBP is lower than the first level of LBP of the subject by a predetermined threshold amount.

[0073] (a) obtaining a first level of one or more biomarkers of a subject having ALS, wherein the first level of the one or more biomarkers of the subject having ALS is based on a blood assay; (b) starting the subject on a regimen of sodium chlorite administration for a period of about six months, at least in part based on the first level of the one or more biomarkers of the subject; (c) after the period, obtaining a second level of the one or more biomarkers of the subject; (d) determining that the second level of the one or more biomarkers in the subject is lower than the first level of the one or more biomarkers in the subject by a predetermined threshold amount; and (e) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of the one or more biomarkers in the subject is higher than the first level of the one or more biomarkers in the subject by a predetermined threshold amount. A method is disclosed herein that includes the foregoing.

[0074] In some embodiments, the method comprises: (a) obtaining a first level of TGFB1 in a subject having ALS, wherein the first level of TGFB1 in the subject having ALS is based on a blood assay; (b) initiating the subject on a regimen of sodium chlorite administration for a period of at least about six months, based at least in part on the first level of TGFB1 in the subject; (c) after the period, obtaining a second level of TGFB1 in the subject; (d) determining that the second level of TGFB1 in the subject is higher than the first level of TGFB1 in the subject by a predetermined threshold amount; and (e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of TGFB1 in the subject is higher than the first level of TGFB1 in the subject by a predetermined threshold amount.

[0075] Obtaining a first level of one or more biomarkers in a subject having ALS, wherein the first level of the one or more biomarkers in the subject having ALS is based on a blood assay; (b) initiating the subject on a regimen of sodium chlorite administration for a period of about six months, based at least in part on the first level of the one or more biomarkers in the subject; (c) after the period, obtaining a second level of the one or more biomarkers in the subject; (d) determining that the second level of the one or more biomarkers in the subject is a decrease of at least a predetermined threshold amount compared to the first level of the one or more biomarkers in the subject; and (e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of the one or more biomarkers in the subject is a decrease of at least a predetermined threshold amount compared to the first level of the one or more biomarkers in the subject. A method is disclosed herein that includes the foregoing.

[0076] In some embodiments, the method comprises: (a) obtaining a first plasma neurofilament light chain level of a subject having ALS, wherein the first plasma neurofilament light chain level of the subject having ALS is based on a blood assay; (b) initiating the subject on a regimen of sodium chlorite administration over a period of about six months, at least partially based on the first plasma neurofilament light chain level of the subject; (c) obtaining a second plasma neurofilament light chain level of the subject after the period; (d) determining that the second plasma neurofilament light chain level of the subject is a decrease of at least a predetermined threshold amount compared to the first plasma neurofilament light chain level of the subject; and (e) recommending that the subject continue the regimen of sodium chlorite administration, at least partially based on determining that the second plasma neurofilament light chain level of the subject is a decrease of at least a predetermined threshold amount compared to the first plasma neurofilament light chain level of the subject.

[0077] In some embodiments, the method includes a method of treating ALS in a subject in need of treatment for ALS, the method comprising: (a) obtaining a first level of a first biomarker in the subject; (b) obtaining a first level of a second biomarker in the subject; (c) after obtaining the first level of the first biomarker in the subject and obtaining the first level of the second biomarker in the subject, initiating the subject on a regimen of sodium chlorite administration for a period of at least about six months; (d) after the period, obtaining a second level of the first biomarker in the subject; (e) after the period, obtaining a second level of the second biomarker in the subject; (f) determining that the first level of the first biomarker in the subject is greater than the second level of the first biomarker in the subject; (g) determining that the first level of the second biomarker in the subject is less than the second level of the second biomarker in the subject; and (h) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the first level of the first biomarker in the subject is greater than the second level of the first biomarker in the subject and determining that the first level of the second biomarker in the subject is less than the second level of the second biomarker in the subject.

[0078] In some embodiments, determining that the first level of the first biomarker in the subject is greater than the second level of the first biomarker in the subject is done by obtaining results from an assay of the subject.

[0079] In some embodiments, determining that the first level of the second biomarker in the subject is less than the second level of the second biomarker in the subject is done by obtaining results from an assay of the subject.

[0080] In some embodiments, determining the ratio of LPS:EGF in the subject is done by obtaining results from an assay of the subject.

[0081] In some embodiments, identifying that a subject has an LPS:EGF ratio associated with ALS is done by obtaining a result from an assay of the subject. In some embodiments, identifying that a subject has a level of TGFB1 associated with ALS is done by obtaining a result from an assay of the subject. In some embodiments, identifying that a subject has a level of LBP associated with ALS is done by obtaining a result from an assay of the subject.

[0082] In some embodiments, the method further includes performing an assay of the subject to obtain a result. In some embodiments, the assay is a blood assay.

[0083] In some embodiments, the assay is the quantification of LPS and EGF in the blood of the subject by high performance liquid chromatography. In some embodiments, the assay is the quantification of TGFB1 in the blood of the subject by high performance liquid chromatography. In some embodiments, the assay is the quantification of LBP in the blood of the subject by high performance liquid chromatography. In some embodiments, the assay is the quantification of a first biomarker and a second biomarker in the blood of the subject by high performance liquid chromatography.

[0084] In some embodiments, the blood assay is the quantification of LPS and EGF in the blood of the subject by high performance liquid chromatography. In some embodiments, the blood assay is the quantification of TGFB1 in the blood of the subject by high performance liquid chromatography. In some embodiments, the blood assay is the quantification of LBP in the blood of the subject by high performance liquid chromatography. In some embodiments, the blood assay is the quantification of the neurofilament light chain level in the blood of the subject by high performance liquid chromatography.

[0085] In some embodiments, the biomarker is selected from A2M, CRP, LPS, EGF, IL-10, IL-18, HGF, HLA-DR, LBP, NFkB, SAA, SOD1, sCD163, TauCl, TDP43, TGFB1, and combinations thereof. In some embodiments, the biomarker is selected from A2M, CRP, LPS, EGF, TGFB1, LBP, and combinations thereof. In some embodiments, the biomarker is selected from LPS, EGF, TGFB1, LBP, and combinations thereof. In some embodiments, the biomarker is selected from LPS and EGF. In some embodiments, the biomarker is LPS. In some embodiments, the biomarker is EGF. In some embodiments, the biomarker is TGFB1. In some embodiments, the biomarker is LBP. In some embodiments, the biomarker is CRP.

[0086] In some embodiments, the first biomarker is LPS.

[0087] In some embodiments, the second biomarker is EGF.

[0088] In some embodiments, the ratio of LPS:EGF associated with ALS is 50 or less. In some embodiments, the ratio of LPS:EGF associated with ALS is 45 or less. In some embodiments, the ratio of LPS:EGF associated with ALS is 40 or less.

[0089] Subjects for treatment herein can be of any suitable age, for example, at least 30 years old, at least 35 years old, at least 40 years old, at least 45 years old, at least 50 years old, at least 55 years old, at least 60 years old, 40 to 80 years old, 40 to 75 years old, 40 to 70 years old, 40 to 65 years old, 40 to 60 years old, 40 to 55 years old, 40 to 50 years old, 80 years old or less, 75 years old or less, 70 years old or less, 65 years old or less, or 80 years old or less.

[0090] The subject described in this specification can be of any suitable age. In some embodiments, the subject is at least 40 years old, at least 41 years old, at least 42 years old, at least 43 years old, at least 44 years old, at least 45 years old, at least 46 years old, at least 47 years old, at least 48 years old, at least 49 years old, at least 50 years old, at least 51 years old, at least 52 years old, at least 53 years old, at least 54 years old, at least 55 years old, at least 56 years old, at least 57 years old, at least 58 years old, at least 59 years old, at least 60 years old, at least 61 years old, at least 62 years old, at least 63 years old, at least 64 years old, or at least 65 years old. In some embodiments, the subject is at least 40 years old, at least 41 years old, at least 42 years old, at least 43 years old, at least 44 years old, at least 45 years old, at least 46 years old, at least 47 years old, at least 48 years old, at least 49 years old, or at least 50 years old. In some embodiments, the subject is at least 51 years old, at least 52 years old, at least 53 years old, at least 54 years old, at least 55 years old, at least 56 years old, at least 57 years old, at least 58 years old, at least 59 years old, at least 60 years old, at least 61 years old, at least 62 years old, at least 63 years old, at least 64 years old, or at least 65 years old. In some embodiments, the subject is at least 40 years old. In some embodiments, the subject is at least 41 years old. In some embodiments, the subject is at least 42 years old. In some embodiments, the subject is at least 43 years old. In some embodiments, the subject is at least 44 years old. In some embodiments, the subject is at least 44 years old. In some embodiments, the subject is at least 45 years old. In some embodiments, the subject is at least 46 years old. In some embodiments, the subject is at least 47 years old. In some embodiments, the subject is at least 48 years old. In some embodiments, the subject is at least 49 years old. In some embodiments, the subject is at least 50 years old. In some embodiments, the subject is at least 51 years old. In some embodiments, the subject is at least 52 years old. In some embodiments, the subject is at least 53 years old.In some embodiments, the subject is at least 54 years old. In some embodiments, the subject is at least 55 years old. In some embodiments, the subject is at least 56 years old. In some embodiments, the subject is at least 57 years old. In some embodiments, the subject is at least 58 years old. In some embodiments, the subject is at least 59 years old. In some embodiments, the subject is at least 60 years old. In some embodiments, the subject is at least 61 years old. In some embodiments, the subject is at least 62 years old. In some embodiments, the subject is at least 63 years old. In some embodiments, the subject is at least 64 years old. In some embodiments, the subject is at least 65 years old.

[0091] In some embodiments, the subject is 40 years old or younger, 41 years old or younger, 42 years old or younger, 43 years old or younger, 44 years old or younger, 45 years old or younger, 46 years old or younger, 47 years old or younger, 48 years old or younger, 49 years old or younger, 50 years old or younger, 51 years old or younger, 52 years old or younger, 53 years old or younger, 54 years old or younger, 55 years old or younger, 56 years old or younger, 57 years old or younger, 58 years old or younger, 59 years old or younger, 60 years old or younger, 61 years old or younger, 62 years old or younger, 63 years old or younger, 64 years old or younger, or 65 years old or younger. In some embodiments, the subject is 41 years old or younger, 42 years old or younger, 43 years old or younger, 44 years old or younger, 45 years old or younger, 46 years old or younger, 47 years old or younger, 48 years old or younger, 49 years old or younger, or 50 years old or younger. In some embodiments, the subject is 51 years old or younger, 52 years old or younger, 53 years old or younger, 54 years old or younger, 55 years old or younger, 56 years old or younger, 57 years old or younger, 58 years old or younger, 59 years old or younger, 60 years old or younger, 61 years old or younger, 62 years old or younger, 63 years old or younger, 64 years old or younger, or 65 years old or younger. In some embodiments, the subject is 40 years old or younger. In some embodiments, the subject is 41 years old or younger. In some embodiments, the subject is 42 years old or younger. In some embodiments, the subject is 43 years old or younger. In some embodiments, the subject is 44 years old or younger. In some embodiments, the subject is 44 years old or younger. In some embodiments, the subject is 45 years old or younger. In some embodiments, the subject is 46 years old or younger. In some embodiments, the subject is 47 years old or younger. In some embodiments, the subject is 48 years old or younger. In some embodiments, the subject is 49 years old or younger. In some embodiments, the subject is 50 years old or younger. In some embodiments, the subject is 51 years old or younger. In some embodiments, the subject is 52 years old or younger. In some embodiments, the subject is 53 years old or younger. In some embodiments, the subject is 54 years old or younger. In some embodiments, the subject is 55 years old or younger. In some embodiments, the subject is 56 years old or younger. In some embodiments, the subject is 57 years old or younger. In some embodiments, the subject is 58 years old or younger. In some embodiments, the subject is 59 years old or younger. In some embodiments, the subject is 60 years old or younger. In some embodiments, the subject is 61 years old or younger. In some embodiments, the subject is 62 years old or younger. In some embodiments, the subject is 63 years old or younger.In some embodiments, the subject is 64 years old or younger. In some embodiments, the subject is 65 years old or younger.

[0092] In some embodiments, the subject is about 40 years old, about 41 years old, about 42 years old, about 43 years old, about 44 years old, about 45 years old, about 46 years old, about 47 years old, about 48 years old, about 49 years old, about 50 years old, about 51 years old, about 52 years old, about 53 years old, about 54 years old, about 55 years old, about 56 years old, about 57 years old, about 58 years old, about 59 years old, about 60 years old, about 61 years old, about 62 years old, about 63 years old, about 64 years old, or about 65 years old. In some embodiments, the subject is about 40 years old, about 41 years old, about 42 years old, about 43 years old, about 44 years old, about 45 years old, about 46 years old, about 47 years old, about 48 years old, about 49 years old, or about 50 years old. In some embodiments, the subject is about 51 years old, about 52 years old, about 53 years old, about 54 years old, about 55 years old, about 56 years old, about 57 years old, about 58 years old, about 59 years old, about 60 years old, about 61 years old, about 62 years old, about 63 years old, about 64 years old, or about 65 years old. In some embodiments, the subject is about 40 years old. In some embodiments, the subject is about 41 years old. In some embodiments, the subject is about 42 years old. In some embodiments, the subject is about 43 years old. In some embodiments, the subject is about 44 years old. In some embodiments, the subject is about 44 years old. In some embodiments, the subject is about 45 years old. In some embodiments, the subject is about 46 years old. In some embodiments, the subject is about 47 years old. In some embodiments, the subject is about 48 years old. In some embodiments, the subject is about 49 years old. In some embodiments, the subject is about 50 years old. In some embodiments, the subject is about 51 years old. In some embodiments, the subject is about 52 years old. In some embodiments, the subject is about 53 years old. In some embodiments, the subject is about 54 years old. In some embodiments, the subject is about 55 years old. In some embodiments, the subject is about 56 years old. In some embodiments, the subject is about 57 years old. In some embodiments, the subject is about 58 years old. In some embodiments, the subject is about 59 years old. In some embodiments, the subject is about 60 years old. In some embodiments, the subject is about 61 years old. In some embodiments, the subject is about 62 years old. In some embodiments, the subject is about 63 years old. In some embodiments, the subject is about 64 years old. In some embodiments, the subject is about 65 years old.

[0093] In some embodiments, the subject has a neurodegenerative disease. In some embodiments, the subject has ALS. In some embodiments, the subject has Alzheimer's disease. In some embodiments, the subject has Parkinson's disease.

[0094] In some embodiments, the subject has a CRP level exceeding 1.13 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 1.15 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 1.17 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 1.2 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 1.5 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 2 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 2.5 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 3 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 3.5 mg / L as determined by a blood assay. In some embodiments, the subject has a CRP level exceeding 4 mg / L as determined by a blood assay.

[0095] In some embodiments, an amount of sodium chlorite is administered to the subject. In some embodiments, an amount of sodium chlorite therapeutically effective for ALS is administered to the subject.

[0096] In some embodiments, the amount is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the amount is from about 0.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the amount is from about 1.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the amount is from about 1.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the amount is from about 2.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the amount is from about 2.5 mg / kg / day to about 3.5 mg / kg / day.

[0097] In some embodiments, the amount is from about 1.0 mg / kg / day to about 10 mg / kg / day. In some embodiments, the amount is from about 2.0 mg / kg / day to about 10 mg / kg / day. In some embodiments, the amount is from about 3.0 mg / kg / day to about 10 mg / kg / day. In some embodiments, the amount is from about 4.0 mg / kg / day to about 10 mg / kg / day. In some embodiments, the amount is from about 5.0 mg / kg / day to about 10 mg / kg / day.

[0098] In some embodiments, the amount is about 0.2 mg / kg / day. In some embodiments, the amount is about 0.5 mg / kg / day. In some embodiments, the amount is about 1.0 mg / kg / day. In some embodiments, the amount is about 1.2 mg / kg / day. In some embodiments, the amount is about 1.4 mg / kg / day. In some embodiments, the amount is about 1.6 mg / kg / day. In some embodiments, the amount is about 1.8 mg / kg / day. In some embodiments, the amount is about 2.0 mg / kg / day. In some embodiments, the amount is about 2.2 mg / kg / day. In some embodiments, the amount is about 2.4 mg / kg / day. In some embodiments, the amount is about 2.6 mg / kg / day. In some embodiments, the amount is about 2.8 mg / kg / day. In some embodiments, the amount is about 3.0 mg / kg / day. In some embodiments, the amount is about 3.2 mg / kg / day. In some embodiments, the amount is about 3.5 mg / kg / day.

[0099] In some embodiments, the amount is about 4.0 mg / kg / day. In some embodiments, the amount is about 5.0 mg / kg / day. In some embodiments, the amount is about 6.0 mg / kg / day. In some embodiments, the amount is about 7.0 mg / kg / day. In some embodiments, the amount is about 8.0 mg / kg / day. In some embodiments, the amount is about 9.0 mg / kg / day. In some embodiments, the amount is about 10.0 mg / kg / day.

[0100] In some embodiments, the administration is oral. In some embodiments, the administration is parenteral. In some embodiments, the administration is intravenous.

[0101] In some embodiments, the subject is on a regimen of sodium chlorite. In some embodiments, the sodium chlorite regimen is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 0.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 1.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 1.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 2.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite regimen is from about 2.5 mg / kg / day to about 3.5 mg / kg / day.

[0102] In some embodiments, the regimen of sodium chlorite is from about 1.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is from about 2.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is from about 3.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is from about 4.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is from about 5.0 mg / kg / day to about 10.0 mg / kg / day.

[0103] In some embodiments, the regimen of sodium chlorite is about 0.2 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 0.5 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 1.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 1.2 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 1.4 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 1.6 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 1.8 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 2.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 2.2 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 2.4 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 2.6 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 2.8 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 3.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 3.2 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 3.5 mg / kg / day.

[0104] In some embodiments, the regimen of sodium chlorite is about 4.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 5.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 6.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 7.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 8.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 9.0 mg / kg / day. In some embodiments, the regimen of sodium chlorite is about 10.0 mg / kg / day.

[0105] In some embodiments, the regimen of sodium chlorite is administered orally. In some embodiments, the regimen of sodium chlorite is administered parenterally. In some embodiments, the regimen of sodium chlorite is administered intravenously.

[0106] In some embodiments, the subject is undergoing treatment for ALS, and the treatment is a therapeutic regimen of sodium chlorite. In some embodiments, the method further comprises determining to discontinue the therapeutic regimen of sodium chlorite. In some embodiments, the method further comprises determining to continue the therapeutic regimen of sodium chlorite.

[0107] In some embodiments, the treatment regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 0.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 1.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 1.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 2.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 2.5 mg / kg / day to about 3.5 mg / kg / day.

[0108] In some embodiments, the treatment regimen of sodium chlorite is from about 1.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 2.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 3.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 4.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is from about 5.0 mg / kg / day to about 10.0 mg / kg / day.

[0109] In some embodiments, the treatment regimen of sodium chlorite is about 0.2 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 0.5 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 1.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 1.2 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 1.4 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 1.6 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 1.8 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 2.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 2.2 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 2.4 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 2.6 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 2.8 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 3.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 3.2 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 3.5 mg / kg / day.

[0110] In some embodiments, the treatment regimen of sodium chlorite is about 4.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 5.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 6.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 7.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 8.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 9.0 mg / kg / day. In some embodiments, the treatment regimen of sodium chlorite is about 10.0 mg / kg / day.

[0111] In some embodiments, the treatment regimen of sodium chlorite is administered orally. In some embodiments, the treatment regimen of sodium chlorite is administered parenterally. In some embodiments, the treatment regimen of sodium chlorite is administered intravenously.

[0112] In some embodiments, the subject is undergoing sodium chlorite treatment. In some embodiments, the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 0.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 1.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 1.5 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 2.0 mg / kg / day to about 3.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 2.5 mg / kg / day to about 3.5 mg / kg / day.

[0113] In some embodiments, the sodium chlorite treatment is from about 1.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 2.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 3.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 4.0 mg / kg / day to about 10.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is from about 5.0 mg / kg / day to about 10.0 mg / kg / day.

[0114] In some embodiments, the sodium chlorite treatment is about 0.2 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 0.5 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 1.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 1.2 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 1.4 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 1.6 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 1.8 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 2.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 2.2 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 2.4 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 2.6 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 2.8 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 3.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 3.2 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 3.5 mg / kg / day.

[0115] In some embodiments, the sodium chlorite treatment is about 4.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 5.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 6.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 7.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 8.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 9.0 mg / kg / day. In some embodiments, the sodium chlorite treatment is about 10.0 mg / kg / day.

[0116] In some embodiments, the method further comprises administering a sodium chlorite treatment to the subject. In some embodiments, the method further comprises orally administering a sodium chlorite treatment to the subject. In some embodiments, the method further comprises parenterally administering a sodium chlorite treatment to the subject. In some embodiments, the method further comprises intravenously administering a sodium chlorite treatment to the subject.

[0117] The subject can be monitored for biomarkers of symptoms before, during, or after receiving treatment for a neurodegenerative disease. For example, a subject who is receiving, has received, or is recommended to receive a sodium chlorite treatment for ALS can be monitored for biomarkers related to symptoms and treatment.

[0118] Non-limiting examples of biomarkers related to the treatments herein include lipopolysaccharide (LPS) and wound healing epidermal growth factor (EGF). For example, monitoring the levels of these biomarkers in a subject by HPLC analysis of a blood sample can provide information useful for treatment decisions. For example, the decision to initiate, continue, or terminate treatment can be based on monitoring the levels of the subject's biomarkers and evaluating the ratio of the levels of the subject's biomarkers over time. A decrease in the ratio of LPS:EGF over time may be associated with treatment success.

[0119] In some embodiments, the biomarker is transforming growth factor beta receptor 1 (TGFB1). In some embodiments, TGFB1 acts as a surrogate marker for the activation of alpha2-macroglobulin (A2M) into a dimeric form. In some embodiments, the biomarker modulates the innate immune system.

[0120] Figure 1 shows the pathogenesis of ALS. Figure 2 shows the same pathway when treated with Compound 1 (sodium chlorite). The figure shows where EGF and LPS are involved in the pathway.

[0121] The compounds of the present disclosure Oxidizing agents that can treat conditions associated with immune system dysregulation are disclosed herein. In some embodiments, the oxidizing agents of the present disclosure can treat conditions associated with immune system dysregulation by inactivating macrophages. In some embodiments, the compounds of the present disclosure can be rapidly converted to regulators of NFkB activation.

[0122] In some embodiments, the compounds of the present disclosure are chlorite (ClO2 - ) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is sodium chlorite (NaClO2). In some embodiments, the compound of the present disclosure is potassium chlorite (KClO2). In some embodiments, sodium chlorite can be converted from a prodrug to the intracellular form of taurine chloramine (TauCl) via a perchlorate intermediate. TauCl is a long-lived effector molecule in macrophages that downregulates NF-kB expression and inhibits the production of pro-inflammatory cytokines, at least in part, through the activation of heme oxygenase-1 (HO-1).

[0123] Any compound in this specification can be purified. The compounds in this specification are at least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure,It can be at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure. In some embodiments, the compounds of the present disclosure can be at least about 90% pure. In some embodiments, the compounds of the present disclosure can be at least about 95% pure. In some embodiments, the compounds of the present disclosure can be at least about 98% pure. In some embodiments, the compounds of the present disclosure can be at least about 99% pure. In some embodiments, the compounds of the present disclosure can be at least about 99.5% pure. In some embodiments, the compounds of the present disclosure can be at least about 99.8% pure.,

[0124] Chlorite composition In some embodiments, the sodium chlorite described herein is an aqueous pharmaceutical formulation. In some embodiments, the aqueous pharmaceutical formulation comprises sodium chlorite and physiological saline.

[0125] In various embodiments, the pH of the aqueous pharmaceutical formulation is from about 7 to about 11. In some embodiments, the pH of the aqueous pharmaceutical formulation is from about 7 to about 9.5. In some embodiments, the aqueous pharmaceutical formulation comprises a buffering agent. Non-limiting examples of buffering agents include phosphate buffers, borate buffers, citrate buffers, and carbonate buffers. In some embodiments, the buffering agent is a phosphate buffer, such as monosodium phosphate or disodium phosphate. In some embodiments, any of the formulations or pharmaceutical formulations described herein comprises a pH adjuster consisting essentially of a phosphate or a mixture of phosphates.

[0126] In some embodiments, the pH of the chlorite formulation for use in the present disclosure can be adjusted between about 7 and about 11.5. In some embodiments, the pH of the chlorite formulation is lowered between about 7 and about 11.5 using a pH adjusting compound that does not expose the formulation to a high local acidity. In some embodiments, the pH adjusting compound is any one or more of sodium monophosphate, sodium diphosphate, or acetic acid.

[0127] In some embodiments, the pH adjuster(s) or pH adjusting compound(s) is a weak acid or weak base having a pKa of from about 4 to about 9, from about 5 to about 9, or from about 5 to about 8, or from about 6 to about 7.5. Examples include, but are not limited to, phosphate buffers having a pKa of from about 4 to about 9, such as monobasic phosphate, or sodium monophosphate and / or disodium phosphate and a lower alkanoic acid, such as acetic acid or propionic acid. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7 and about 11.5 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7 and about 10 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7 and about 9.5 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7 and about 9.0 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7 and about 8.5 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound. In some embodiments, the pH of the acidity-sensitive formulation is lowered to between about 7.1 and about 7.7 using a pH adjusting compound that does not expose the formulation to an acidity, including but not limited to, a high local acidity in the region surrounding the pH adjusting compound.

[0128] Injectable preparations, such as sterile aqueous or oily suspensions, can be formulated, for example, using suitable dispersing or wetting agents and suspending agents. The injectable preparation can be a sterile injectable solution, suspension, or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as in 1,3-butanediol. Non-limiting examples of suitable vehicles and solvents include isotonic solutions such as water for injection (WFI, USP), sterile water for injection (SWFI, USP), Ringer's solution, USP, and isotonic sodium chloride solution. In some embodiments, a sterile fixed oil is used as the solvent or suspending medium. In some embodiments, fatty acids such as oleic acid are formulated for injection.

[0129] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. In some embodiments, the injectable formulation is sterilized, pyrogen-free, and particulate-free according to USP-NF standards. In some embodiments, the sterility, pyrogenicity, and particulate assays are performed according to USP-NF protocols.

[0130] In some embodiments, a pharmaceutically acceptable chlorite is administered in an amount in the range of 0.1 to 10 mg / kg body weight. In some embodiments, the chlorite is administered more than once a month, for example, at least once a week over at least one month. In some embodiments, the chlorite is administered for at least one year.

[0131] In some embodiments, the chlorite preparation for use in the present invention contains small amounts of chlorate ions, sulfate ions, or chloride ions. In some embodiments, the composition is substantially free of sulfate ions.

[0132] In some embodiments, the formulations herein contain chlorite ions in an amount less than about 1.9% by mass in the formulation, such as less than about 1.8%; less than about 1.5%; less than about 1.0%; less than about 0.5%; less than about 0.3%; less than about 0.1%; less than about 0.05%; less than about 0.01%; less than about 0.001%; from about 0.001% to about 0.1%; from about 0.1% to about 0.5%; from about 0.5% to about 1.0%; from about 1.0% to about 1.5%; or from about 1.5% to about 1.8% chloride ions.

[0133] In some embodiments, the formulations herein contain chlorate ions in an amount less than about 1.5% by mass in the formulation, such as less than about 1.4%; less than about 1.3%; less than about 1.0%; less than about 0.5%; about 0.3%; less than about 0.1%; less than about 0.01%; less than about 0.001%; from about 0.001% to about 0.1%; from about 0.001% to about 0.01%; from about 0.01% to about 0.1%; from about 0.1% to about 0.5%; from about 0.5% to about 1.0%; or from about 1.0% to about 1.4% chlorate ions. In some embodiments, the formulations herein are substantially free of chlorate ions. In some embodiments, the formulations herein contain chlorate ions in an amount less than about 0.5% by mass in the formulation. In some embodiments, the formulations herein contain chlorate ions in an amount less than about 0.19% by mass in the formulation. In some embodiments, the formulations herein contain chlorate ions in an amount less than about 0.1% by mass in the formulation. In some embodiments, the level of chlorate ions is below the detection level using HPLC.

[0134] In some embodiments, the formulations herein contain less than about 0.7% by mass of sulfate ions in the formulation, for example, less than about 0.65%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.08%, less than about 0.07%, less than about 0.06%, less than about 0.05%, less than about 0.005%, less than about 0.0005%, from about 0.001% to about 0.1%, from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.06% to about 0.08%, or from about 0.5% to about 0.65%. In some embodiments, the formulations herein are substantially free of sulfate ions. In some embodiments, the formulations herein contain less than about 0.5% by mass of sulfate ions in the formulation. In some embodiments, the formulations herein contain less than about 0.08% by mass of sulfate ions in the formulation. In some embodiments, the level of sulfate ions is below the detection level using HPLC.

[0135] In some embodiments, the formulations herein contain less than about 0.5% by mass of chloride ions in the formulation, for example, less than about 0.24%, less than about 0.2%, or less than about 0.1%. In some embodiments, the formulations herein contain less than about 0.2% by mass of chloride ions in the formulation. In some embodiments, the formulations herein contain less than about 0.1% by mass of chloride ions in the formulation. In some embodiments, the level of chloride ions is below the detection level using HPLC.

[0136] In some embodiments, the chlorite formulations described herein contain by-products or impurities of about 10% (by weight) or less present in commercially available industrial grade chlorites. Non-limiting examples of by-products or impurities present in commercially available industrial grade chlorites include chlorates, sulfates, chlorine dioxide, chlorides, sodium bicarbonate, and sodium carbonate. In some embodiments, the chlorite formulations described herein contain 1 or more decomposition products or impurities present in commercially available industrial grade sodium chlorite that do not exceed any of about 15%, about 12%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.3%, about 0.1%, between about 0.1 and about 5%; between about 5 and about 10%; or between about 10 and about 15% (by weight). In some embodiments, the chlorite formulations described herein contain decomposition products or impurities of about 0.5% (by weight) or less present in commercially available industrial grade sodium chlorite. In some embodiments, the chlorite formulations described herein contain decomposition products or impurities of about 5% (by weight) or less present in commercially available industrial grade sodium chlorite. In some embodiments, the sodium chlorite formulations described herein are substantially free of decomposition products or impurities present in commercially available industrial grade sodium chlorite.

[0137] In some embodiments, the chlorite formulations described herein contain purified sodium chlorite. In some embodiments, the chlorite formulations described herein contain purified sodium chlorite, the purified sodium chlorite contains sodium chloride not exceeding 2.0%, the purified sodium chlorite contains sodium chlorate not exceeding 1.0%, the chlorite composition contains sodium dibasic phosphate, and has a pH between 7.5 and 9.5.

[0138] In some embodiments, the chlorite formulation described herein comprises purified sodium chlorite, the purified sodium chlorite comprises sodium chloride not exceeding about 1.0%, the purified sodium chlorite comprises sodium chlorate not exceeding about 1.0%, the chlorite composition comprises a buffer, and has a pH between about 7 and about 8. In some embodiments, the chlorite formulation described herein comprises purified sodium chlorite, the purified sodium chlorite comprises sodium chloride not exceeding about 0.8%, the purified sodium chlorite comprises sodium chlorate not exceeding about 0.8%, the chlorite composition comprises a buffer, and has a pH between about 7 and about 8. In some embodiments, the chlorite formulation described herein comprises purified sodium chlorite, the purified sodium chlorite comprises sodium chloride not exceeding about 0.6%, the purified sodium chlorite comprises sodium chlorate not exceeding about 0.6%, the chlorite composition comprises a buffer, and has a pH between about 7 and about 8. In some embodiments, the chlorite formulation described herein comprises purified sodium chlorite, the purified sodium chlorite comprises sodium chloride not exceeding about 0.5%, the purified sodium chlorite comprises sodium chlorate not exceeding about 0.5%, the chlorite composition comprises a buffer, and has a pH between about 7 and about 8. In some embodiments, the chlorite formulation described herein comprises purified sodium chlorite, the purified sodium chlorite comprises sodium chloride not exceeding about 0.5%, the purified sodium chlorite comprises sodium chlorate not exceeding about 0.5%, the chlorite composition comprises a buffer, and has a pH between about 7.5 and about 7.7.

[0139] The dosing regimen can include administration in amounts and frequencies that provide the desired effect. For example, the chlorite or chlorite-containing agent can be administered for 2, 3, 4, 5, 6, 7, 8, 9, 10 or more consecutive days. Administration can be daily, for example once a day. In some embodiments, sodium chlorite is administered daily.

[0140] In some embodiments, the pharmaceutical composition can be administered in cycles. Non-limiting examples of cycles provide: a) a first period in which the pharmaceutical composition is administered a first number of times at a first dose; and b) a second period in which the pharmaceutical composition is administered a second number of times at a second dose. In some embodiments, the cycle is performed about 2 to 4 times.

[0141] In some embodiments, the dosing schedule provides dosing periods alternating with non-dosing periods. In some embodiments, sodium chlorite is administered in a 4-week cycle. In some embodiments, sodium chlorite is administered in a 3-week cycle. In some embodiments, the cycle can be repeated as necessary to achieve the desired result. In some embodiments, sodium chlorite is administered in a 2-week cycle. In some embodiments, a total of 2 to 4 cycles are performed. In some embodiments, a total of about 4 cycles, about 5 cycles, about 6 cycles, about 7 cycles, about 8 cycles, about 9 cycles, about 10 cycles, about 11 cycles, about 12 cycles, about 13 cycles, or about 14 cycles are performed. In some embodiments, a total of about 6 cycles are performed. In some embodiments, a total of about 10 cycles are performed. In some embodiments, a total of about 12 cycles are performed.

[0142] In some embodiments, the chlorite formulation described herein is administered daily for a first number of days continuously in the first month and then daily for a second number of days in subsequent months. In some embodiments, the first number of days is about 2, about 3, about 4, about 5, about 6, or about 7. In some embodiments, the first number of days is about 2. In some embodiments, the first number of days is about 2. In some embodiments, the first number of days is about 3. In some embodiments, the first number of days is about 4. In some embodiments, the first number of days is about 5. In some embodiments, the first number of days is about 6. In some embodiments, the first number of days is about 7. In some embodiments, the first number of days is about 2. In some embodiments, the second number of days is about 2. In some embodiments, the second number of days is about 3. In some embodiments, the second number of days is about 4. In some embodiments, the second number of days is about 5. In some embodiments, the second number of days is about 6. In some embodiments, the second number of days is about 7.

[0143] In some embodiments, the chlorite preparation described herein is first administered daily for 5 consecutive days in the first month and then daily for 3 consecutive days in subsequent months. In some embodiments, the chlorite preparation described herein is first administered daily for 5 consecutive days in the first month and then daily for 3 consecutive days in subsequent months. The chlorite preparation comprises purified sodium chlorite, the purified sodium chlorite is at least 97% pure, the purified sodium chlorite contains no more than 2.0% sodium chloride, the purified sodium chlorite contains no more than 1.0% sodium chlorate, the chlorite composition contains dibasic sodium phosphate, and has a pH between about 7.5 and about 9.5. In some embodiments, the chlorite preparation described herein is first administered daily for 5 consecutive days in the first month and then daily for 3 consecutive days in subsequent months. The chlorite preparation comprises purified sodium chlorite, the purified sodium chlorite is at least 97% pure, the purified sodium chlorite contains no more than 2.0% sodium chloride, the purified sodium chlorite contains no more than 1.0% sodium chlorate, the chlorite composition contains dibasic sodium phosphate, and has a pH between about 7.5 and about 8.5. In some embodiments, the chlorite preparation described herein is first administered daily for 5 consecutive days in the first month and then daily for 3 consecutive days in subsequent months. The chlorite preparation comprises purified sodium chlorite, the purified sodium chlorite is at least 97% pure, the purified sodium chlorite contains no more than 2.0% sodium chloride, the purified sodium chlorite contains no more than 1.0% sodium chlorate, the chlorite composition contains dibasic sodium phosphate, and has a pH between about 7.5 and about 8.

[0144] Any of the compositions and pharmaceutical formulations described herein can be used in a kit. In some embodiments, the kit is intended for administration of sodium chlorite or a sodium chlorite-containing agent, or a pharmaceutical formulation comprising such an agent. The kit can include unit doses of the agents or formulations described herein. In some variations, the kit includes appropriate packaging. In some embodiments, the kit includes instructions for use of the active agent in the neurodegenerative disease described above. In some embodiments, the kit contains instructions for using a sodium chlorite formulation to treat the neurodegenerative diseases described herein. In some embodiments, the kit contains appropriate instructions for performing any of the treatment methods described herein with the formulations described herein. In some embodiments, the kit is used to treat any one or more of the diseases or conditions described herein. The kit can include aids for administration of the active agent formulation, such as a syringe for injection or a pressure pack for oral forms.

[0145] Pharmaceutical composition The pharmaceutical compositions of the present invention can be a combination of any of the compounds described herein with other chemical components such as carriers, stabilizers, solubilizers, tonics, buffers, preservatives, diluents, dispersants, suspending agents, thickeners and / or excipients. The pharmaceutical composition can include at least one pharmaceutically acceptable carrier, stabilizer, solubilizer, tonic, buffer, preservative, diluent, dispersant, suspending agent, thickener, and / or excipient, and a compound described herein in free base or pharmaceutically acceptable salt form. The pharmaceutical composition facilitates the administration of the compound to a living being. The pharmaceutical composition can be administered therapeutically effectively in an amount as a pharmaceutical composition by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ocular, subcutaneous, transdermal, nasal, vaginal and topical administration. The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate the processing of the active compound into a preparation that can be pharmaceutically used. The formulation can be modified according to the selected route of administration.

[0146] The pharmaceutical composition can be administered in a topical manner, for example, via direct injection of the compound into an organ in a depot or sustained release formulation or implant, as needed. The pharmaceutical composition can be provided in the form of an immediate release formulation, a sustained release formulation, or an intermediate release formulation. The immediate release form can provide immediate release. The sustained release formulation can provide controlled release or sustained delayed release.

[0147] In some embodiments, the pharmaceutical composition can be formulated for oral administration. In some embodiments, a pharmaceutical composition formulated for oral administration can be formulated by combining one or more compounds of the present disclosure with one or more pharmaceutically acceptable carriers or excipients. Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries or suspensions for oral ingestion by a subject. Non-limiting examples of solvents used in orally soluble formulations can include water, ethanol, isopropanol, saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffered saline (PBS), sodium phosphate buffer, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES) and sodium chloride sodium citrate buffer (SSC). Non-limiting examples of co-solvents used in orally soluble formulations can include sucrose, urea, cremophor, DMSO and potassium phosphate buffer.

[0148] In some embodiments, the pharmaceutical composition can be formulated for intravenous administration. The pharmaceutical composition can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulations such as suspending agents, stabilizers and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. Suspensions of the active compound can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to enable the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0149] In some embodiments, the pharmaceutical composition can be formulated for topical administration. In some embodiments, the pharmaceutical composition can be formulated into various topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizing agents, stabilizers, tonics, buffers and preservatives. In some embodiments, the pharmaceutical compositions of the present disclosure can be applied topically to the skin or body cavities, such as the subject's oral cavity, vagina, bladder, skull, spinal cord, chest or pelvic cavity. In some embodiments, the compounds or pharmaceutical compositions of the present disclosure can be applied to accessible body cavities.

[0150] In practicing the methods of treatment or use provided herein, a therapeutically effective amount of the compounds described herein is administered to a subject having a disease or condition to be treated in a pharmaceutical composition. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds can be used alone or in combination with one or more therapeutic agents as components of a mixture.

[0151] The pharmaceutical compositions containing the compounds described in this specification can be manufactured, for example, by processes such as mixing, dissolving, emulsifying, encapsulating, enclosing, or compressing. The method for preparing a composition containing the compounds described herein involves formulating the compounds using one or more inert pharmaceutically acceptable excipients or carriers to form solid, semi-solid, or liquid compositions. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The composition can be a liquid solution or suspension, a solid form suitable for a solution or suspension in a liquid before use, or an emulsion. These compositions can also contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, and other pharmaceutically acceptable additives.

[0152] Non-limiting examples of dosage forms suitable for use in the present invention include liquids, powders, gels, nanosuspensions, nanoparticles, microgels, aqueous or oily suspensions, emulsions, elixirs, nanosuspensions, aqueous or oily suspensions, droplets, syrups, and any combination thereof.

[0153] Non-limiting examples of pharmaceutically acceptable excipients suitable for use include binders, disintegrants, anti-adhesion agents, anti-static agents, surfactants, antioxidants, coating agents, colorants, plasticizers, preservatives, suspending agents, emulsifiers, antibacterial agents, spheronizing agents, granulating agents, lubricants, sweeteners, flow promoters, gums, flavoring agents, plant cellulose-based materials, and any combination thereof.

[0154] The pharmaceutical composition of the present invention can be, for example, in an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compound to act rapidly. Non-limiting examples of immediate release formulations include readily soluble formulations. A controlled release formulation is a pharmaceutical formulation that is adapted or programmed to provide release of the active agent at a rate and release profile that can meet physiological and chronotherapeutic requirements. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gelling dietary fibers), matrix-based formulations (e.g., formulations containing a polymeric material in which at least one active ingredient is dispersed), granules within a matrix, polymer mixtures, and agglomerates of granules.

[0155] In some embodiments, the controlled release formulation is a delayed release formulation. A delayed release formulation can be formulated to delay the action of the compound for an extended period. The delayed release form can be formulated to delay the release of an effective dose of one or more compounds for, for example, about 4, about 8, about 12, about 16, or about 24 hours.

[0156] In some embodiments, the controlled release formulation can be a sustained release formulation. A sustained release formulation can be formulated to, for example, sustain the action of the compound over an extended period. The sustained release form can be formulated to provide an effective dose of any of the compounds described herein (e.g., provide a physiologically effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.

[0157] Non-limiting examples of pharmaceutically acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0158] Depending on the intended mode of administration, the pharmaceutical composition can be in solid, semi-solid or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, solutions, suspensions, lotions, creams or gels, for example, in unit dosage forms suitable for single administration of an exact dosage.

[0159] In the case of solid compositions, non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose and magnesium carbonate.

[0160] The pharmaceutical compositions described herein can be in unit dosage forms suitable for single administration of an exact dosage. In unit dosage forms, the formulation is divided into unit doses containing an appropriate amount of one or more than one compound. The unit dosage can be in the form of a package containing separate amounts of the formulation. Non-limiting examples are packaged injections, vials or ampoules. The aqueous suspension composition can be packaged in a non-reclosable container for single administration. A reclosable container for multiple doses can be used, for example, in combination with a preservative or without a preservative. Injectable formulations can be provided in unit dosage forms, for example in ampoules, or in multiple-dose containers containing a preservative.

[0161] The pharmaceutical composition can have a pH adjusted to about 7 to about 11.5. In some embodiments, the pH of the pharmaceutical composition of the present disclosure can be adjusted using agents that do not expose the formulation to a high local acidity. In some embodiments, the pH of the pharmaceutical composition of the present disclosure can be adjusted using, for example, monosodium phosphate, disodium phosphate, dibasic sodium phosphate or acetic acid.

[0162] In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of about 7 to about 7.5, about 7.5 to about 8, about 8 to about 8.5, about 8.5 to about 9, about 9 to about 9.5, about 9.5 to about 10, about 10 to about 10.5, about 10.5 to about 11, about 11 to about 11.5, or about 11.5 to about 12. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of about 7 to about 7.5. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of about 7.5 to about 8. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of about 8 to about 8.5. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of about 7.5 to about 9.5.

[0163] In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of less than about 12. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of less than about 11.5, less than about 11, less than about 10.5, less than about 10, less than about 9.5, less than about 9, less than about 8.5, less than about 8, less than about 7.5, less than about 7, less than about 6.5, or less than about 6. In some embodiments, the pH of the pharmaceutical composition of the present disclosure can have a pH of less than about 11.5. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of less than about 10.5. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of less than about 8.5. In some embodiments, the pharmaceutical composition of the present disclosure can have a pH of less than about 7.5. In some embodiments, the pharmaceutical composition of the present disclosure has a pH of about 7.4. In some embodiments, the pharmaceutical composition of the present disclosure has a pH that is at a physiological level.

[0164] In some embodiments, the pharmaceutical composition of the present disclosure can include a solvent. In some embodiments, the pharmaceutical composition of the present disclosure can include water as a solvent. In some embodiments, the pharmaceutical composition of the present disclosure is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is at least about 80% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is at least about 90% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is at least about 95% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is at least about 98% (v / v) water.

[0165] In some embodiments, the pharmaceutical composition of the present disclosure is about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 98% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is about 80% to about 90% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is about 90% to about 95% (v / v) water. In some embodiments, the pharmaceutical composition of the present disclosure is about 90% to about 98% (v / v) water.

[0166] In some embodiments, the pharmaceutical composition comprises from about 1 μM to about 1.5 M of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 1 μM to about 10 μM, about 10 μM to about 50 μM, about 50 μM to about 100 μM, about 0.1 mM to about 0.5 mM, about 0.5 mM to about 1 mM, about 1 mM to about 25 mM, about 25 mM to about 100 mM, about 100 mM to about 250 mM, about 250 mM to about 500 mM, about 500 mM to about 750 mM, or about 750 mM to about 1000 mM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 1 μM to about 10 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 10 μM to about 50 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 50 μM to about 100 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 100 μM to about 250 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 250 μM to about 500 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises from about 1 mM to about 5 mM of a compound of the present disclosure.

[0167] In some embodiments, the pharmaceutical composition comprises at least about 1 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 1 μM, at least about 10 μM, at least about 50 μM, at least about 100 μM, at least about 250 μM, at least about 500 μM, at least about 750 μM, at least about 1 mM, at least about 25 mM, at least about 50 mM, at least about 75 mM, at least about 100 mM, at least about 250 mM, at least about 500 mM, at least about 750 mM, or at least about 1000 mM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 1 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 10 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 25 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 50 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 60 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 65 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 100 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 250 μM of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises at least about 500 μM of a compound of the present disclosure.

[0168] In some embodiments, the pharmaceutical composition comprises about 1 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 1 μM, about 10 μM, about 50 μM, about 100 μM, about 250 μM, about 500 μM, about 750 μM, about 1 mM, about 25 mM, about 50 mM, about 75 mM, about 100 mM, about 250 mM, about 500 mM, about 750 mM, or about 1000 mM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 1 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 10 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 25 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 50 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 100 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 250 μM of the compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises about 500 μM of the compound of the present disclosure.

[0169] In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 0.5 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 0.5 mg / mL, at least about 1 mg / mL, at least about 1.5 mg / mL, at least about 2 mg / mL, at least about 2.5 mg / mL, at least about 3 mg / mL, at least about 3.5 mg / mL, at least about 4 mg / mL, at least about 4.5 mg / mL, at least about 5 mg / mL, at least about 5.5 mg / mL, at least about 6 mg / mL, at least about 6.5 mg / mL, at least about 7 mg / mL, at least about 7.5 mg / mL, at least about 8 mg / mL, at least about 8.5 mg / mL, at least about 9 mg / mL, at least about 9.5 mg / mL, or at least about 10 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 2 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 4 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 5 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 5.6 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 5.5 mg / mL of sodium chlorite. In some embodiments, the pharmaceutical composition of the present disclosure comprises at least about 4 mg / mL of chlorite.

[0170] In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 0.5 mg / mL to about 10 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 0.5 mg / mL to about 1 mg / mL, from about 1 mg / mL to about 2 mg / mL, from about 2 mg / mL to about 3 mg / mL, from about 3 mg / mL to about 4 mg / mL, from about 4 mg / mL to about 5 mg / mL, from about 5 mg / mL to about 6 mg / mL, from about 6 mg / mL to about 7 mg / mL, from about 7 mg / mL to about 8 mg / mL, from about 8 mg / mL to about 9 mg / mL, or from about 9 mg / mL to about 10 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 4 mg / mL to about 5 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 5 mg / mL to about 6 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 4 mg / mL to about 5 mg / mL of chlorite. In some embodiments, the pharmaceutical composition of the present disclosure comprises from about 5 mg / mL to about 6 mg / mL of sodium chlorite.

[0171] In some embodiments, the pharmaceutical composition of the present disclosure comprises about 0.5 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 2 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 4 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 5 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 5.6 mg / mL of the compound of the present disclosure. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 5.5 mg / mL of sodium chlorite. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 4 mg / mL of chlorite.

[0172] In some embodiments, the pharmaceutical composition of the present disclosure is formulated for intravenous administration. In some embodiments, the pharmaceutical composition of the present disclosure comprises dibasic sodium phosphate. In some embodiments, the pharmaceutical composition of the present disclosure has a pH of about 7.5 to about 9.5. In some embodiments, the pharmaceutical composition of the present disclosure does not contain a preservative. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 4 mg / mL of chlorite. In some embodiments, the pharmaceutical composition of the present disclosure comprises about 5.5 mg / mL of sodium chlorite.

Examples

[0173] Examples The following examples are provided for illustrative purposes only and do not limit the claims provided herein.

[0174] Abbreviations A2M: Alpha-2-macroglobulin;

[0175] ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale score

[0176] CNS: Central nervous system;

[0177] CRP: C-reactive protein;

[0178] DP: Disease progression;

[0179] LPS: Lipopolysaccharide;

[0180] EGF: Epidermal growth factor;

[0181] IL-10: Interleukin 10;

[0182] IL-18: Interleukin 18;

[0183] HGF: Hepatocyte growth factor;

[0184] HLA-DR: Human leukocyte antigen-DR isotype;

[0185] LBP: LPS-binding protein;

[0186] MT: Microbial translocation;

[0187] NFkB: Nuclear factor kappa B;

[0188] SAA: Serum amyloid A;

[0189] SOD1: Superoxide dismutase 1

[0190] sCD163: Soluble CD163;

[0191] TauCl: Tau chloramine;

[0192] TDP43: Transactive response DNA-binding protein 43;

[0193] TGFB1: Transforming Growth Factor Beta 1;

[0194] VC: Vital capacity.

[0195] Example 1: Microbial translocation in ALS Research objective The objective of this study was to test whether ALS patients in a phase 2 study of sodium chlorite, a regulator of innate immune function, would show changes in plasma biomarkers related to microbial translocation (MT) over a 6-month placebo-controlled trial.

[0196] MT is a dynamic process that leads to chronic inflammatory conditions involved in most neurodegenerative diseases. A recent post hoc evaluation of the phase 2 study showed that sodium chlorite treatment in ALS patients with plasma CRP levels above 1.13 mg / L slowed disease progression compared to placebo. The rate of decline in ALSFRS-R and vital capacity was slowed compared to placebo.

[0197] Methods Plasma specimens collected at baseline and 6 months after the sodium chlorite phase 2A study were evaluated by ELISA for levels of biomarkers related to MT. The results of MT marker quantification were compared between the treatment group and the placebo group.

[0198] Results From the sodium chlorite 2A study, 14 sodium chlorites and 16 placebos with CRP > 1.13 mg / L completed the trial. The 6-month decline in ALSFRS-R (p = 0.02) and VC (p = 0.03) was significantly decelerated by sodium chlorite compared to placebo. Baseline markers of MT, including lipopolysaccharide (LPS), LPS-binding protein (LBP), monocyte transport molecule soluble CD163, and inflammasome-related interleukin 18 (IL-18), all decreased compared to placebo values. In patients treated with sodium chlorite, the level of wound healing epidermal growth factor (EGF) increased.

[0199] MT is a biological process in which persistent macrophage activation leads to both progressive ND activity and continuous intestinal epithelial cell dysfunction. Factors produced by LPS-activated macrophages continuously drive this process. Sodium chlorite is a regulator of macrophage activation, and in the current study, the coupling of anti-MT activity and EGF induction is associated with decelerated ALS disease progression.

[0200] Figure 3 shows the ratio of LPS to EGF in the study patients. This trend indicates that the ratio decreased over time in patients treated with sodium chlorite. In contrast, in patients receiving placebo, the ratio increased over time.

[0201] Figure 4 shows the activation cycle of the innate immune cycle. The innate inflammatory response is associated with oxidative burst and production of HClO. HClO is converted to taurine chloramine, which regulates NFkB and inflammation.

[0202] Figure 5 shows the change in ALSFRS-R from baseline over time and the percentage change in VC from baseline for the NP001 treatment group and the placebo treatment group.

[0203] Figure 6 shows the increased change of IL-10 from NP001. Figure 8 shows the changes in plasma neurofilament light chain levels in NP001-treated progressors, NP001-treated non-progressors, and placebo-treated groups.

[0204] Figure 7 shows the mechanisms for microbial translocation in ALS patients, as well as the changes in the levels of EGF, IL10, IL18, LPS, LBP, and sCD163 related to the microbial translocation process in NP001 treatment. Figure 9 shows the effect of NP001 on macrophage activation in the (a) early and (b) advanced systemic stages of ALS. Figure 10 shows the effect of taurine chloramine (TauCl) on the regulation of NFkB.

[0205] Figure 11 shows the disease-modifying activity of NP001 in the early and advanced systemic stages of ALS.

[0206] Figure 12 shows the NP001 treatment-related ALS disease stability with respect to the baseline CRP level.

[0207] Table 2 shows the analysis of biomarkers as the median percentage change from baseline over 6 months for placebo and NP001 treatment groups of individuals aged 40 - 65 with CRP > 1.13 mg / L.

Table 2

[0208] Table 3 shows the percentage change in plasma biomarkers in ALS patients with an average CRP > 1.13 mg / L 20 months after symptom onset.

Table 3

[0209] Table 4 shows the average percentage change in predicted vital capacity from baseline over 6 months in a population aged ≤ 65 and having CRP > 1.13 mg / L.

Table 4-1

Table 4-2

[0210] Example 2: Regulation of macrophage activation in ALS Research objective Amyotrophic lateral sclerosis (ALS) is a fatal disease with motor neuron degeneration that leads to paralysis and death within only 2 - 5 years after disease onset. Approximately 10 - 15% of ALS patients have a familial form of the disease associated with genetic abnormalities, while the majority of individuals have a sporadic form of the disease.

[0211] A possible approach to treatment is to focus on subsets of patients who are most responsive to treatment. Non-limiting examples of treatment targets include ALS-related gene mutations, reactive oxygen species, misfolded proteins, dysfunctional mitochondria, blood-derived macrophage function, growth factor deficiencies, and neuroinflammation.

[0212] An intravenous formulation of sodium chlorite is under development for ALS. One example of the mechanism of action is the regulation of macrophage activation by modulation of the respiratory burst function. Sodium chlorite is a regulator of innate immune function. In a phase 1 dose escalation study in ALS patients, sodium chlorite administration was associated with a dose-dependent downregulation of the monocyte activation markers CD16 and HLA-DR. Normally, phagocytes undergo an oxidative burst and produce hypochlorous acid (HOCl) when activated by infectious agents. This toxic byproduct is rapidly converted to taurine chloramine (TauCl), which delivers an anti-inflammatory signal to macrophages, turns off NFkB, and upregulates phagocytosis / wound healing functions. Sodium chlorite, as a prodrug, is converted to TauCl upon contact with heme-related iron, resulting in anti-inflammatory, phagocytic, and wound healing effects in macrophages.

[0213] Post hoc analysis of data from 6-month phase 2A and phase 2B clinical trials of sodium chlorite in combination in ALS patients defined a large subset of clinically responsive patients. This subset was between 40 and 65 years old and had baseline plasma C-reactive protein (CRP) levels > 1.13 mg / L. The aim of this study was to test plasma biomarker levels in treatment compared to control patients to determine whether the clinical response was associated with some form of macrophage-targeted immunomodulation.

[0214] Methods ALS phase 2A trial and participant description: Participants received a total of 20 infusions administered intravenously over 6 cycles during a 25-week double-blind treatment period. There were 4 weeks between the start of each cycle. Cycle 1 consisted of 5 consecutive daily infusions. Cycles 2, 3, 4, 5, and 6 each consisted of 3 consecutive daily infusions. Plasma specimens for biomarker analysis were obtained at the start and end of the study.

[0215] Analysis of clinical outcome data: The predefined endpoint from the phase 2A study was not achieved, but when used as a cut-off point for outcome analysis, participants with plasma CRP median (across all participants) > 1.13 mg / L showed a tendency to decelerate disease progression as measured by assessing the change from baseline levels of the Revised ALS Functional Rating Scale (ALS / FRS-R) over a 6-month trial. ALS patients with < 1.13 mg / L at baseline were also evaluated monthly for ALS FRS-R score loss. In addition to observing that ALS patients decelerated their progression over time, a subset halted their progression over 6 months and all of these non-progressors were within the age range of 40 - 65 years.

[0216] Source of patient specimens: Plasma specimens were stored at -80°C after the end of the clinical trial and were all evaluated for biomarker levels. All patients with CRP > 1.13 mg / L in the 2 mg / kg and placebo arms who had completed a 6-month study and had baseline and end-of-study plasma available were included in the current analysis (14 in NP001, 15 in placebo).

[0217] Plasma factors evaluated: Phase 2A data showed that plasma IL-18 and LPS were elevated at baseline in patients treated with the drug (2 mg / kg) and decreased significantly towards normal by 6 months compared to placebo. Based on these results, markers were evaluated for: 1) microbial translocation / LPS activation: (LPS-binding protein), HGF (hepatocyte growth factor), LPS; 2) classical pro-inflammatory factors produced by activated macrophages IL-6, IL-8, TNF-a; 3) immunomodulatory and wound healing: IL-10, neopterin and EGF (epidermal growth factor); 4) monocyte trafficking factor, soluble CD163.

[0218] Results NP001 decelerates loss of ALSFRS-R: There were no significant demographic differences between the two patient groups at baseline. The number of 2 mg / kg NP001 and placebo recipients eligible for the current biomarker analysis was 14 and 15, respectively. All were within the same CRP and age range and had baseline and end-of-study plasma specimens available for analysis. The mean plasma CRP value for this subgroup was 3.2 mg / L. The treatment arm lost 1.2 units of the ALSFRS-R score over 6 months, while the placebo lost 4.6 units (p = 0.03) (Figure 13). ALS patients with CRP < 1.13 mg / L were also followed for 6 months (Figure 13), and no significant difference was observed in clinical outcome (p = 0.69). The mean CRP value for this group was 0.71 mg / L. Biomarker analysis was not performed in this group. Figure 14 shows that ALS patients treated with the drug had a non-progression rate of 35%, compared to less than 10% for placebo (p = 0.08).

[0219] Plasma biomarkers from Phase 2A Plasma specimens were evaluated at baseline, and the percent change from baseline was analyzed for 10 biomarkers. Table 5 shows the baseline values for all the biomarkers analyzed. No statistically significant difference was observed between the drug group and the placebo group at baseline. An example of the change from the baseline value over the 6-month study is shown in Figure 15 for LBP. Table 6 shows the results divided into two categories based on whether the treatment-to-placebo values A) decreased or B) increased. The values of IL-6, IL-8, and TNFa were within the normal range and did not change over the 6-month study. The factors that decreased over the 6 months in relation to placebo were factors related to microbial translocation (LPS, LBP, HGF), factors related to monocyte transport (sCD163), and factors related to inflammasome activation (IL-18). The increased values were values related to either inflammation suppression (IL-10, neopterin) or wound healing (EGF). A schematic diagram depicting the various functional changes resulting in microbial translocation and resolution by the drug is shown in Figure 17.

[0220] NfL (neurofilament light chain) levels change in the majority of non-progressor NP001-treated patients The biomarkers measured and recorded in Tables 5 and 6 were for testing whether the drug could regulate microbial translocation. Plasma NfL levels were evaluated to test whether the drug had a measurable effect on CNS biomarkers of disease activity. Figure 16 shows the direct relationship between the change in NfL levels and the change in ALSFRS-R score in drug-treated subjects, rather than placebo subjects. The treated patients who showed the greatest loss of NfL were those who had halted progression during the 6-month study. Figure 17 shows that treated non-progressors had a tendency towards loss of plasma NfL compared to progressors (loss of at least 1 ALSFRS-R unit over 6 months, p = 0.09). Similarly, non-progressors showed a decrease in NfL levels compared to placebo non-progressors.

[0221] ALS patients show evidence of microbial translocation with detectable levels of LPS in plasma. A non-limiting example of the mechanism of this process is outlined in Figure 17. Left: 1) The progression of ALS proceeds until abnormal neurons stimulate local microglia, activating blood monocytes to produce pro-inflammatory factors that become pro-inflammatory. 2) Inflammatory macrophages do not phagocytose microorganisms or are not involved in wound healing. Colonic epithelial cells turn over every five days, and wound healing functions are important to maintain the integrity of the colonic epithelium. Leakage of bacteria / bacterial products into the blood occurs. 3) Bacterial endotoxin (LPS) activates blood monocytes and tissue macrophages, leading to a systemic pro-inflammatory state. 4) Monocytes are mobilized from the blood to damaged tissues to initiate repair. However, LPS activation results in the transport of non-wound-healing, non-phagocytic pro-inflammatory cells to damaged tissues, leading to disease persistence.

[0222] Treatment resulted in the resolution of biomarker levels associated with the microbial translocation process. A non-limiting example of the mechanism of this process is outlined on the right in Figure 17: 1) Drug-induced TauCL downregulates NFkB and pro-inflammatory factors. 2) Increased EGF enhances intestinal epithelial repair. Bacterial translocation is resolved. 3) Macrophages have converted to phagocytic and wound-healing. 4) The decrease in sCD163 means that the transport of blood monocytes to the CNS has decreased.

[0223] Discussion The Phase 2A study evaluated drug activity in all ALS patients with symptoms onset in the past three years. This study did not show significant clinical activity. However, patients with plasma CRP levels above the median (1.13 mg / L) across the study showed a dose-response relationship between the drug and the change in ALSFRS-R score over six months. The initial study was underpowered to confirm that this level of CRP would be required to observe the disease-specific activity of NP001. The aim of this study was to test whether clinical outcomes were associated with changes in biomarkers that reflected the mechanism of action of the drug. The plasma specimens evaluated were from all participants in this trial who received either 2 mg / kg of the drug or placebo and were within the age range of 40 - 65 years old.

[0224] The Phase 2A analysis included biomarker evaluation results from patients (drug treatment vs placebo) who did not show loss of ALSFRS score over the six-month study. In the original description of the Phase 2A trial, drug treatment resulted in normalization of plasma IL-18 and reduction of plasma LPS levels, both of which were significant findings compared to placebo. Based on these changes, the biomarkers evaluated in this study were biomarkers related to macrophage activation associated with microbial translocation.

[0225] Figure 13 shows important clinical findings during the re - analysis of the Phase 2A study. Using an age cut - off, clinical outcomes were evaluated for ALS patients above and below the 1.13 mg / L cut - off of CRP with respect to the change in ALSFRS - R over time. Note the highly significant difference (p = 0.03) between CRP > 1.13 NP001 and placebo, compared to no observable difference in patients with CRP < 1.13 mg / L. These two groups had median CRP values of 3.2 vs 0.7 mg / L, respectively. In addition to evaluating the rate of loss of ALSFRS - R score at CRP > 1.13 mg / L, a significant subset of patients had progression halted, defined by no loss of ALSFRS - R score over 6 months. Based on these results, plasma specimens from age - restricted patients with CRP > 1.13 mg / L were evaluated to test whether clinical outcomes were associated with changes in NP001 - related biomarkers.

[0226] Rather than testing a broad range of inflammatory markers, this study focused on those that could reflect drug - related mechanisms of action associated with microbial translocation. One of the aims of this study was to confirm whether sodium chlorite treatment could modulate microbial translocation and thereby act as a general neuroinflammatory disease modifier.

[0227] The biomarker evaluation approach in this study had several features. First, it was to identify a cohort of patients treated with sodium chlorite that had a significant benefit in terms of slowing disease progression. Second, it was the selection of biomarkers that reflected the drug - induced activity of macrophage regulation. The schematic shown in Figure 17 maps their responses in the context of microbial translocation regulation. Third, it was to identify biomarkers that could be utilized to test this clinical approach in other neuroinflammatory diseases.

[0228] The first marker to track clinical outcomes was CRP. Pneumococcal CRP (C-(capsular) polysaccharide has been mainly considered as a non-specific protein marker of inflammation produced by the liver in response to infection or inflammatory diseases. However, there are two pathways for CRP activation in response to inflammatory stimuli. Pathogen-associated molecular patterns (PAMPs) drive NFκB activation and other inflammatory pathways by surface-expressed toll-like receptors (TLRs), inducing the release of inflammatory cytokines (e.g., IL-6, IL-8, TNF-a) from macrophages. The PAMP pathway is most active in upregulating CRP release from the liver in response to bacteria or other infectious agents. In a parallel activation pathway, major tissue injury activates the sterile inflammatory pathway by the release of damage (or danger)-associated molecular patterns (DAMPs), activating the inflammasome-mediated processing of IL-1β and IL-18 after binding to endosomal receptors. This pathway induces CRP not via the liver but, in part, via the activation of anti-inflammatory molecules from adipose tissue. Both pathways result in the production of CRP, a pentameric protein that downregulates pro-inflammatory processes as a biologically active molecule while promoting the clearance of infected material and damaged tissue from the body. The absence of an increase in the pro-inflammatory factors IL-6, IL-8, and TNFa from this subset, in combination with the regulation of elevated IL-18, suggests that CRP observed in the blood of drug-responsive patients is induced in response to tissue injury. In this regard, the increase in CRP will provide the effector molecule, the CRP pentamer, to enhance the innate response to tissue injury.

[0229] Factors that are downregulated in drug-responsive patients were generally followed for their effect on macrophage activation induced by the TauCl-inducing activity of the drug. TauCl-exposed macrophages block NFkB-related genes, and wound healing in the gut enables the cessation of microbial translocation and the reconstitution of effective innate immunity. When LPS is removed as a permanent driver of MT signaling, LPS-responsive factors such as hepatocyte growth factor (HGF), neopterin, LPS-binding protein (LBP), IL-18, and epidermal growth factor are upregulated and downregulated relatively rapidly. This end point is important considering that ALS patients in whom the disease halted during drug administration must rapidly reverse disease drivers to maintain ALSFRS-R score stability.

[0230] Many of the biomarkers regulated by the drug in the studies presented herein are abnormal in patients with AD, PD, and other neuroinflammatory diseases. In the periodic activation and autoregulatory cycles that occur with innate immune function, any measurable unregulated factor suggests the potential use of sodium hypochlorite. For example, both AD and PD patients have lower EGF (a growth factor known to promote wound healing and restore function in the gut in animal models) than normal.

[0231] Another factor that best defines the phenomenon of the periodic autoregulatory pathway is related to neopterin levels. Disease activity associated with macrophage activation is related to the upregulation of neopterin. Based on the evaluation of specimens from drug-responsive patients, biomarker changes reflect the constructive disease-modulating activity of the biomarker. Neopterin is induced by LPS and acts to regulate the degree of innate immune activation through the induction of alternative activation-type factors in macrophages such as heme oxygenase 1 and nrf-2.

[0232] In conclusion, this study utilized a clinically responsive patient population for sodium chlorite, a macrophage activation regulator. Biomarker analysis confirmed the drug activity during MT regulation in patients who had already responded to tissue damage signals by upregulating CRP. Since a significant subset halted disease progression over the 6-week study, regulation should have occurred in these patients.

[0233] Table 5. Baseline plasma biomarker levels in the NP001 treatment group and placebo group in ALS patients aged 40 - 65 years and CRP > 1.13 mg / L

Table 5

[0234] Table 6. Plasma biomarker changes from baseline in the NP001 treatment group and placebo group in ALS patients aged 40 - 65 years and CRP > 1.13 mg / L

Table 6 - 1

Table 6 - 2

[0235] Example 3: Regulation of the innate immune system in ALS Research objective The objective of this study was to test whether the pathogenesis of ALS is associated with innate immune system dysfunction by using data generated from an ALS clinical trial involving the innate immune system regulator NP001.

[0236] The following study investigated the relationship between innate immune function and disease activity as defined by a quantitative assessment of VC functional measures in NP001 treatment compared to control ALS patients.

[0237] Method Participants received a total of 20 infusions administered intravenously monthly over 6 cycles during a 6-month double-blind treatment period. Three groups were enrolled, including placebo, 1 mg / kg NP001, and 2 mg / kg NP001. The start of each cycle was separated by 4 weeks. Cycle 1 consisted of a 30-minute infusion for 5 consecutive days. Cycles 2, 3, 4, 5, and 6 each consisted of 3 consecutive daily infusions. Measurements of ALSFRS-R and vital capacity were performed monthly. The mean ALS disease progression rate at baseline (mean DP rate) was defined as the change in ALSFRS-R score per month [(48 - ALSFRS-R score at baseline) / number of months from baseline to ALS symptom onset]. Baseline high-sensitivity CRP (hs-CRP) measurements of all participants were evaluated, and a baseline plasma hs-CRP of 1.13 mg / L was used as a cut-off point to evaluate the role of inflammation in the change in VC over the 6-month study. Plasma specimens for biomarker analysis were obtained at the start and end of the study (month 6, 1 month after the last dose). All patients had to complete the study to provide end-of-study plasma. The units expressed in this example are hs-CRP units, abbreviated as CRP.

[0238] Clinical outcome data evaluated for this study were forced vital capacity measurements performed monthly on all patients at baseline and until the end of the study. Using the age and height of patients with the measured actual respiratory volume, the predicted vital capacity (VC)% was calculated as described. Patients who received 1 mg / kg NP001 were excluded from the current efficacy analysis, and 31 placebo (18 above CRP 1.13 mg / L and 13 below) and 30 NP001 2 mg / kg-treated (16 above CRP 1.13 mg / L and 14 below) patients who were eligible for the VC efficacy analysis remained.

[0239] Plasma specimens from the Phase 2A clinical trial were obtained at baseline and at the end of the study. All patients (6-month completers) in the 2 mg / kg NP001 treatment and placebo arms who had completed the 6-month study and had plasma available at baseline and at the end of the study were included in the current biomarker study.

[0240] Acute phase reactant molecules, CRP and serum amyloid A (SAA), were measured directly, and TGFB1 was measured as a surrogate marker for alpha2-macroglobulin (A2M) activation into a dimeric form that releases pre-formed TGFB1 when stimulated by hypochlorite. Biomarker levels in plasma specimens at baseline and at the end of the study were evaluated simultaneously.

[0241] Statistical analyses were performed using JMP Pro 16 (SAS Institute, Cary, NC, USA). In general, data were summarized using counts and percentages for categorical data and standard univariate descriptive statistics (number of participants, mean, standard deviation, median) for continuous data. Analysis of covariance models were used to compare placebo to each NP001 group for continuous data. Natural logarithm (Ln)-transformed data were used for data analysis of non-Gaussian distribution datasets. For all analyses, two-sided p-values < 0.05 were considered statistically significant.

[0242] Results Using a baseline plasma CRP value of 1.13 mg / L, a high-level patient set and a low-level patient set were distinguished in the clinical outcomes in previous studies. Figure 18 shows that the application of that cutoff point to the NP001 Phase 2A clinical trial participants split the participants into two CRP level groups. The two groups above and below that cut point had significantly different CRP medians (0.70 mg / L vs 2.17 mg / L for the low group vs high group; p < 0.0001). In the NP001 Phase 2A study, no relationship was observed between the baseline value of CRP and the ALSFRS-R score or age.

[0243] The CRP value was independent of age, but in participants over 65 years old, A) the progression rate of ALS disease (positive correlation with the baseline value of CRP, Figure 19, R 2 = 0.25, p = 0.04, n = 17) and B) the duration of ALS symptom onset (negative correlation with the baseline CRP value, Figure 20, R 2 = 0.27, p = 0.03, n = 17) of the disease activity variables were significantly different. Due to the baseline disease activity fluctuations in patients >65, these patients were excluded from further analysis.

[0244] As shown in Figure 21, the main difference between high-CRP patients and low-CRP patients in relation to age was that the high-CRP group (R 2 = 0.00, p = 0.98, n = 62) with a baseline VC value not related to age had patients with low CRP (R 2 = 0.16, p = 0.007, n = 44) with a very significant age-related decrease in the baseline level of VC. This age-related VC variation at CRP < 1.13 mg / L is the main baseline difference between the high-CRP group and the low-CRP group.

[0245] To test whether the VC discrepancy is related to different clinical outcomes in patients treated with NP001, a Phase 2A study was evaluated in patients treated with NP001 vs placebo in the high vs low baseline CRP groups. Figure 22 shows that while VC was improved with NP001 treatment compared to placebo, in patients in the low baseline CRP group, NP001 treatment did not show an effect superior to placebo (Figure 23). The high-CRP group placebo lost an average of 2.1% of VC per month, while NP001 treatment had a 0.75% loss of VC per month, and the rate of VC loss was >64% slower with NP001 (p = 0.05).

[0246] These two groups of patient demographics, including disease progression rate, age, and disease severity at onset, were essentially the same. Table 7 shows the comparison between the NP001 treatment group and the placebo group with ≤65 and baseline CRP > 1.13 mg / L. Table 8 shows the same age group with baseline CRP < 1.13 mg / L.

[0247]

Table 7-1

Table 7-2

[0248] Abbreviations: n, number of participants. SD, standard deviation. 1 ALSFRS-R score: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. 2 Number of months from ALS symptom onset to baseline. 3 Baseline plasma level of C-reactive protein.

[0249]

Table 8

[0250] Abbreviations: n, number of participants. SD, standard deviation. 1 ALSFRS-R score: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. 2 Number of months from ALS symptom onset to baseline. 3 Baseline plasma level of C-reactive protein.

[0251] To test whether the VC sparing activity shown in FIG. 22 becomes more prominent earlier after symptom onset, the patient groups (placebo and 2 mg / kg NP001) were divided into two based on the median time after symptom onset of 16.2 months. FIG. 24 shows that the change in VC over time from baseline in ALS patients below the median is significantly different from placebo in treatment starting from 2 months after treatment. FIG. 25 shows that even though the above-mentioned median time point treated had a slower decline rate than placebo, the difference was not statistically significant.

[0252] To test whether NP001 affects the innate immune system function, factors related to innate immune system regulation were measured. FIG. 26 shows the direct relationship between the plasma levels of the acute-phase reactants serum amyloid A (SAA) and CRP (R 2 =0.25, p = 0.004, n = 31), and it is confirmed that immune activation in patients with CRP>1.13 mg / L is not isolated and is a component of the general acute-phase reaction.

[0253] Plasma TGFB1 was evaluated for evidence of activation of alpha 2 macroglobulin (A2M), another major component of the innate immune system, in patients clinically responsive to NP001. FIG. 27 shows that TGFB1 levels increased significantly in patients with baseline CRP>1.13 mg / L who received NP001 over a 6-month trial compared to placebo controls. An increase of more than 95% in plasma TGFB1 after exposure to NP001 compared to placebo suggests that NP001 caused A2M dimerization with the release of TGFB1. The elevated levels of TGFB1 1 month after the last dose of NP001 also suggest that other functions of the A2M dimer, the clearance of misfolded proteins, may reset the innate immune activation cycle.

[0254] Figure 28 shows a schematic diagram demonstrating how the innate immune system can be normally self-regulated and enhanced by the addition of NP001. The acute phase response occurs in response to aggregates or misfolded proteins such as TDP-43. Both CRP and SAA respond in parallel as in the case of a normal acute phase response, but in a subset of ALS patients, the persistence of these factors is observed in plasma (step 1). The innate inflammatory response is associated with an oxidative burst and the production of hypochlorous acid (HCLO) that activates alpha2-macroglobulin (A2M) to bind and remove proteases (step 2). The normal oxidative burst byproduct HClO is converted to NFkB and taurine chloramine (TauCL), a regulator of inflammation. In the presence of excess HClO, A2M dimerizes and releases pre-formed TGFB1, which binds and removes misfolded proteins (step 3). TGFB1 feeds back on pro-inflammatory cells and turns NFkB off. (step 4). NP001 is converted to HCLO in vivo and stimulates steps 3 and 4 of the innate immune system regulatory cycle (step 5). Plasma levels of increased TGFB1 in over 95% of ALS patients showing a clinical response in vital capacity upon receiving NP001 help confirm these activities. In the evaluation of CRP plasma levels as an independent variable in this clinical trial, no relationship was found between CRP levels and age or baseline ALSFRS-R score. Indirect measures of ALS disease activity, disease duration prior to the study, and rate of ALSFRS-R score loss showed significant differences in both measures in relation to CRP, being independent of CRP levels except for patients >65 years old. Subsequent evaluations were performed only for patients ≤65. The only major variable associated with baseline CRP levels was the age-related loss of VC in patients with low values compared to high plasma CRP, suggesting a relationship between the innate immune system and respiratory function.

[0255] Figure 28 shows how NP001 enhances the innate immune activation cycle in ALS patients with elevated baseline plasma CRP. The innate immune activation cycle is a rapid and controlled multi-step self-regulatory process that occurs after the immune system's exposure to infection or tissue damage. In the case of ALS, the most likely initiator of innate immune system activation is the presence of misfolded and / or aggregated proteins (e.g., TDP43 or SOD1, etc.) at the neuromuscular junction. Step 1: Blood-derived macrophages are activated, initiating the clearance of cells and tissues containing pathogenic proteins, producing factors that initiate the acute-phase response, and producing hypochlorous acid as a byproduct of activated oxidative burst activity. Step 2: A rapid increase in acute-phase reactants including CRP and SAA (both >30X amplified); CRP promotes the clearance of damaged tissues and cells, and SAA binds to and removes bacterial byproducts such as LPS. Alpha2 macroglobulin is activated and absorbs and removes damaged cell products such as proteases. Anti-inflammatory signaling begins. Step 3: Hypochlorous acid 1) stimulates the production of the immunomodulatory factor taurine chloramine (TauCl). TauCl regulates macrophages to become phagocytic and wound-healing, and 2) dimerizes A2M to change its function. The A2M dimer removes misfolded proteins, releases pre-synthesized TGFB1, and feeds back against pro-inflammatory processes such as those driven by NFkB. Step 4: TGFB1 is a potent regulator of NFkB and inflammation. Macrophages exposed to TGFB1 become regulators of pro-inflammatory cells, and the innate immune activation cycle is completed. Step 5: NP001 is converted to hypochlorite by heme iron, which stimulates Steps 3 and 4. TauCl regulates macrophages, and hypochlorite stimulates further dimerization of A2M and the release of TGFB1.

[0256] To test whether the observed VC sparing effect associated with NP001 treatment is more prominent early in the disease, patients were divided into two groups based on the median time from symptom onset of 16.2 months. The following median groups showed a significant difference between treatment and placebo starting from the 2-month time point that was maintained throughout the 6-month study. The group that exceeded the median after symptom onset showed less robust activity in VC sparing, with only borderline significance at the 4-month time point. The data presented here confirm that respiratory function is measurably dysfunctional early in the disease, as augmentation of innate immunity by NP001 decelerates VC loss from the earliest time points. Second, even in ALS patients with a late start of NP001, the rate of VC loss is still slower than that of VC loss in placebo.

[0257] To show the baseline stability of VC in ALS patients stratified by age, a CRP level of at least 1.13 mg / L was required. The finding of a significant age-related loss of VC in patients with low CRP suggests that CRP plays a role in stabilizing the innate immune system with respect to respiratory function. Furthermore, NP001 can enhance components of the immune activation cycle through the production of the immunomodulatory molecules TauCL and TGFB1.

[0258] Another important component of the humoral innate immune system is alpha-2-macroglobulin (A2M). A2M is a large plasma protein that binds to and removes proteases, which are by-products of the oxidative burst process. A2M forms dimers when it comes into contact with excess HOCl, which is a product of the oxidative burst process. These dimers bind to misfolded and aggregated proteins, which are thought to be initiators of the inflammatory processes associated with neurodegenerative diseases, and remove them. The dimers also release pre-formed TGFB1, thereby signaling the immune system to suppress pro-inflammatory signals such as those driven by NFkB. The steps in the successful innate immune system regulatory cycle described in this study include: 1) initiation of the CRP promotion and feedback loop; 2) the oxidative burst by-product HOCL, which is converted to the immunomodulatory factor taurine chloramine (TauCl); 3) release of TGFB1 from the A2M dimer, further suppressing inflammation. NP001, which is converted to HOCL, has an amplifying effect on this self-regulatory cycle. In the data presented, plasma TGFB1 levels were 95% higher in the NP001 treatment compared to placebo after 6 months. Considering the 2-minute plasma half-life of TGFB1 and the fact that NP001 was last administered 1 month prior to testing the plasma specimens, the results suggest re-establishment of the control of the innate immune system that had become ineffective in the disease situation.

[0259] In this study, VC in ALS patients was measured over time after initiation. High CRP patients showed >64% improvement in VC function compared to the high CRP placebo; low CRP patients did not show a response to NP001. These results suggest that VC can be monitored in conjunction with plasma TGFB1 levels following disease activity and response to innate immune system-directed therapies.

[0260] Embodiments Embodiment 1. a) Identifying that a subject has an LPS:EGF ratio associated with ALS; and b) determining that a subject is eligible for sodium chlorite treatment for ALS based on identification that the subject has an LPS:EGF ratio associated with ALS; A method comprising.

[0261] Embodiment 2. The method according to embodiment 1, wherein the LPS:EGF ratio associated with ALS is 50 or less.

[0262] Embodiment 3. The method according to embodiment 1 or 2, wherein the subject has ALS.

[0263] Embodiment 4. The method according to any one of embodiments 1 to 3, wherein the subject is at least 40 years old.

[0264] Embodiment 5. The method according to any one of embodiments 1 to 4, wherein the subject has a CRP level of greater than 1.13 mg / L as determined by a blood assay.

[0265] Embodiment 6. The method according to any one of embodiments 1 to 5, wherein the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0266] Embodiment 7. The method according to any one of embodiments 1 to 6, further comprising recommending that the subject receive sodium chlorite treatment for ALS based on determining that the subject is eligible for sodium chlorite treatment for ALS.

[0267] Embodiment 8. The method according to any one of embodiments 1 to 7, further comprising administering sodium chlorite treatment to the subject.

[0268] Embodiment 9. The method according to any one of embodiments 1 to 8, further comprising orally administering sodium chlorite treatment to the subject.

[0269] Embodiment 10. The method according to any one of embodiments 1 to 8, further comprising parenterally administering sodium chlorite treatment to the subject.

[0270] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein identifying that a subject has an LPS:EGF ratio associated with ALS is performed by obtaining a result from an assay of the subject.

[0271] Embodiment 12. The method according to Embodiment 11, further comprising performing an assay of the subject to obtain a result.

[0272] Embodiment 13. The method according to Embodiment 11 or 12, wherein the assay is a blood assay.

[0273] Embodiment 14. The method according to any one of Embodiments 11 to 13, wherein the assay is quantification of LPS and EGF in the blood of the subject by high performance liquid chromatography.

[0274] Embodiment 15. A method of treating ALS in a subject in need thereof, a) identifying that the subject has an LPS:EGF ratio associated with ALS; and b) based on the identification that the subject has an LPS:EGF ratio associated with ALS, administering to the subject an amount of sodium chlorite that is therapeutically effective for ALS. comprising the method.

[0275] Embodiment 16. The method according to Embodiment 15, wherein the LPS:EGF ratio associated with ALS is 50 or less.

[0276] Embodiment 17. The method according to Embodiment 15 or 16, wherein the subject is at least 40 years old.

[0277] Embodiment 18. The method according to any one of Embodiments 15 to 17, wherein the amount is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0278] Embodiment 19. The method according to any one of Embodiments 15 to 18, wherein the administration is oral.

[0279] Embodiment 20. The method according to any one of Embodiments 15 to 18, wherein the administration is parenteral.

[0280] Embodiment 21. The method according to any one of Embodiments 15 to 20, wherein identifying that the subject has an LPS:EGF ratio associated with ALS is performed by obtaining a result from an assay of the subject.

[0281] Embodiment 22. The method according to Embodiment 21, further comprising performing an assay of the subject to obtain a result.

[0282] Embodiment 23. The method according to Embodiment 21 or 22, wherein the assay is a blood assay.

[0283] Embodiment 24. The method according to any one of Embodiments 21 to 23, wherein the assay is quantification of LPS and EGF in the blood of the subject by high performance liquid chromatography.

[0284] Embodiment 25. a) Determining the LPS:EGF ratio in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a treatment regimen of sodium chlorite; and b) Determining whether to continue the treatment regimen of sodium chlorite based on the LPS:EGF ratio, comprising the method.

[0285] Embodiment 26. The method according to Embodiment 25, wherein the LPS:EGF ratio in the subject is 50 or less.

[0286] Embodiment 27. The method according to Embodiment 25 or 26, wherein the subject is at least 40 years old.

[0287] Embodiment 28. The method according to any one of Embodiments 25 to 27, wherein the treatment regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0288] Embodiment 29. The method according to any one of Embodiments 25 to 28, wherein the treatment regimen of sodium chlorite is administered orally.

[0289] Embodiment 30. The method according to any one of Embodiments 25 to 28, wherein the treatment regimen of sodium chlorite is administered parenterally.

[0290] Embodiment 31. The method according to any one of Embodiments 25 to 30, further comprising determining to continue the treatment regimen of sodium chlorite.

[0291] Embodiment 32. The method according to any one of Embodiments 25 to 30, further comprising determining to discontinue the treatment regimen of sodium chlorite.

[0292] Embodiment 33. The method according to any one of Embodiments 25 to 32, wherein determining the LPS:EGF ratio in a subject is performed by obtaining a result from an assay of the subject.

[0293] Embodiment 34. The method according to Embodiment 33, further comprising performing an assay of the subject to obtain a result.

[0294] Embodiment 35. The method according to Embodiment 33 or 34, wherein the assay is a blood assay.

[0295] Embodiment 36. The method according to any one of Embodiments 33 to 35, wherein the assay is quantification of LPS and EGF in the blood of the subject by high performance liquid chromatography.

[0296] Embodiment 37. a) obtaining a first level of inflammatory macrophages in the intestinal epithelium of a subject having ALS, wherein the first level of inflammatory macrophages in the intestinal epithelium of a subject having ALS is based on a blood assay; b) initiating the subject on a regimen of sodium chlorite administration for a period of about six months, based at least in part on a first level of inflammatory macrophages in the intestinal epithelium of the subject; c) obtaining a second level of inflammatory macrophages in the intestinal epithelium of the subject after the period; d) determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject; and e) recommending that the subject continue the regimen of sodium chlorite administration, based at least in part on determining that the second level of inflammatory macrophages in the intestinal epithelium of the subject is lower by a predetermined threshold amount than the first level of inflammatory macrophages in the intestinal epithelium of the subject, A method comprising.

[0297] Embodiment 38. The method according to embodiment 37, wherein the subject is at least 40 years old.

[0298] Embodiment 39. The method according to embodiment 37 or 38, wherein the subject has a CRP level of greater than 1.13 mg / L as determined by a blood assay.

[0299] Embodiment 40. The method according to any one of embodiments 37 to 39, wherein the regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0300] Embodiment 41. The method according to any one of embodiments 37 to 40, wherein the regimen of sodium chlorite is administered orally.

[0301] Embodiment 42. The method according to any one of embodiments 37 to 40, wherein the regimen of sodium chlorite is administered parenterally.

[0302] Embodiment 43. The method according to any one of embodiments 37 to 42, further comprising determining to continue the regimen of sodium chlorite.

[0303] Embodiment 44. The method according to any one of Embodiments 37 to 42, further comprising determining to interrupt the regimen of sodium chlorite.

[0304] Embodiment 45. The method according to any one of Embodiments 37 to 44, wherein the blood assay is quantification of inflammatory macrophages in the subject's blood by high performance liquid chromatography.

[0305] Embodiment 46. a) Obtaining a first plasma neurofilament light chain level of a subject having ALS, wherein the first plasma neurofilament light chain level of the subject having ALS is based on a blood assay; obtaining the first plasma neurofilament light chain level; b) Initiating the subject on a regimen of sodium chlorite administration for a period of about 6 months, at least in part based on the subject's first plasma neurofilament light chain level; c) After the period, obtaining a second plasma neurofilament light chain level of the subject; d) Determining that the subject's second plasma neurofilament light chain level is at least a predetermined threshold amount of decrease compared to the subject's first plasma neurofilament light chain level; and e) Recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the subject's second plasma neurofilament light chain level is at least a predetermined threshold amount of decrease compared to the subject's first plasma neurofilament light chain level. A method comprising.

[0306] Embodiment 47. The method according to Embodiment 46, wherein the subject is at least 40 years old.

[0307] Embodiment 48. The method according to Embodiment 46 or 47, wherein the subject has a CRP level of greater than 1.13 mg / L as determined by a blood assay.

[0308] The method according to any one of embodiments 46 to 48, wherein the regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0309] Embodiment 50. The method according to any one of embodiments 46 to 49, wherein the regimen of sodium chlorite is administered orally.

[0310] Embodiment 51. The method according to any one of embodiments 46 to 49, wherein the regimen of sodium chlorite is administered parenterally.

[0311] Embodiment 52. The method according to any one of embodiments 46 to 51, further comprising determining to continue the regimen of sodium chlorite.

[0312] Embodiment 53. The method according to any one of embodiments 46 to 51, further comprising determining to discontinue the regimen of sodium chlorite.

[0313] Embodiment 54. The method according to any one of embodiments 46 to 53, wherein the blood assay is quantification of the level of neurofilament light chain in the blood of the subject by high performance liquid chromatography.

[0314] Embodiment 55. A method of treating ALS in a subject in need of treatment for ALS, a) obtaining a first level of a first biomarker in the subject; b) obtaining a first level of a second biomarker in the subject; c) starting the subject on a regimen of sodium chlorite administration for a period of at least about 6 months after obtaining the first level of the first biomarker in the subject and obtaining the first level of the second biomarker in the subject; d) obtaining a second level of the first biomarker in the subject after the period; e) obtaining a second level of the second biomarker in the subject after the period; f) determining that a first level of a first biomarker in a subject is greater than a second level of the first biomarker in the subject; g) determining that a first level of a second biomarker in the subject is less than a second level of the second biomarker in the subject; and h) recommending that the subject continue a regimen of sodium chlorite administration, at least in part based on determining that a first level of a first biomarker in the subject is greater than a second level of the first biomarker in the subject and determining that a first level of a second biomarker in the subject is less than a second level of the second biomarker in the subject; A method comprising.

[0315] Embodiment 56. The method according to embodiment 55, wherein the subject is at least 40 years old.

[0316] Embodiment 57. The method according to embodiment 55 or 56, wherein the first biomarker is LPS.

[0317] Embodiment 58. The method according to any one of embodiments 55 to 57, wherein the second biomarker is EGF.

[0318] Embodiment 59. The method according to any one of embodiments 55 to 58, wherein the subject has a CRP level of greater than 1.13 mg / L as determined by a blood assay.

[0319] Embodiment 60. The method according to any one of embodiments 55 to 59, wherein the regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0320] Embodiment 61. The method according to any one of embodiments 55 to 60, wherein the regimen of sodium chlorite is administered orally.

[0321] Embodiment 62. The method according to any one of embodiments 55 to 60, wherein the regimen of sodium chlorite is administered parenterally.

[0322] Embodiment 63. The method according to any one of Embodiments 55 to 62, further comprising determining to continue a regimen of sodium chlorite.

[0323] Embodiment 64. The method according to any one of Embodiments 55 to 62, further comprising determining to interrupt a regimen of sodium chlorite.

[0324] Embodiment 65. The method according to any one of Embodiments 55 to 64, wherein determining that a first level of a first biomarker in a subject is greater than a second level of the first biomarker is performed by obtaining a result from an assay of the subject.

[0325] Embodiment 66. The method according to any one of Embodiments 55 to 65, wherein determining that a first level of a second biomarker in a subject is less than a second level of the second biomarker is performed by obtaining a result from an assay of the subject.

[0326] Embodiment 67. The method according to any one of Embodiments 55 to 66, further comprising performing an assay of the subject to obtain a result.

[0327] Embodiment 68. The method according to Embodiment 67, wherein the assay is a blood assay.

[0328] Embodiment 69. The method according to Embodiment 67 or 68, wherein the assay is quantification of a first biomarker and a second biomarker in the blood of the subject by high performance liquid chromatography.

[0329] Embodiment 70. a) identifying that a subject has a level of TGFB1 associated with ALS; and b) determining, based on the identification that the subject has a level of TGFB1 associated with ALS, that the subject is eligible for sodium chlorite treatment for ALS, A method comprising.

[0330] Embodiment 71. The method according to embodiment 70, wherein the subject has ALS.

[0331] Embodiment 72. The method according to embodiment 70 or 71, wherein the subject is at least 40 years old.

[0332] Embodiment 73. The method according to any one of embodiments 70 to 72, wherein the subject has a CRP level of more than 1.13 mg / L as determined by a blood assay.

[0333] Embodiment 74. The method according to any one of embodiments 70 to 73, wherein the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0334] Embodiment 75. The method according to any one of embodiments 70 to 74, further comprising recommending that the subject receive sodium chlorite treatment for ALS based on a determination that the subject is eligible for sodium chlorite treatment for ALS.

[0335] Embodiment 76. The method according to any one of embodiments 70 to 75, further comprising administering sodium chlorite treatment to the subject.

[0336] Embodiment 77. The method according to any one of embodiments 70 to 76, further comprising orally administering sodium chlorite treatment to the subject.

[0337] Embodiment 78. The method according to any one of embodiments 70 to 76, further comprising parenterally administering sodium chlorite treatment to the subject.

[0338] Embodiment 79. The method according to any one of embodiments 70 to 78, wherein identifying that the subject has a level of TGFB1 associated with ALS is performed by obtaining a result from an assay of the subject.

[0339] The method according to embodiment 79, further comprising performing an assay on a subject to obtain a result.

[0340] The method according to embodiment 79 or 80, wherein the assay is a blood assay.

[0341] The method according to any one of embodiments 79 to 81, wherein the assay is quantification of TGFB1 in the blood of the subject by high performance liquid chromatography.

[0342] A method for treating ALS in a subject in need of treatment for ALS, comprising: a) identifying that the subject has a level of TGFB1 associated with ALS; and b) administering to the subject an amount of sodium chlorite that is therapeutically effective for ALS, based on the identification that the subject has a level of TGFB1 associated with ALS. Including the method.

[0343] The method according to embodiment 83, wherein the subject is at least 40 years old.

[0344] The method according to embodiment 83 or 84, wherein the amount is about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0345] The method according to any one of embodiments 83 to 85, wherein the administration is oral.

[0346] The method according to any one of embodiments 83 to 85, wherein the administration is parenteral.

[0347] The method according to any one of embodiments 83 to 87, wherein identifying that the subject has a level of TGFB1 associated with ALS is performed by obtaining a result from an assay of the subject.

[0348] The method according to embodiment 88, further comprising performing an assay on a subject to obtain a result.

[0349] Embodiment 90. The method according to embodiment 88 or 89, wherein the assay is a blood assay.

[0350] Embodiment 91. The method according to any one of embodiments 88 to 90, wherein the assay is quantification of TGFB1 in the blood of a subject by high performance liquid chromatography.

[0351] Embodiment 92. a) Determining the level of TGFB1 in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a therapeutic regimen of sodium chlorite; and b) Determining whether to continue the therapeutic regimen of sodium chlorite based on the level of TGFB1. A method comprising.

[0352] Embodiment 93. The method according to embodiment 92, wherein the subject is at least 40 years old.

[0353] Embodiment 94. The method according to embodiment 92 or 93, wherein the therapeutic regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0354] Embodiment 95. The method according to any one of embodiments 92 to 94, wherein the therapeutic regimen of sodium chlorite is administered orally.

[0355] Embodiment 96. The method according to any one of embodiments 92 to 94, wherein the therapeutic regimen of sodium chlorite is administered parenterally.

[0356] Embodiment 97. The method according to any one of embodiments 92 to 96, further comprising determining to continue the therapeutic regimen of sodium chlorite.

[0357] The method according to any one of Embodiments 92 to 96, further comprising determining to interrupt the treatment regimen of sodium chlorite.

[0358] Embodiment 99. The method according to any one of Embodiments 92 to 99, wherein determining the level of TGFB1 in a subject is performed by obtaining a result from an assay of the subject.

[0359] Embodiment 100. The method according to Embodiment 99, further comprising performing an assay of the subject to obtain a result.

[0360] Embodiment 101. The method according to Embodiment 99 or 100, wherein the assay is a blood assay.

[0361] Embodiment 102. The method according to any one of Embodiments 99 to 101, wherein the assay is quantification of TGFB1 in the blood of the subject by high performance liquid chromatography.

[0362] Embodiment 103. a) obtaining a first level of TGFB1 in a subject having ALS, wherein the first level of TGFB1 in the subject having ALS is based on a blood assay; b) starting the subject on a regimen of sodium chlorite administration for a period of at least about 6 months, at least in part based on the first level of TGFB1 in the subject; c) obtaining a second level of TGFB1 in the subject after the period; d) determining that the second level of TGFB1 in the subject is higher than the first level of TGFB1 in the subject by a predetermined threshold amount; and e) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of TGFB1 in the subject is higher than the first level of TGFB1 in the subject by a predetermined threshold amount. A method comprising.

[0363] Embodiment 104. The method according to Embodiment 103, wherein the subject is at least 40 years old.

[0364] Embodiment 105. The method according to Embodiment 103 or 104, wherein the subject has a CRP level exceeding 1.13 mg / L as determined by a blood assay.

[0365] Embodiment 106. The method according to any one of Embodiments 103 to 105, wherein the regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0366] Embodiment 107. The method according to any one of Embodiments 103 to 106, wherein the regimen of sodium chlorite is administered orally.

[0367] Embodiment 108. The method according to any one of Embodiments 103 to 106, wherein the regimen of sodium chlorite is administered parenterally.

[0368] Embodiment 109. The method according to any one of Embodiments 103 to 108, further comprising determining to continue the regimen of sodium chlorite.

[0369] Embodiment 110. The method according to any one of Embodiments 103 to 108, further comprising determining to interrupt the regimen of sodium chlorite.

[0370] Embodiment 111. The method according to any one of Embodiments 103 to 110, wherein the assay is quantification of TGFB1 in the blood of the subject by high performance liquid chromatography.

[0371] Embodiment 112. a) identifying that the subject has a level of LBP associated with ALS; and b) determining that the subject is eligible for sodium chlorite treatment for ALS based on the identification that the subject has a level of LBP associated with ALS, A method comprising.

[0372] Embodiment 113. The method according to embodiment 112, wherein the subject has ALS.

[0373] Embodiment 114. The method according to embodiment 112 or 113, wherein the subject is at least 40 years old.

[0374] Embodiment 115. The method according to any one of embodiments 112 to 114, wherein the subject has a CRP level exceeding 1.13 mg / L as determined by a blood assay.

[0375] Embodiment 116. The method according to any one of embodiments 112 to 115, wherein the sodium chlorite treatment is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0376] Embodiment 117. The method according to any one of embodiments 112 to 116, further comprising recommending that the subject receive sodium chlorite treatment for ALS based on a determination that the subject is eligible for sodium chlorite treatment for ALS.

[0377] Embodiment 118. The method according to any one of embodiments 112 to 117, further comprising administering sodium chlorite treatment to the subject.

[0378] Embodiment 119. The method according to any one of embodiments 112 to 118, further comprising orally administering sodium chlorite treatment to the subject.

[0379] Embodiment 120. The method according to any one of embodiments 112 to 118, further comprising parenterally administering sodium chlorite treatment to the subject.

[0380] Embodiment 121. The method according to any one of embodiments 112 to 120, wherein identifying that the subject has a level of LBP associated with ALS is performed by obtaining results from an assay of the subject.

[0381] The method according to embodiment 121, further comprising performing an assay on a subject to obtain a result.

[0382] The method according to embodiment 121 or 122, wherein the assay is a blood assay.

[0383] The method according to any one of embodiments 121 to 123, wherein the assay is quantification of LBP in the blood of the subject by high performance liquid chromatography.

[0384] A method of treating ALS in a subject in need of treatment for ALS, a) identifying that the subject has a level of LBP associated with ALS; and b) based on the identification that the subject has a level of LBP associated with ALS, administering to the subject a therapeutically effective amount of sodium chlorite for ALS, comprising the method.

[0385] The method according to embodiment 125, wherein the subject is at least 40 years old.

[0386] The method according to embodiment 125 or 126, wherein the amount is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0387] The method according to any one of embodiments 125 to 127, wherein the administration is oral.

[0388] The method according to any one of embodiments 125 to 128, wherein the administration is parenteral.

[0389] The method according to any one of embodiments 125 to 129, wherein identifying that the subject has a level of LBP associated with ALS is performed by obtaining a result from an assay of the subject.

[0390] The method according to embodiment 130, further comprising performing an assay on a subject to obtain a result.

[0391] The method according to embodiment 130 or 131, wherein the assay is a blood assay.

[0392] The method according to any one of embodiments 130 to 132, wherein the assay is quantification of LBP in the blood of a subject by high performance liquid chromatography.

[0393] a) determining the level of LBP in a subject having ALS, wherein the subject is undergoing treatment for ALS and the treatment is a treatment regimen of sodium chlorite; and b) determining whether to continue the treatment regimen of sodium chlorite based on the level of LBP, comprising a method.

[0394] The method according to embodiment 134, wherein the subject is at least 40 years old.

[0395] The method according to embodiment 134 or 135, wherein the treatment regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0396] The method according to any one of embodiments 134 to 136, wherein the treatment regimen of sodium chlorite is administered orally.

[0397] The method according to any one of embodiments 134 to 136, wherein the treatment regimen of sodium chlorite is administered parenterally.

[0398] The method according to any one of embodiments 134 to 138, further comprising determining to continue the treatment regimen of sodium chlorite.

[0399] The method according to any one of embodiments 134 to 138, further comprising determining to discontinue the treatment regimen of sodium chlorite.

[0400] Embodiment 141. The method according to any one of embodiments 134 to 140, wherein determining the level of LBP in a subject is performed by obtaining a result from an assay of the subject.

[0401] Embodiment 142. The method according to embodiment 141, further comprising performing an assay of the subject to obtain a result.

[0402] Embodiment 143. The method according to embodiment 141 or 142, wherein the assay is a blood assay.

[0403] Embodiment 144. The method according to any one of embodiments 140 to 143, wherein the assay is quantification of LBP in the blood of the subject by high performance liquid chromatography.

[0404] Embodiment 145. a) obtaining a first level of LBP in a subject having ALS, wherein the first level of TGFB1 in the subject having ALS is based on a blood assay; b) starting the subject on a regimen of sodium chlorite administration for a period of at least about 6 months, at least in part based on the first level of LBP in the subject; c) obtaining a second level of LBP in the subject after the period; d) determining that the second level of LBP is lower than the first level of TGFB1 in the subject by a predetermined threshold amount; and e) recommending that the subject continue the regimen of sodium chlorite administration, at least in part based on determining that the second level of LBP in the subject is lower than the first level of LBP in the subject by a predetermined threshold amount. A method comprising.

[0405] Embodiment 146. The method according to embodiment 145, wherein the subject is at least 40 years old.

[0406] Embodiment 147. The method according to embodiment 145 or 146, wherein the subject has a CRP level exceeding 1.13 mg / L as determined by a blood assay.

[0407] Embodiment 148. The method according to any one of embodiments 145 to 147, wherein the regimen of sodium chlorite is from about 0.2 mg / kg / day to about 3.5 mg / kg / day.

[0408] Embodiment 149. The method according to any one of embodiments 145 to 148, wherein the regimen of sodium chlorite is administered orally.

[0409] Embodiment 150. The method according to any one of embodiments 145 to 148, wherein the regimen of sodium chlorite is administered parenterally.

[0410] Embodiment 151. The method according to any one of embodiments 145 to 150, further comprising determining to continue the regimen of sodium chlorite.

[0411] Embodiment 152. The method according to any one of embodiments 145 to 150, further comprising determining to discontinue the regimen of sodium chlorite.

[0412] Embodiment 153. The method according to any one of embodiments 145 to 152, wherein the assay is quantification of LBP in the subject's blood by high performance liquid chromatography.

Claims

1. A sodium chlorite composition for use in the treatment of a subject having one or more levels of a biomarker associated with neurodegenerative disease, wherein the one or more biomarkers are selected from TGFB1, SAA, NfL, HGF, A2M, EGF, IL10, neopterin, and LPS:EGF ratio.

2. The sodium chlorite composition according to claim 1, wherein the subject is a human.

3. The sodium chlorite composition according to claim 2, wherein the subject is at least 40 years old.

4. The sodium chlorite composition according to claim 1, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

5. The sodium chlorite composition according to claim 1, wherein the pharmaceutical is formulated for administration to the subject at a dose of about 0.1 mg to about 10 mg of sodium chlorite per kg of the subject's body weight.

6. The sodium chlorite composition according to claim 1, wherein the pharmaceutical is formulated for administration to the subject at a dose of about 0.2 mg to about 3.5 mg of sodium chlorite per kg of the subject's body weight.

7. The sodium chlorite composition according to claim 1, wherein the pharmaceutical is formulated for oral administration.

8. The sodium chlorite composition according to claim 1, wherein the pharmaceutical is formulated for parenteral administration.

9. The sodium chlorite composition according to claim 1, wherein the administration of the drug slows down the loss of lung capacity in the subject.

10. The sodium chlorite composition according to claim 1, wherein the one or more biomarkers include TGFB1.

11. A sodium chlorite composition for use in the treatment of a neurodegenerative disease in a subject having the neurodegenerative disease, characterized by a change in the level of one or more biomarkers selected from TGFB1, SAA, NfL, HGF, A2M, EGF, IL10, neopterin, and the LPS:EGF ratio, wherein the change in the level of each of the one or more biomarkers in the subject is a) Obtain a first level of each of the one or more biomarkers from the first assay; b) After obtaining the first level of each of the biomarkers described above (1 or more), administer a sodium chlorite treatment regimen to the subject; c) After administering the sodium chlorite treatment regimen to the subject, obtain a second level of each of the 1 or more biomarkers from a second assay; d) After obtaining the second level of each of the 1 or more biomarkers, compare the first level and the second level of each biomarker to identify the change at the level of each biomarker in the subject. A sodium chlorite composition determined by [the specified method].

12. The method according to claim 11, wherein the subject is a human being at least 40 years old.

13. The method according to claim 11, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

14. The method according to claim 11, wherein the pharmaceutical is formulated for administration to the subject in a dose of about 0.1 mg to about 10 mg of sodium chlorite per kg of the subject's body weight.

15. The method according to claim 12, wherein the pharmaceutical is formulated for administration to the subject in a dose of approximately 0.2 mg to approximately 3.5 mg of sodium chlorite per kg of the subject's body weight.

16. The sodium chlorite composition according to claim 11, characterized in that the 1 or more biomarkers include TGFB1, and the sodium chlorite composition is administered to the subject when the change in the level of TGFB1 is increasing.

17. (a) A probe for quantifying one or more biomarkers selected from TGFB1, SAA, NfL, HGF, A2M, EGF, IL10, neopterin, and the ratio of LPS:EGF; and (b) A composition comprising a chlorite salt and a pharmaceutically acceptable carrier. A kit that includes this.

18. The kit according to claim 17, wherein the probe quantifies TGFB1.

19. The kit according to claim 17, further comprising instructions for measuring the level of each of the one or more biomarkers.

20. The kit according to claim 18, further comprising instructions for measuring changes at each level of one or more of the biomarkers.

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