Treatment of motor neurone disease

Abstract

The present disclosure relates to a method of treating or ameliorating symptoms of a motor neurone disease and improving motor neuron survival in a subject, more specifically treating or ameliorating symptoms of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders. The treatment method comprises administering a Janus kinase (JAK) inhibitor in combination with one or more compounds selected from a glutamate antagonist and an N-methyl-D-aspartate (NMDA) receptor antagonist, in particular baricitinib in combination with riluzole and / or memantine, and compositions and kits thereof for same.

Description

[0001] TREATMENT OF MOTOR NEURONE DISEASE

[0002] CROSS REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of Australian Provisional Application No. 2024903909 filed on 27 November 2024, the entire contents of which is incorporated by reference herein.

[0004] FIELD OF INVENTION

[0005] The present disclosure relates to methods and compositions for treating or ameliorating symptoms of a motor neurone disease. In one example, the present disclosure relates to combination therapies for treating or ameliorating symptoms of amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders.

[0006] BACKGROUND OF THE INVENTION

[0007] Neurological diseases encompass a range of disorders affecting the brain, spinal cord, and nerves, often resulting in significant impairments in movement, sensation, cognition, and overall quality of life. Many of these diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), involve chronic neurodegeneration, characterized by a slow, progressive loss of nerve cells over years, leading to a gradual decline in physical and mental abilities.

[0008] A subset of these conditions is motor neurone disease, a progressive neurological disorder marked by the degeneration of motor neurons and related pathways in the central nervous system. As motor neurons deteriorate, the ability to move, speak, swallow, and breathe is progressively lost, with symptoms often beginning as muscle weakness or stiffness and worsening over time. Among the various forms of motor neurone disease, ALS is the most common and devastating. ALS is a rapidly fatal disease defined by the selective degeneration of motor neurons in the brain and spinal cord, leading to progressive weakness and paralysis and ultimately impairing essential functions like speaking, swallowing, and breathing. ALS is a heterogeneous disease with complex, poorly understood causes. Approximately 10% of ALS cases, known as familial ALS (fALS), have a family history and are associated with mutations in over 40 identified ALS-related genes. The remaining 90%, with no known familial connection, are classified as sporadic ALS (sALS), though environmental and genetic factors may contribute. Both forms share similar clinical progression, underscoring the challenging and multifaceted nature of ALS within the broader category of neurological diseases. Therapeutic options for ALS patients are limited. Riluzole remains the most widely prescribed treatment for ALS and is the only approved medication to extend life, albeit only to a modest extent. Edaravone and AMX0035 have also been granted regulatory approval in some countries, although poor clinical evidence for their efficacy have limited the approval of edaravone in major jurisdictions and the removal of AMX0035 from market. With current treatment and care, people diagnosed with ALS have an average life expectancy of less than 2.3 years. Since the discovery of riluzole over 30 years ago, over 160 drugs have been tested in clinical trials to slow or prevent disease progression in ALS patients. However, few of these drugs have translated into clinically effective drugs in clinical trials.

[0009] Accordingly, there is a need for the development of new therapies that provide greater efficacy, longer-term survival, and improved quality of life for patients with motor neurone diseases such as ALS.

[0010] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each of the appended claims.

[0011] SUMMARY OF INVENTION

[0012] The therapeutic landscape for neurological diseases remains limited, with current treatments primarily focused on symptomatic relief and slowing disease progression rather than halting or reversing neuronal degeneration.

[0013] The present invention is based, inter alia, on findings that support a novel approach to treating neurological diseases. This invention is based on the surprising identification that the targeting of at least two components of the neurotransmission and / or cellular signalling axis provides for an enhanced therapeutic effect when compared to the effect of known drugs such as riluzole. In particular, the inhibition of Janus kinase (JAK), which may include specifically inhibiting JAK1, JAK2 and JAK3 or a combination thereof, in combination with the targeting of an N-methyl-D- aspartate (NMDA) receptor and / or a glutamate antagonist provides for an enhanced therapeutic effect such that these combinations effectively slow or delay motor neuron cell death. Exemplified herein are combinations of JAK inhibitors, which may include baricitinib in one embodiment, with one or both of riluzole; a glutamate antagonist, and memantine; an NMDA receptor antagonist. Importantly, the described dual or triple combinations are capable yielding a synergistic effect, significantly enhancing therapeutic efficacy beyond what each drug achieves individually. These findings have significant implications in the treatment of motor neuron disease and neurological disorders more broadly as the inventors have demonstrated their utility in sALS, fALS, spinal and bulbar muscular atrophy (SBMA), spinal muscular atrophy (SMA), flail limb syndrome and primary lateral sclerosis (PLS).

[0014] The present disclosure therefore provides a method of treating a neurological disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0015] In another aspect of the invention, there is provided use of a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D- aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof in the manufacture of a medicament for the treatment of a neurological disease, wherein at least one of the compounds is a JAK inhibitor.

[0016] In another aspect of the invention, there is provided a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D- aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof for use in the treatment of a neurological disease, wherein at least one of the compounds is a JAK inhibitor.

[0017] In some examples, the neurological disease is selected from the group consisting of motor neuron disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), multiple system atrophy, prion diseases, or other neurodegenerative or demyelinating conditions. In one example, the neurological disease is a motor neurone disease. In other examples, the motor neurone disease is spinal and bulbar muscular atrophy (SBMA; also known as Kennedy’s disease), spinal muscular atrophy (SMA), progressive bulbar palsy (PBP), flail limb syndrome, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), pseudobulbar palsy or amyotrophic lateral sclerosis (ALS). In further examples, the ALS is familial or sporadic ALS. In particular examples, the ALS is sporadic ALS. Thus, in an aspect of the invention, there is provided a method of treating a motor neurone disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0018] In another aspect of the invention, there is provided use of a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D- aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof in the manufacture of a medicament for the treatment of a motor neurone disease, wherein at least one of the compounds is a JAK inhibitor.

[0019] In another aspect of the invention, there is provided a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D- aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof for use in the treatment of a motor neurone disease, wherein at least one of the compounds is a JAK inhibitor.

[0020] In another aspect of the invention, the present disclosure provides a method of improving motor neuron survival, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0021] In another aspect of the invention, the present disclosure provides use of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, in the manufacture of a medicament for improving motor neuron survival in a subject, wherein at least one of the compounds is a JAK inhibitor.

[0022] In another aspect of the invention, the present disclosure provides a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, in the manufacture of a medicament for use in improving motor neuron survival in a subject, wherein at least one of the compounds is a JAK inhibitor. In another aspect of the invention, the present disclosure further provides a method of inhibiting (i) Janus kinase (JAK), optionally JAK1 and JAK2, (ii) an N-methyl-D-aspartate (NMDA) receptor and / or (iii) neuronal release of glutamate in neurons of a subject, the method comprising administering to the subject a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0023] In another aspect of the invention, the present disclosure further provides use of a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof in the manufacture of a medicament for inhibiting (i) Janus kinase (JAK), optionally JAK1 and JAK2, (ii) an N-methyl- D-aspartate (NMDA) receptor and / or (iii) neuronal release of glutamate in neurons of a subject.

[0024] In another aspect of the invention, the present disclosure further provides a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof for use in inhibiting (i) Janus kinase (JAK), optionally JAK1 and JAK2, (ii) an N-methyl-D-aspartate (NMDA) receptor and / or (iii) neuronal release of glutamate in neurons of a subject.

[0025] Suitably, the glutamate antagonist is selected from the group consisting of riluzole, ketamine, amantadine, dextromethorphan, perampanel, talampanel, topiramate and gabapentin, or analogues, derivatives or salts thereof. In one example, the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof.

[0026] Suitably, the JAK inhibitor is one or more or all of a JAK1 inhibitor, a JAK2 inhibitor and a JAK3 inhibitor. In some examples, the JAK inhibitor is selected from the group consisting of baricitinib, tofacitinib, upadacitinib, fedratinib, ruxolitinib, pacritinib, momelotinib and abrocitinib, or analogues, derivatives or salts thereof. In particular examples, the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof.

[0027] In other examples, the JAK inhibitor is a highly selective inhibitor of a particular JAK isoform but may also have selectivity for other JAK isoforms. For example, the JAK inhibitor may be highly selective for JAK3. In this embodiment, a suitable example is TCS21311 or an analogue, derivative or salt thereof. Suitably, the JAK inhibitor may therefore be a JAK3 inhibitor. Examples of suitable JAK3 inhibitors include decernotinib, ritlecitinib, peficitinib and FM-381.

[0028] In another example, the JAK inhibitor may be a pan JAK inhibitor. In this embodiment, a suitable example is SAR20347 or an analogue, derivative or salt thereof.

[0029] Suitably, the NMDA receptor antagonist is selected from the group consisting of memantine, minocycline, gabapentin, amantadine, ketamine, agmatine and dextromethorphan, or analogues, derivatives or salts thereof. In one example, the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

[0030] In some examples, the present disclosure provides a combination comprising or consisting of baricitinib and memantine, or analogues, derivatives or salts thereof.

[0031] In other examples, the combination comprises or consists of riluzole and baricitinib, or analogues, derivatives or salts thereof.

[0032] In further examples, the combination comprises or consists of riluzole, baricitinib and memantine, or analogues, derivatives or salts thereof.

[0033] In an example, the combination further comprises a sodium channel blocker. In another example, the sodium channel blocker is selected from the group consisting of lamotrigine, phenytoin, carbamazepine, topiramate, valproate (valproic acid), mexiletine, and lacosamide.

[0034] In examples described herein, a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor provides for a synergistic effect when compared to the effect of the individual compound. In one embodiment, the combination that provides for a synergistic effect is a Janus kinase (JAK) inhibitor and an N-methyl-D-aspartate (NMDA) receptor antagonist, or analogues, derivatives or salts thereof. In another embodiment, the combination that provides for a synergistic effect is a Janus kinase (JAK) inhibitor and a glutamate antagonist, or analogues, derivatives or salts thereof. In another embodiment, the combination that provides for a synergistic effect is a Janus kinase (JAK) inhibitor, a glutamate antagonist, and an N-methyl-D- aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof. In another embodiment, the combination comprising or consisting of baricitinib, SAR20347 or TCS21311 and memantine, or analogues, derivatives or salts thereof provides for a synergistic effect when compared to the effect of the individual compound. In another example, the combination comprising or consisting of baricitinib, SAR20347 or TCS21311 and riluzole, or analogues, derivatives or salts thereof provides for a synergistic effect when compared to the effect of the individual compound. In another example, the combination comprising or consisting of baricitinib, SAR20347 or TCS21311, riluzole and memantine, or analogues, derivatives or salts thereof provides for a synergistic effect when compared to the effect of the individual compound.

[0035] In one example, the combination may include one or more Janus kinase (JAK) inhibitors, one or more glutamate antagonists, and / or one or more N-methyl-D-aspartate (NMDA) receptor antagonists or analogues, derivatives or salts thereof. For example, the combination may suitably include two JAK inhibitors, one glutamate antagonist, and one NMDA receptor antagonists or analogues, derivatives or salts thereof. In another example, the combination may suitably include two JAK inhibitors, one glutamate antagonist, and two NMDA receptor antagonists or analogues, derivatives or salts thereof. In such examples, the two JAK inhibitors may preferentially target different JAK isoforms, for example JAK1 and JAK3.

[0036] Suitably, riluzole is administered in a dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg per day. In other examples, riluzole is administered at a dosage of about between about lOmg to 400 mg per day. In other examples, riluzole is administered at a dosage of about between about 50mg to 350 mg per day. In other examples, riluzole is administered at a dosage of about between about lOOmg to 300 mg per day. In other examples, riluzole is administered at a dosage of about between about 150mg to 250 mg per day. In further examples, riluzole is administered at a dosage of about 200 mg per day.

[0037] Accordingly, riluzole is administered at a dosage that achieves a plasma concentration of about 0.125 pM, 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM, 4.0 pM, 4.5 pM, 5.0 pM, 5.5 pM, 6.0 pM, 6.5 pM, 7.0 pM, 7.5 pM, 8.0 pM, 8.5 pM, 9.0 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM, 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM per day. In other examples, riluzole is administered at a dosage that achieves a plasma concentration of about 0.125 pM, 0.5 pM, 1.0 pM, 1.5 pM, 2.0 pM, 2.5 pM, 3.0 pM, 3.5 pM, 4.0 pM, 4.5 pM, 5.0 pM or 10 pM. In yet further examples, riluzole is administered at a dosage that achieves a plasma concentration of 2.5 pM.

[0038] Suitably, baricitinib, SAR20347 or TCS21311 is administered in a dosage of about 0.5 mg, 1 mg,

[0039] 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg or 8 mg per day. In other examples, baricitinib is administered at a dosage of between about 0.5mg to 8 mg per day. In further examples, baricitinib is administered at a dosage of about 1 mg to 6 mg per day. In further examples, baricitinib is administered at a dosage of about 2 mg to 4 mg per day. In some examples, baricitinib is administered at a dosage of 2 mg per day. In other examples, baricitinib is administered at a dosage of 4 mg per day.

[0040] In certain examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage that achieves a plasma concentration of about 0.0025 pM, 0.04 pM , 0.0525 pM, 0.1025 pM, 0.1525 pM, 0.2025 pM, 0.2525 pM, 0.3025 pM, 0.3525 pM, 0.4025 pM, 0.4525 pM, 0.5 pM, 1 pM, 1.5 pM, 2 pM,

[0041] 2.5 pM, 3 pM, 3.5 pM, 4 pM, 4.5 pM, 5 pM, 5.5 pM, 6 pM, 6.5 pM, 7 pM, 7.5 pM, 8 pM, 8.5 pM, 9 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM,

[0042] 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM per day. In some examples, baricitinib is administered at a dosage that achieves a plasma concentration of about 0.0025 pM, 0.1525 pM, 1 pM, 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM, 5.5 pM,

[0043] 6.5 pM, 7.5 pM, 8.5 pM, 9.5 pM or 10 pM. In other examples, baricitinib is administered at a dosage that achieves a plasma concentration of 2.5 pM. In other examples, TCS-21311 is administered at a dosage that achieves a plasma concentration of IpM. In yet other examples, SAR-20347 is administered at a dosage that achieves a plasma concentration of IpM.

[0044] Suitably, memantine is administered in a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg or 80 mg per day. In other examples, memantine is administered at a dosage of between about 5 mg to 80 mg about per day. In further examples, memantine is administered at a dosage of between about 10 mg to 70 mg about per day. In further examples, memantine is administered at a dosage of between about 15 mg to 65 mg about per day. In further examples, memantine is administered at a dosage of between about 20 mg to 60 mg about per day. In further examples, memantine is administered at a dosage of between about 25 mg to 55 mg about per day. In further examples, memantine is administered at a dosage of between about 30 mg to 50 mg about per day. In further examples, memantine is administered at a dosage of between about 35 mg to 45 mg about per day. In some examples, memantine is administered at a dosage of 40 mg per day.

[0045] In other examples, memantine is administered at a dosage that achieves a plasma concentration of about 0.15 pM, 0.2 pM, 0.25 pM, 0.3 pM, 0.35 pM, 0.4 pM, 0.45 pM, 0.5 pM, 1 pM, 1.5 pM, 2 pM, 2.5 pM, 3 pM, 3.5 pM, 4 pM, 4.5 pM, 5 pM, 5.5 pM, 6 pM, 6.5 pM, 7 pM, 7.5 pM, 8 pM, 8.5 pM, 9 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM, 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM. In further examples, memantine is administered at a dosage that achieves a plasma concentration of about 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM, 5.5 pM, 6.5 pM, 7.5 pM, 8.5 pM, 9.5 pM or 10 pM. In further examples, wherein memantine is administered at a dosage that achieves a plasma concentration of 2.5 pM.

[0046] In some examples, the compounds in the combination are formulated as separate pharmaceutical compositions, each pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient. In other examples, the compounds in the combination are formulated in the same pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0047] In a further example, the pharmaceutical compositions are administered together. In particular examples, the compounds in the combination are administered separately. In certain examples, the compounds in the combination are administered sequentially.

[0048] In one example, the combination is administered once daily. In other examples, the combination is administered twice daily. In another example, the glutamate antagonist, preferably riluzole, and / or the NMD A receptor antagonist, preferably memantine, is / are administered daily or twice daily and the JAK inhibitor, optionally baricitinib, is administered daily. Where riluzole and / or memantine is / are administered twice daily with a particular dosage per day, it is envisaged that the dosage taken a twice a day will equal the total daily dosage. For example, if the daily dosage of riluzole is 200mg per day, one dosage may comprise lOOmg and the other dosage may comprise lOOmg. In another example, if the daily dosage of riluzole is 200mg per day, one dosage may comprise 150mg and the other dosage may comprise 50mg, and so forth.

[0049] In some examples, the administration route of the combination is selected from the group consisting of parenteral administration, oral administration, intranasal administration, sublingual administration, rectal administration, intramuscular administration, intravenous administration, subcutaneous administration, intradermal administration, intrathecal administration, intra-arterial administration, intraperitoneal administration, and inhalation administration. In other examples, the administration is oral or parental administration.

[0050] In one example, the subject has previously received been treated with riluzole.

[0051] In one example, the subject has previously received a treatment and / or is receiving a treatment for the neurological disease, preferably a motor neurone disease. In this example, the treatment may be selected from the group consisting of edaravone, mexiletine, dextromethorphan and quinidine, anticholinergic medications, psychiatric medications such as but not limited to antidepressants, antipsychotics, anxiolytics / hypnotics, mood stabilizers, stimulants, muscle relaxants, physiotherapy, oxygen therapy and assisted ventilation.

[0052] In one example, the combination delays the progression of, stabilises, ameliorates, eliminates and / or reduces one or more symptoms or pathological signs of a motor neurone disease in the subject.

[0053] Pathological signs of motor neurone disease, preferably ALS, include the progressive degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness and atrophy. Other pathological features include the accumulation of abnormal protein aggregates, glial cell activation and chronic neuroinflammation. In some examples, the pathological sign is motor neuron cell death. Symptoms include muscle aches, cramps, twitching, clumsiness, stumbling, weakness in hands, arms, legs, slurred speech, swallowing or chewing difficulty, fatigue, muscle wasting, weight loss, emotional lability, cognitive changes or respiratory changes.

[0054] In another aspect of the invention, the present disclosure provides a composition or admixture comprising a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N-methyl-D-aspartate (NMD A) receptor antagonist or analogues, derivatives or salts thereof, and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor. The glutamate antagonist, Janus kinase (JAK) inhibitor and N-methyl-D-aspartate (NMDA) receptor antagonist may be any antagonist or inhibitor disclosed herein or known in the art. In an example, the compounds in the composition as described herein are formulated together or separately.

[0055] In an example, the composition or admixture further comprises a sodium channel blocker. In another example, the sodium channel blocker is selected from the group consisting of lamotrigine, phenytoin, carbamazepine, topiramate, valproate (valproic acid), mexiletine, and lacosamide.

[0056] In another aspect of the invention, the present disclosure provides a method of making the composition as described herein, wherein the method comprises formulating a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N- methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor.

[0057] In one example, the method as described herein suitably includes formulating a composition in which the glutamate antagonist is riluzole, or its analogues, derivatives, or salts; the JAK inhibitor is baricitinib, TCS21311 or SAR-20347, or its analogues, derivatives, or salts; and the NMDA receptor antagonist is memantine, or its analogues, derivatives, or salts.

[0058] In particular examples, the method as described herein may further include formulating a combination that comprises or consists of the combination of baricitinib, TCS21311 or SAR-20347 and memantine, or their analogues, derivatives, or salts.

[0059] In other examples, the method as described herein may further include formulating a combination that comprises or consists of baricitinib, TCS21311 or SAR-20347 and riluzole or analogues, derivatives or salts thereof.

[0060] In further examples, the method as described herein may further include formulating a combination that comprises or consists of baricitinib, TCS21311 or SAR-20347, memantine and riluzole or analogues, derivatives or salts thereof.

[0061] In other examples, the present disclosure provides a kit for treating a neurological disease, preferably motor neurone disease, more preferably amyotrophic lateral sclerosis (ALS), the kit comprising: (i) at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMD A) receptor antagonist or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor; and optionally

[0062] (ii) instructions for administering the at least two compounds of (i) according to a method as described herein.

[0063] In one example, the kit comprises a composition or admixture comprising a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N- methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor.

[0064] In one example, the glutamate antagonist is riluzole; the JAK inhibitor is baricitinib, TCS21311 or SAR-20347; and the NMDA receptor antagonist is memantine or analogues, derivatives or salts thereof.

[0065] In one example, the kit as described herein comprises a combination of at least two compounds selected from riluzole, baricitinib TCS21311 or SAR-20347; and memantine or analogues, derivatives or salts thereof, wherein at least one of the compounds is baricitinib, TCS21311 or SAR-20347.

[0066] In another example, the kit comprises the combination of baricitinib and memantine or analogues, derivatives or salts thereof.

[0067] In another example, the kit comprises formulating the combination of baricitinib, TCS21311 or SAR-20347 and riluzole or analogues, derivatives or salts thereof.

[0068] In another example, the kit comprises formulating the combination of baricitinib, TCS21311 or SAR-20347, memantine and riluzole or analogues, derivatives or salts thereof.

[0069] In an example, the kit further comprises a sodium channel blocker. In another example, the sodium channel blocker is selected from the group consisting of lamotrigine, phenytoin, carbamazepine, topiramate, valproate (valproic acid), mexiletine, and lacosamide. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] The following figures form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these figures in combination with the detailed description of specific embodiments presented herein. It will be appreciated by persons skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0071] Figure 1: ALS iPSC library generation. A. Schematic of iPSC library donor composition and workflow, each human figure represents approximately ten donors. B. Clinical subtype classification of ALS donors according to upper and lower motor neuron involvement. Key measures of clinical heterogeneity in disease course of ALS donors; C. site of onset, D. age of onset (early onset <50 years and late onset >70 years indicated on scatter plot), E. median ALSFRS-R rate of decline (rapid progression > -1.5 / month and slow progression < -0.25 / month indicated on scatter plot), F. longitudinal ALSFRS-R, and G. survival time (short survival <24 months and long survival > 50 months indicated on scatter plot). H. Pathogenic / likely pathogenic variants in causal ALS genes previously reported in ALS cases identified in library donors using whole genome sequencing (C9ORF72, 3 cases; SOD1, 4 cases; TARDBP, VCP and UBQLN2, 1 case). I. Schematic of optimised spinal motor neuron differentiation and phenotyping protocol. J. Representative immunohistochemistry of terminally differentiated spinal motor neurons from control and K. sALS donors immunoreactive for HB9-tGFP, ChAT and Tuj l at day 40. L. Quantification of spinal motor neuron 1143 (HB9+, ChAT+, Tuj l+), neuron (Tuj l+), astrocyte (GFAP+) and microglia (CD11B+) number as percentage of total cells in culture at D40 (mean ± SEM, n=5 control and 16 ALS donors). M. Representative whole well live-1145 cell image and magnified inserts of viral Hb9-tGFP reporter expression in spinal motor neurons.

[0072] Figure 2: Reassessment of ALS clinically tested drugs in sporadic ALS donors’ motor neurons. A. Schematic of drug screen with 110 drugs previously tested in ALS clinical trials using patient-derived motor neurons from ALS donors across patient population. B. Longitudinal quantification of total Hb9-tGFP+ motor neuron neurite length following treatment with ALS clinically tested drugs in a representative sporadic ALS (sALS) donor (2.5 pM, expressed as percentage of pre-treatment (Day 35), mean 2 wells ± SEM). C. Images of motor neuron health at screen endpoint (Hb9-tGFP+ motor neuron clusters and neurites at 20x). D. Quantification of average motor neuron health (expressed as % pre-treatment, Day 35) at screen endpoint in 16 sporadic ALS donors (one dot per donor, mean ± SEM, Brown -Forsythe ANOVA with Dunnett's T3 multiple comparisons test, * P < 1230 0.05, n=16 donors). Blue, DMSO control; Green, riluzole; Black, drugs with no effect; White, Untreated; Orange / Purple, clinically tested drugs. E. Quantification of cumulative effect on motor neuron health (% DMSO control, LD50 ± 5 days) in 16 sporadic ALS donors (one dot per donor, mean ± SEM, Brown -Forsythe ANOVA with Dunnett's T3 multiple comparisons test, *P < 0.05, n=16 donors). Blue, DMSO control; Green, riluzole; Black, drugs with no effect; White, Untreated; Orange / Purple, top performing clinically tested drugs. Scale bar C, 100 pm Abbreviations: DMSO; dimethyl sulfoxide.

[0073] Figure 3: Pre-clinical testing of baricitinib, memantine and riluzole in sporadic ALS donor motor neurons. A. Longitudinal quantification of total Hb9-tGFP+ motor neuron neurite length in a representative sporadic ALS (sALS) donor treated with riluzole, memantine and baricitinib as monotherapies or combinations (total Hb9- tGFP+ motor neuron neurite length, mean 4 wells ± SEM). B. Images of motor neuron health at screen endpoint (Hb9-tGFP+ motor neuron clusters and neurites at 20x). C. Quantification of average days of rescue. D. Days of rescue per individual (treated LD50 - untreated LD50) of motor neurons from 15 sporadic ALS donors treated with riluzole, baricitinib and memantine as monotherapies or combinations (one dot per donor, mean ± SEM, Brown-Forsythe ANOVA with Dunnett's T3 multiple comparisons test, *p < 0.05, n=15 donors). Scale bar B, 100 pm Abbreviations: DMSO; dimethyl sulfoxide; LD50, lethal day 50%. E-F Longitudinal quantification of total Hb9-tGFP+ motor neuron neurite length in familial ALS (fALS) donors treated with riluzole, baricitinib and memantine as monotherapies or combinations (total Hb9-tGFP+ motor neuron neurite length, mean 4 wells ± SEM).

[0074] Figure 4. Synergistic action of JAK1, JAK2, JAK3 and / or TYK2 inhibition in combination with riluzole and memantine. A Treatment of motor neurons derived from sporadic ALS donors with 1 uM of TCS-21311, a selective JAK3 inhibitor with an IC50 of 8nm, resulted in a significant rescue of motor neuron health when combined with riluzole and memantine (2.5uM). B Treatment of motor neurons derived from sporadic ALS donors with 0.04 uM of SAR-20347, a pan JAK inhibitor (IC50s TYK2 (0.6 nM), JAK1 (23 nM), JAK2 (26 nM) and JAK3 (41 nM)), resulted in a significant rescue of motor neuron health when combined with riluzole and memantine (2.5uM).

[0075] Figure 5. Dose response matrix of riluzole (R), memantine (M) and baricitinib (B). All concentrations in uM, heatmaps indicate number of days of rescue of motor neuron health following treatment. DETAILED DESCRIPTION

[0076] General Techniques and Definitions

[0077] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in genomics, immunology, molecular biology, immunohistochemistry, biochemistry, oncology, and pharmacology).

[0078] Aspects of the present disclosure are performed using conventional techniques of molecular biology, microbiology, recombinant DNA technology and immunology. Such procedures are described, for example in Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, New York, Fourth Edition (2012), whole of Vols I, II, and III; DNA Cloning: A Practical Approach, Vols. I and II (D. N. Glover, Second Edition., 1995), IRL Press, Oxford, whole of text; Oligonucleotide Synthesis: A Practical Approach (M. J. Gait, ed, 1984) IRL Press, Oxford, whole of text, and particularly the papers therein by Gait, ppi -22; Atkinson et al, pp35-81; Sproat et al, pp 83-115; and Wu et al, pp 135-151; 4. Nucleic Acid Hybridization: APractical Approach (B. D. Hames & S. J. Higgins, eds., 1985) IRL Press, Oxford, whole of text; Immobilized Cells and Enzymes: A Practical Approach (1986) IRL Press, Oxford, whole of text; Perbal, B., A Practical Guide to Molecular Cloning (1984) and Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.), whole of series.

[0079] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0080] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions and methods are clearly within the scope of the disclosure, as described herein.

[0081] Each feature of any particular aspect or embodiment or embodiment of the present disclosure may be applied mutatis mutandis to any other aspect or embodiment or embodiment of the present disclosure. Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0082] As used herein, the singular forms of “a”, “and” and “the” include plural forms of these words, unless the context clearly dictates otherwise. For example, a reference to “a bacterium” includes a plurality of such bacteria, and a reference to “an allergen” is a reference to one or more allergens.

[0083] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0084] Throughout this specification, the word “comprise’ or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0085] The term “about” and the use of ranges in general, whether or not qualified by the term about, means that the number comprehended is not limited to the exact number set forth herein, and is intended to refer to ranges substantially within the quoted range while not departing from the scope of the invention. As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10%, more preferably 5%, more preferably 1%, of the particular term.

[0086] All computer programs, algorithms, patent and scientific literature referred to herein is incorporated herein by reference.

[0087] Neurological diseases, disorders and conditions

[0088] In the context of the present disclosure, a neurological disease refers to any disease affecting the central or peripheral nervous system, including but not limited to diseases that impair motor, sensory, cognitive, or autonomic functions. This may encompass neurodegenerative diseases, neuroinflammatory conditions, neurodevelopmental disorders, and other pathological states impacting neurons, glial cells, or supporting neural structures, leading to progressive or acute neurological deficits.

[0089] As used herein, the terms “disease”, “disorder” or “condition” refers to a disruption of or interference with a normal physiological or biological function of a subject. Diseases, disorders, and / or conditions that may be treated by the method or composition as described herein.

[0090] Accordingly, the term “neurodegenerative disease” refers to any disease, disorder and / or condition that comprises a progressive decline and / or deterioration in the structure, function, signalling and / or population of the neurons or neural tissue. In particular, the neurodegenerative disease, disorder or condition can be or comprise a neuromuscular disease, disorder or condition. As used herein, “a neuromuscular disease, disorder or condition” refers to any disease, disorder and / or condition that comprises a progressive decline and / or deterioration in the structure, function, signalling and / or population of the neurons or neural tissue that innervate and / or communicate, whether directly or indirectly, with the muscles. The aetiology of a neurodegenerative disease, disorder or condition may involve, but is not limited to, inflammation, particular neuroinflammation, genetic mutations, protein misfolding and / or aggregation, autoimmune disorders, mitochondrial dysfunction, defective axonal transport, aberrant apoptosis and / or autophagy and elevated oxidative stress and / or reactive oxygen species (ROS) production.

[0091] Without limitation, neurological diseases, disorders or conditions can include Parkinson’s disease and related disorders, Huntington’ s disease, Alzheimer’s disease and other forms of dementia, Spinocerebellar ataxia, Friedreich ataxia, Tay-Sachs disease, Lewy body disease, Parkinson’s disease and related disorders, Prion diseases (e.g. Creutzfeldt-Jakob disease), Multiple sclerosis (MS), Pick disease, Shy-Drager syndrome, pontocerebellar hypoplasia, neuronal ceroid lipofuscinoses, Gaucher disease, neurodegeneration with brain iron accumulation, spastic ataxia / paraplegia, supranuclear palsy, mesolimbocortical dementia, thalamic degeneration, cortical- striatal- spinal degeneration, cortical -basal ganglionic degeneration, cerebrocerebellar degeneration, Leigh syndrome, post-polio syndrome, hereditary muscular atrophy, encephalitis, neuritis, hydrocephalus and the motor neurone diseases, such as amyotrophic lateral sclerosis (ALS). For the present disclosure, the subject with a n neurological disease, disorder or condition may be undergoing a treatment regimen (preventative and / or therapeutic). In this regard, the subject may have been determined to either (i) have an existing neurological disease, disorder or condition; or (ii) be predisposed to such a disease, disorder or condition. Suitably, the neurological disease, disorder or condition described herein is a motor neurone disease. Motor neurone diseases include, but are not limited to, ALS, spinal muscular atrophy (SMA), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), progressive bulbar palsy (PBP), flail limb syndrome, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA).

[0092] Broadly, motor neurone diseases are a form of neurological diseases that typically involve the motor neurons of an affected subject. As used herein, the term “motor neurone disease” are understood in the art and used herein to denote a progressive neurological disease that affects upper motor neurons (motor neurons in the brain) and / or lower motor neurons (motor neurons in the spinal cord) and typically results in motor neuron degeneration and / or death. As will be readily understood by a skilled artisan, motor neurons are nerve cells that control the voluntary muscles of the trunk, limbs and phalanges, as well as those muscles that influence speech, swallowing and respiration. Accordingly, the clinical symptoms of motor neurone disease may include muscle weakness and / or wasting, muscle cramps, dysphagia, slurred speech, muscle tremors / fasciculations, reduced cognition, dyspnoea, respiratory failure, fatigue and weight loss without limitation thereto.

[0093] Methods of treating neurological diseases

[0094] As aforementioned, neurological diseases encompass a broad range of disorders impacting the central and peripheral nervous systems and are frequently associated with a progressive decline in motor, sensory, and cognitive functions. At a cellular level, neurological diseases commonly involve mechanisms such as protein misfolding, oxidative stress, mitochondrial dysfunction, and neuroinflammation, which collectively contribute to neuronal injury and death. This degeneration manifests in clinical symptoms ranging from motor impairments, such as muscle weakness and tremors, to cognitive deficits, including memory loss and behavioural changes. Conditions such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis and motor neurone disease (MND), and exemplify neurodegenerative processes where selective neuronal populations are progressively compromised, each displaying distinct pathophysiological hallmarks while often sharing underlying molecular pathways of cellular dysfunction.

[0095] Accordingly, the present disclosure provides a method of treating a neurological disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, wherein at least one of the compounds is a JAK inhibitor. As used herein, the terms “treat” or "treating" refer to both therapeutic treatments and prophylactic or preventative measures, wherein the objective is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e. not worsening) state of condition, disorder or disease; delay or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state; remission (whether partial or total), whether detectable or undetectable; or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a cellular response that is clinically significant, without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0096] In some examples, the neurological disease is a motor neurone disease. In certain examples, the motor neurone disease is ALS. ALS, also known as Lou Gehrig's disease, is a fatal motor neurone disease characterized by the progressive degeneration of nerve cells in the brain and spinal cord. ALS typically affects individuals between the ages of 40 and 70, though it can also occur in younger people. This disease affects people across all races and ethnic groups. ALS is a complex and multifactorial disease and multiple mechanisms hypothesized as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, inflammation, protein misfolding and aggregation, aberrant RNA metabolism, and altered gene expression.

[0097] ALS occurs in two forms: familial ALS (fALS), a genetic form, and sporadic ALS (sALS). Familial ALS accounts for around 10% of cases, typically exhibiting Mendelian dominant inheritance with high penetrance, where a family history of the disease is evident. Several genes have been associated with familial ALS, including SOD1, C9orf72, TARDBP, n FUS. Mutations in these genes disrupt normal cellular functions, such as protein processing and RNA regulation, leading to motor neuron death. The remaining 90-95% of cases are classified as sporadic ALS, with no documented family history, likely influenced by a combination of environmental factors, genetic polymorphisms, somatic mutations, and potential gene-environment interactions. Despite these differences in origin, both forms of ALS are clinically indistinguishable, suggesting they may share a common underlying pathogenesis. Accordingly, in some examples, the motor neurone disease is ALS. In more particular examples, the ALS is sALS. Exemplary clinical symptoms of ALS include muscle weakness, muscle wasting, muscle cramping, muscle twitching, slurred or slow speech, difficulty swallowing, and slow, uncoordinated movements. The term “treating” thus encompasses achieving a decrease in one or more clinical symptoms, which decrease may have desirable concomitant effects, such as to palliate, ameliorate, stabilize, reverse, slow or delay progression of disease, delay and / or even prevent onset of disease.

[0098] In an example, the motor neurone disease is spinal muscular atrophy (SMA). SMA, usually diagnosed in infancy, is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. The most common form of the disease is caused by changes to the survival motor neurone gene 1 (SMN1).

[0099] In an example, the motor neurone disease is spinal and bulbar muscular atrophy (SBMA). SBMA, also known as Kennedy's disease, is a rare, adult-onset, X-linked recessive lower motor neuron disease caused by trinucleotide CAG repeat expansions in exon 1 of the androgen receptor gene, which results in both loss of AR function and toxic gain of function

[0100] In an example, the motor neurone disease is progressive bulbar palsy (PBP). PBP is a phenotype of ALS that involves lower motor neuron damage, leading to excessive drooling, difficulty swallowing and talking, muscle twitching, and weakness in the face and tongue. PBP is a disease that attacks the nerves supplying the bulbar muscles and is characterised by the degeneration of motor neurons in the cerebral cortex, spinal cord, brain stem, and pyramidal tracts.

[0101] In an example, the motor neurone disease is flail limb syndrome. Flail limb syndrome is also known as brachial amyotrophic diplegia, Vulpian -Bernhardt Syndrome (VBS), flail arm syndrome, or man-in-barrel syndrome, and is often considered to be a phenotype or regional variant of amyotrophic lateral sclerosis. Flail arm syndrome is characterised by progressive, predominantly proximal weakness and atrophy of the upper limbs.

[0102] In an example, the motor neurone disease is primary lateral sclerosis (PLS). PLS is a rare neurological disorder which causes the selective deterioration of the upper motor neurons, sparing the lower motor neurons. The clinical course is defined by a progressive motor disability due to muscle spasticity which typically involves lower extremities and bulbar muscles. In an example, the motor neurone disease is progressive muscular atrophy (PMA). PMA is a rare, sporadic, adult-onset motor neuron disease, clinically characterised by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. This leads to generalised, progressive loss of muscle function, muscle atrophy and fasciculations.

[0103] The term “therapeutically effective amount” shall be taken to mean a sufficient quantity of a pharmaceutical composition that prevents or inhibits or delays the onset of one or more detectable symptoms of a clinical condition. The skilled person will be aware that such an amount will vary depending on, for example, the particular subject and / or the type or severity or level of condition. Accordingly, this term is not to be construed to limit the present invention to a specific quantity, e.g., weight or amount of nucleic acid or a pharmaceutical composition thereof, rather the present invention encompasses any amount of a pharmaceutical composition thereof sufficient to achieve the stated result in a subject.

[0104] As used herein, the term “subject” includes any human or non -human animal. A subject of this invention can be a mammal and in particular examples, is a human, which can be an infant, a child, an adult or an elderly adult. In some examples, the subject may have a neurological disease. In particular, the subject may have a motor neurone disease. More particularly, the subject has been diagnosed with ALS. A subject may also be identified as being at risk or is predisposed for developing ALS, based on genetic analysis. Genetic variants associated with ALS are known in the art (See., e.g., Taylor et al. Nature 539: 197-206, 2016; Brown and Al-Chalabi N Engl J Med 377: 162-72, 2017; and http: / / alsod.iop.kcl.ac.uk). In some examples, the subject can carry mutations in one or more genes associated with familial and / or sporadic ALS. Exemplary genes associated with ALS include but are not limited to: ANG, TARDBP, VCP, VAPB, SQSTM1, DCTNi, FUS, UNCI 3 A, ATXN2, HNRNPA1, CHCHD10, MOBP, C210RF2, NEK1, TUBA4A, TBK1, MATR3, PFN1, UBQLN2, TAF15, OPTN, TDP-43, and DAO. Additional description of genes associated with ALS can be found at Therrien et al. Curr Neurol Neurosci Rep 16:59-71, 2016; Peters etal. J Clin Invest 125:2548, 2015, and Pottier et al. J Neurochem, 138:Supp 1 :32-53, 2016.

[0105] It is envisaged that the methods as described herein can encompass any particular combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor. In some examples, the methods described herein include the administration of a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist, such as riluzole, a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0106] In other examples, the methods described herein include the administration of a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist, such as riluzole, a JAK inhibitor, such as baricitinib; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0107] In further examples, the methods described herein include the administration of a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist, such as riluzole, a JAK inhibitor, such as baricitinib; and an NMDA receptor antagonist, such as memantine, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0108] In particular examples, the methods described herein include the administration of a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist, such as riluzole, a JAK inhibitor, such as baricitinib; and an NMDA receptor antagonist, such as memantine, or analogues, derivatives or salts thereof, wherein at least one of the compounds is baricitinib.

[0109] In more particular examples, the methods described herein include the administration of a therapeutically effective amount of a combination comprising at least two compounds selected from riluzole, baricitinib and memantine, or analogues, derivatives or salts thereof, wherein at least one of the compounds is baricitinib.

[0110] As used herein, the term “analogues, derivatives, or salts thereof’ refers to compounds that are chemically related to the specified substance, including, but not limited to, structural modifications, changes in functional groups, or salts, all of which retain similar properties or biological activity. For example, this could include compounds with slight structural alterations that do not significantly alter their function or activity in relation to the original substance. Accordingly, analogues, derivatives, or salts thereof of riluzole may include, but are not limited to, N-(3-chlorophenyl)-2-amino-l-(4-methylphenyl)ethenone (riluzole-like compounds), O- desmethyl riluzole, riluzole derivatives with modified or altered functional groups (aimed at altering pharmacological properties such as improving bioavailability, extending half-life, or enhancing selectivity for specific receptors), riluzole prodrugs, 4-substituted riluzole derivatives, benzothiazole derivatives of riluzole, as well as salts such as riluzole hydrochloride, riluzole sulfate, riluzole phosphate, riluzole citrate, and riluzole tartrate and the like.

[0111] Similarly, analogues, derivatives, or salts thereof of baricitinib, TCS21311 or SAR-20347 may include, but are not limited to, prodrugs, derivatives with modified functional groups (to alter pharmacological properties such as improving bioavailability, extending half-life, or enhancing selectivity for specific JAK isoforms), N-acyl baricitinib derivatives, baricitinib hydrochloride, baricitinib sulfate, baricitinib phosphate, baricitinib citrate, and baricitinib tartrate and the like.

[0112] Suitably, analogues, derivatives, or salts thereof of memantine may include, but are not limited to, amantadine, rimantadine, memantine hydrochloride, memantine sulfate, memantine citrate, O- desmethyl memantine, memantine prodrugs, and memantine derivatives with modified functional groups (to improve bioavailability, extend half-life, or enhance selectivity for NMDA receptors) and the like.

[0113] Glutamate antagonists

[0114] There is currently no cure for ALS, with treatment options focusing only on symptom management. At present, the only FDA-approved drug, riluzole (Rilutek), offers limited benefit, extending life expectancy by only 2-3 months when taken consistently over 18 months. Riluzole, a member of the benzothiazole class, is a glutamate antagonist that modulates glutamate transmission and is used to slow the progression of neurodegenerative conditions, such as ALS, by inhibiting glutamate release, blocking voltage-gated sodium channels, and providing neuroprotective effects through mechanisms that reduce exci totoxi city in motor neurons.

[0115] As used herein, the term “antagonist” refers to a compound that binds to a specific receptor or target molecule and inhibits its activity, thus blocking or dampening the physiological response typically triggered by that receptor’s activation. Specifically, the term “glutamate antagonist” refers to any compound, agent, or composition that modulates, inhibits, or reduces the activation, signalling, or downstream effects of glutamate receptors, either directly or indirectly. Glutamate antagonists may act on one or more types of glutamate receptors, including but not limited to NMDA (N-methyl-D-aspartate), AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate receptors.

[0116] A glutamate antagonist can include one or more of the following: an AMPA receptor antagonist, a kainate receptor antagonist, a mGluRl antagonist, a mGluR5 antagonist, a glutamate release inhibitor, a glycine co-agonist site inhibitor, or a glutamate transporter enhancer. This antagonism may occur through various mechanisms, such as competitive inhibition (where the antagonist competes with glutamate at the receptor binding site), non-competitive inhibition (where the antagonist binds to an allosteric site distinct from the glutamate binding site, modifying receptor function without directly blocking glutamate binding), or uncompetitive inhibition (where the antagonist binds only to the receptor after it has been activated by glutamate, resulting in an activity-dependent blockade).

[0117] Glutamate antagonists may also reduce excitatory signalling by modulating glutamate release from presynaptic neurons, thereby limiting synaptic glutamate availability, or by inhibiting or blocking ion channels associated with glutamate receptors. Additionally, these antagonists may enhance the reuptake or degradation of extracellular glutamate, further reducing receptor activation. The term “glutamate antagonist” therefore encompasses a range of compounds that target glutamate signalling pathways.

[0118] Examples of glutamate antagonists that may be used in the method as described herein include riluzole, ketamine, amantadine, dextromethorphan, perampanel, talampanel, topiramate, and gabapentin, as well as analogues, derivatives, or salts thereof. Such antagonists may be administered alone or in combination with other neuroprotective agents to mitigate excitotoxicity, reduce neurodegeneration, and potentially stabilize or improve clinical symptoms associated with glutamate-mediated disorders. In particular examples, the glutamate antagonist is riluzole or an analogue, derivative, or salt thereof. Riluzole is thought to reduce glutamate release and increase synaptic glutamate uptake, thereby reducing NMDA receptor-mediated neuronal excitotoxicity.

[0119] While riluzole’s mechanism of action is not fully understood, it is also known to be a sodium channel blocker, which reduces intracellular sodium leading to less neuronal membrane depolarization. Thus, riluzole not only reduces glutamate release and increases synaptic glutamate uptake, thereby reducing NMDA receptor-mediated neuronal excitotoxicity, it also reduces intracellular sodium. It is through either or both of these mechanisms that riluzole is believed to exert its neuroprotective effects on the motor neurons. Specifically, sodium channels play a critical role in the initiation and propagation of action potentials in neurons, and their dysregulation can lead to exci totoxi city- a harmful process driven by excessive neuronal activity. By blocking these channels, riluzole reduces neuronal excitability and limits the release of glutamate, a neurotransmitter associated with excitotoxic damage in neurodegenerative diseases. Suitably, other sodium channel blockers may also include lamotrigine, phenytoin, carbamazepine, topiramate, valproate (valproic acid), mexiletine, and lacosamide.

[0120] Thus, a skilled person would understand that either or both of a glutamate antagonist and a sodium channel blocker would have utility in the treatment of a suitable neurological disease such as motor neurone disease in a subject. Riluzole, as referred to herein, may be collectively referred to as either a glutamate antagonist and / or a sodium channel blocker.

[0121] However, riluzole does not effectively slow disease progression or improve muscle function, highlighting its limitations as a therapeutic option.

[0122] JAK inhibitors

[0123] Progressive neuronal loss in neurological diseases such as ALS, is often accompanied by chronic inflammation and immune system dysregulation. There is mounting evidence suggesting that neuroinflammation plays a critical role in disease progression across these disorders. As used herein, the term “neuroinflammation” refers to the inflammatory response within the central nervous system, including the brain and spinal cord, typically involving the activation of glial cells such as microglia and astrocytes. Neuroinflammation may be triggered by various factors, including infection, injury, toxins, or neurodegenerative processes, and is characterized by the release of cytokines, chemokines, and other inflammatory mediators. This response, while initially protective, can contribute to neuronal damage and exacerbate disease progression when it becomes chronic or dysregulated.

[0124] The JAK pathway, a key signalling pathway in immune responses, has emerged as an important mediator in the inflammatory processes associated with neurodegeneration. The JAK family, consisting of JAK1, JAK2, JAK3, and TYK2 kinases, is responsible for transmitting signals from cytokines and growth factors through the JAK / STAT (signal transducer and activator of transcription) pathway. Activation of this pathway regulates gene expression that controls cell growth, survival, and immune cell activity. In the context of neurodegenerative diseases, overactivation of the JAK / STAT pathway can lead to exaggerated inflammatory signalling, which in turn can promote neurotoxic responses from glial cells, such as microglia and astrocytes. For instance, in ALS, hyperactivation of the JAK / STAT pathway has been linked to heightened inflammatory responses by microglia and astrocytes, which can exacerbate motor neuron degeneration. By selectively inhibiting JAKs, JAK inhibitors can modulate inflammatory signaling and reduce excessive neuroinflammation. This inhibition can help to prevent the harmful effects of prolonged inflammation on neurons, which would otherwise drive cellular dysfunction and neuronal death. Targeting kinase activity, including JAK inhibition to control inflammation, and promoting cell survival are strategies aimed at restoring balance within these pathways, potentially slowing neurodegeneration and disease progression in ALS and other neurological conditions.

[0125] Suitably, the present disclosure also provides a method of inhibiting (i) JAK, optionally JAK1 and JAK2, (ii) an NMDA receptor and / or (iii) neuronal release of glutamate in neurons of a subject, the method comprising administering to the subject a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0126] As used herein, the term "inhibiting" refers to the reduction or suppression of the activity, function, or expression of a particular molecule, pathway, or biological process. In the context of this invention, "inhibiting" may involve partial or complete interference with the target's normal activity, thereby modulating its role in disease progression or cellular function. As used herein, the term "inhibitor" refers to a compound that blocks, reduces or modulates an activity of an enzyme or system of enzymes, receptors, or other pharmacological targets. An inhibitor can act with competitive, uncompetitive, or noncompetitive inhibition. An inhibitor can bind reversibly or irreversibly, and therefore the term includes compounds that are suicide substrates of an enzyme. An inhibitor can modify one or more sites on or near the active site of the enzyme, or it can cause a conformational change elsewhere on the enzyme. The term inhibitor may also encompass other classes of pharmacologically or therapeutically useful agents, such as agonists, antagonists, stimulants, co-factors, and the like.

[0127] The JAK inhibitor can be or comprise one or more of a JAK1 inhibitor, a JAK2 inhibitor, a JAK3 inhibitor, a TYK2 inhibitor, a STAT3 inhibitor, an IL-6 inhibitor, an IFNy inhibitor, and a SOCS inhibitor. In some examples, the JAK inhibitor primarily inhibits JAK1. In other examples, the JAK inhibitor primarily inhibits JAK2. In further examples, the JAK inhibitor primarily inhibits JAK3. In particular examples, the JAK inhibitor primarily inhibits JAK1, JAK2 and JAK3. In preferred examples, the JAK inhibitor primarily inhibits JAK1 and JAK2.

[0128] In further examples, a JAK3 inhibitor may be used, including selective JAK3 inhibitors such as TCS-21311 (also known as NIBR-3049), or analogues, derivatives or salts thereof. In additional examples, a pan-JAK or multi-target JAK-TYK2 inhibitor may be used, including compounds such as SAR-20347, which exhibits inhibitory activity against TYK2, JAK1, JAK2 and JAK3. Accordingly, the present disclosure contemplates the use of selective, dual-target, or pan- JAK / TYK2 inhibitors in combination therapies to modulate neuroinflammatory signalling in ALS and related neurodegenerative conditions.

[0129] In some examples, the JAK inhibitor that may be used in the method as described herein is selected from the group consisting of baricitinib, tofacitinib, upadacitinib, fedratinib, ruxolitinib, pacritinib, momelotinib and abrocitinib, or analogues, derivatives or salts thereof. Several JAK inhibitors, such as ruxolitinib, tofacitinib, baricitinib, and fedratinib, are already in clinical use for inflammatory diseases, including rheumatoid arthritis, myelofibrosis, and ulcerative colitis. In pre- clinical neurodegenerative disease models, JAK inhibitors such as ruxolitinib and tofacitinib have shown promise in reducing neuroinflammation, decreasing cytokine production, and inhibiting microglial activation, potentially reducing neurodegenerative damage. Other selective JAK1 inhibitors like filgotinib and upadacitinib are under investigation for their targeted modulation of inflammation.

[0130] Suitably, the JAK1 and JAK2 inhibitors as described herein include baricitinib and ruxolitinib. In preferable examples, the JAK1 and JAK2 inhibitor is baricitinib or an analogue, derivative, or salt thereof.

[0131] NMDA receptor antagonists

[0132] Dysregulated NMDA signaling plays a critical role in the progression of neurodegenerative disorders, including ALS. Excessive NMDA receptor activation leads to an influx of calcium ions into neurons, triggering exci totoxi city — a damaging process where overstimulation causes cellular injury and neuron death. In ALS, this excitotoxic damage predominantly affects motor neurons, accelerating the progressive loss of motor function. Similar patterns of NMDA dysregulation contribute to neuronal degeneration in Alzheimer’s and Parkinson’s disease. Therefore, modulating NMDA signaling could offer therapeutic benefits by reducing excitotoxic damage and potentially slowing disease progression in these conditions. NMDA receptor antagonists act by blocking or dampening NMDA receptor activity, thereby reducing calcium influx and protecting neurons from excitotoxic damage. For instance, dextromethorphan, a low-affinity NMDA receptor antagonist, has demonstrated neuroprotective effects and is used in combination with quinidine to treat pseudobulbar affect (emotional lability) in ALS and multiple sclerosis patients. Memantine, another NMDA receptor antagonist, is approved for the treatment of moderate to severe Alzheimer’s disease and has shown benefits in preserving cognitive function and daily living skills. By targeting NMDA receptors, these antagonists offer therapeutic potential in neurodegenerative diseases and conditions where exci totoxi city contributes to disease pathology, though precise dosing is essential to avoid disrupting normal glutamate signaling critical for brain function.

[0133] Accordingly, the NMDA receptor antagonist used in the method as described herein may be or may comprise one or more of an NMDA receptor blocker, glycine site antagonist, polyamine site antagonist, magnesium channel blocker, glutamate release inhibitor, competitive antagonist, noncompetitive antagonist, or uncompetitive antagonist. More specifically, the NMDA receptor antagonist is or comprises one or more of a glycine site antagonist, non-competitive antagonist, or glutamate release inhibitor. Even more particularly, the NMDA receptor antagonist can be or comprise a non-competitive antagonist (memantine).

[0134] In suitable examples, the NMDA receptor antagonist is selected from the group consisting of memantine, minocycline, gabapentin, amantadine, ketamine, agmatine, and dextromethorphan, or their analogues, derivatives, or salts. In specific examples, the NMDA receptor antagonist is memantine or an analogue, derivative, or salt thereof.

[0135] Combination therapy

[0136] In the present disclosure, the inventors demonstrate that particular combination therapies that target components of the neurotransmitter signalling axis provide for a synergistic effect on the survival of neurons, thus having a significant therapeutic implication for the treatment of diseases or conditions where the integrity of the neuron is compromised. In particular, the combination of a glutamate antagonist and a JAK inhibitor; a JAK inhibitor and a NMDA receptor antagonist; or a glutamate antagonist, a JAK inhibitor and a NMDAreceptor antagonist; or analogues, derivatives or salts thereof, can enhance therapeutic efficacy in a manner that is synergistic beyond what each compound could achieve individually. As used herein, the term “combination” or “combination therapy” refers to the use of two or more therapeutic agents administered together or sequentially to produce a synergistic or additive effect on a targeted biological pathway, condition, or disease. Preferred combination therapies are the combination of a glutamate antagonist and a JAK inhibitor; a JAK inhibitor and a NMDA receptor antagonist; or a glutamate antagonist, a JAK inhibitor and a NMDA receptor antagonist; or analogues, derivatives or salts thereof. Even more preferably, the combination therapies are combinations of baricitinib with one or both of riluzole and memantine. The present disclosure further contemplates that JAK inhibition may be achieved using selective, dual-target, or pan- JAK / TYK2 inhibitors, including but not limited to TCS-21311 (selective JAK3 inhibitor) and SAR-20347 (pan-JAK / TYK2 inhibitor), or analogues, derivatives or salts thereof.

[0137] As used herein, the term "synergy" or "synergistic" refers to the interaction between two or more agents that results in an enhanced therapeutic effect greater than the sum of their individual effects. In other words, a synergistic effect can be considered to be an effect that is greater than an additive effect. This synergistic interaction may involve complementary mechanisms of action that, when combined, produce a more potent or effective outcome in treating a particular disease or condition. Such synergy may be achieved through co-administration or sequential administration of agents, thereby optimizing therapeutic efficacy and potentially reducing the required dosage of each agent.

[0138] In one example, the combination comprises or consists of a JAK inhibitor and a NMDA receptor antagonist. In a further example, the combination comprises or consists of baricitinib and memantine, or analogues, derivatives or salts thereof. The combination may employ JAK inhibition to attenuate neuroinflammatory pathways, in conjunction with NMDA receptor antagonism to mitigate excitotoxic neuronal damage.

[0139] In other examples, the combination comprises or consists of a glutamate antagonist and a JAK inhibitor. In further examples, the combination comprises or consists of riluzole and baricitinib, or analogues, derivatives or salts thereof. The combination may leverage both glutamate inhibition and JAK inhibition to provide a dual mechanism of action, targeting exci totoxi city and modulating neuroinflammatory pathways for enhanced therapeutic efficacy.

[0140] In some examples, the combination comprises or consists of a glutamate antagonist, a JAK inhibitor and a NMDA receptor antagonist. In specific examples, the combination comprises or consists of riluzole, baricitinib and memantine, or analogues, derivatives or salts thereof. The combination may employ mechanisms of glutamate inhibition, JAK -mediated modulation of neuroinflammatory pathways, and NMDA receptor modulation, collectively targeting exci totoxi city and neurodegenerative processes through a multifaceted therapeutic strategy.

[0141] In a combined therapy according to the invention, the at least two drugs may be administered together or separately, at the same time or sequentially. Also, the at least two drugs may be administered through different routes and protocols. For example, the two or more drugs may initially be administered sequentially to assess potential side effects, after which they may be administered simultaneously. In another example, the drugs may be administered initially at a low dose, followed by gradual dose escalation to an optimal therapeutic level, based on the patient’s response and tolerability, in order to achieve the desired therapeutic effect while minimizing side effects. In a particular example, the JAK inhibitor, in particular baricitinib, may be administered initially at a low dose. As a result, although they may be formulated together, the drugs of a combination may also be formulated separately.

[0142] It is also contemplated that any of the compositions or admixtures described herein can further include one or more additional therapeutic agents in amounts effective for treating or achieving a modulation of at least one symptom of a neurological disease, preferably ALS. Any known ALS therapeutic agents known in the art can be used as an additional therapeutic agent. Exemplary therapeutic agents include edaravone (e.g. sold under the trade names Radi cava® and Radicut®), mexiletine (e.g. sold under the trade names Mexitil and NaMuscla), a combination of dextromethorphan and quinidine (e.g. Nuedexta®), anticholinergic medications, and psychiatric medications such as but not limited to antidepressants, antipsychotics, anxiolytics / hypnotics, mood stabilizers, and stimulants.

[0143] In light of the combined effects of the combination as described herein, the present disclosure provides that the combination delays progression, stabilizes, ameliorates, reduces, or eliminates one or more symptoms or pathological indicators of a neurological disease in the subject. In some examples, the neurological disease is ALS.

[0144] Symptoms of ALS may include: muscle weakness- often beginning in the hands, arms, legs, or muscles involved in speech and swallowing; muscle atrophy, characterized by the progressive shrinking and weakening of muscles due to motor neuron degeneration; fasciculations, or muscle twitches commonly observed in the arms, legs, or tongue; spasticity, which manifests as muscle stiffness or rigidity, leading to limited movement and muscle spasms; dysphagia, or difficulty swallowing, which may result in weight loss and increased risk of aspiration; dysarthria, presenting as slurred or slow speech due to weakened muscles of the mouth and throat; hyperreflexia, involving exaggerated reflexes, including brisk or spastic responses in affected limbs; respiratory decline, where weakened respiratory muscles lead to shortness of breath and, in advanced stages, may require ventilatory support; and emotional lability, including involuntary emotional expression, such as uncontrollable laughing or crying, known as pseudobulbar affect.

[0145] Pathological indicators of ALS may include: motor neuron degeneration - progressive loss of upper and lower motor neurons within the motor cortex, brainstem, and spinal cord, resulting in impaired neuromuscular transmission; glial cell activation - upregulation and proliferation of glial cells, including microglia and astrocytes, contributing to a sustained neuroinflammatory response and further neuronal injury; proteinopathies and aggregation - aberrant accumulation of misfolded proteins, such as TAR DNA-binding protein 43 (TDP-43), within motor neurons, disrupting cellular processes and promoting neurodegeneration; chronic neuroinflammation - persistent elevation of pro-inflammatory cytokines, chemokines, and other markers within the central nervous system, exacerbating neural injury and promoting a toxic microenvironment; and corticospinal tract degeneration - progressive deterioration of the descending motor pathways, specifically within the corticospinal tract, impairing voluntary motor control and resulting in loss of coordinated muscular function.

[0146] Suitably, the combination therapy addresses one or more symptoms or pathological indicators associated with neurodegeneration, including muscle weakness, spasticity, dysphagia, respiratory decline, and emotional lability, as well as cellular-level mechanisms such as protein aggregation, neuroinflammation, and corticospinal tract degeneration. In further examples, the combination therapy slows the progression, stabilizes, mitigates, reduces, or potentially prevents motor neuron cell death.

[0147] In this regard, the present disclosure further provides a method of improving motor neuron survival by addressing key symptoms and pathological indicators of the neurological disease. Suitably, the method comprises administering a therapeutically effective amount of a combination of compounds as described herein.

[0148] Motor neuron survival as used herein refers to the ability of motor neurons to maintain viability, function, and structure despite adverse conditions, such as neurological diseases like ALS. Accordingly, in this context, survival refers to a greater number of motor neurons remaining viable and functional with treatment, as compared to those without treatment. Assessing motor neuron survival may involve a combination of methods that measure various aspects of neuronal health as described herein.

[0149] In a cellular model, measuring motor neuron survival may encompass analysing neurite innervation, which is a process by which neurites, which are the extensions of a neuron (including axons and dendrites), grow and form connections with target cells, such as muscle fibers or other neurons. In the context of motor neurons, neurite innervation specifically refers to the extension of axons from motor neurons to muscle fibers, allowing for the transmission of electrical signals that control muscle movement. The degree of innervation, or the extent of axonal growth and branching, is a key indicator of motor neuron survival and function. Impaired or reduced neurite innervation can signify motor neuron degeneration or dysfunction, which is characteristic of neurodegenerative diseases. Imaging techniques such as optical coherence tomography (OCT) or confocal microscopy allow for the observation of the growth and branching of neurites in animal models or human-derived neuronal cultures. For example, measuring neurite length using a fluorescent marker such as HB9-tGFP+ allows for real-time visualization of neurite outgrowth and branching. Assessment of motor neuron survival can then be performed by quantifying neurite length. Further examples of measuring motor neuron survival include performing cell viability assays, such as the MTT assay, lactate dehydrogenase (LDH) release assay, and live / dead assays using fluorescent dyes, which provide a clear and quantitative measure of motor neuron survival. These assays are commonly used in both in vitro and in vivo models to evaluate the effectiveness of treatments aimed at promoting motor neuron survival or protecting against neurodegeneration. Functional assays such as electrophysiological recording (for example, patch-clamp or multielectrode array techniques) and calcium imaging may also be performed to assess the survival of motor neurons based on their ability to maintain normal electrical activity and intracellular signalling, both of which are critical for their survival and function. Additionally, assessing the expression of certain genes and proteins (for example, anti-apoptotic proteins such as Bcl-2 and survivin, expression of neurotrophic factors such as BDNF (brain-derived neurotrophic factor) and GDNF (glial cell-derived neurotrophic factor), and the presence of apoptotic markers such as caspase-3 and cleaved PARP) can serve as biomarkers for motor neuron survival.

[0150] Measuring motor neuron survival in humans, particularly in clinical settings, presents several challenges, but there are various techniques available to assess motor neuron health and function. One such method involves magnetic resonance imaging (MRI), particularly diffusion tensor imaging (DTI), which can assess changes in the integrity of the corticospinal tract. This pathway is crucial for motor neuron function, and in conditions like ALS, degeneration of motor neurons often leads to disruptions in these tracts, which can be detected via MRI scans. Changes in the white matter integrity of these tracts are indicative of motor neuron damage or loss. Genetic and molecular imaging techniques, such as positron emission tomography (PET), can also be used to detect changes in brain metabolism and motor neuron function. In particular, PET scans using tracers that bind to specific receptors or metabolic processes could offer insights into the health and survival of motor neurons in humans.

[0151] Electrophysiological assessments are another way to measure motor neuron survival in humans. Techniques like motor evoked potentials (MEPs), measured via transcranial magnetic stimulation (TMS), provide insights into the function of motor pathways. A decline in MEP amplitude or latency is often associated with motor neuron dysfunction or degeneration. Nerve conduction studies (NCS) also assess motor neuron health by measuring the speed and strength of electrical signals traveling along the nerves.

[0152] In patients with neurological diseases, a reduction in neurite outgrowth or a loss of innervation to muscle fibers can indicate motor neuron degeneration. This loss of innervation often leads to muscle weakness and atrophy. Electromyography (EMG) is a diagnostic tool that can assess the muscle response to neural input and provide indirect information about the extent of neurite innervation. By measuring the electrical activity of muscles, EMG can detect changes in motor unit recruitment. A decrease in motor unit recruitment or altered electrical activity may correlate with a loss of motor neuron function, reflecting the extent of motor neuron degeneration. As motor neurons deteriorate, their ability to properly innervate muscles diminishes, which is often detected through reduced amplitude or absent motor unit potentials during EMG testing.

[0153] In a further example, biomarkers found in blood or cerebrospinal fluid (CSF) can provide indirect measures of motor neuron survival. For example, elevated levels of neurofilament light chain (NFL) in the CSF or blood are often associated with neurodegeneration, and higher concentrations of NFL can correlate with disease severity, offering a potential biomarker for motor neuron damage and survival.

[0154] It is further contemplated that the method as described herein also provides an improvement to other pathological indicators associated with neurodegeneration, including but not limited to, glial cell activation, protein aggregation and misfolding, chronic neuroinflammation, and damage to the corticospinal tract. Pharmaceutical compositions

[0155] The present disclosure provides a composition or admixture comprising a combination of at least two compounds selected from a glutamate antagonist; a JAK inhibitor; an NMDA receptor antagonist and a pharmaceutically acceptable carrier, diluent or excipient, wherein at least one of the compounds is a JAK inhibitor.

[0156] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject. The term "pharmaceutically acceptable" refers to ligands, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Suitably, the term “pharmaceutically-acceptable carrier, diluent or excipient” refers to a solid or liquid filler, diluent or encapsulating substance that may be safely used in systemic administration. Depending upon the particular route of administration, a variety of carriers, well known in the art may be used. These carriers may be selected from a group including sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulfate, liposomes and other lipid-based carriers, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and salts such as mineral acid salts including hydrochlorides, bromides and sulfates, organic acids such as acetates, propionates and malonates and pyrogen-free water. Pharmaceutically acceptable salts for use in the invention include and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. Organic or inorganic acids also include, and are not limited to, hydriodic, perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic, hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p- toluenesulfonic, cyclohexanesulfamic, saccharinic or trifluoroacetic acid. Pharmaceutically acceptable basic / cationic salts include, and are not limited to aluminum, 2-amino-2- hydroxymethyl-propane-l,3-diol (also known as tris(hydroxymethyl)aminomethane, tromethane or “Tris”), ammonia, benzathine, t-butylamine, calcium, chloroprocaine, choline, cyclohexylamine, diethanolamine, ethylenediamine, lithium, lysine, magnesium, meglumine, N- methyl-D-glucamine, piperidine, potassium, procaine, quinine, sodium, triethanolamine, or zinc. A useful reference describing pharmaceutically acceptable carriers, diluents and excipients is Remington’s Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991), which is incorporated herein by reference.

[0157] The combination of compounds as described herein may be an admixture. As used herein, the term "admixture" refers to a composition produced by mixing or commingling compounds of the disclosure (i.e. a composition comprising two or more substances that are combined or blended). This admixture may consist of active ingredients, excipients, carriers, or other components that remain physically distinct or homogeneously mixed, depending on the formulation. An admixture may be created to achieve a specific therapeutic effect, facilitate administration, improve stability, or enhance the pharmacokinetic properties of the components when used in combination. In the case that the combinations disclosed herein are formulated in an admixture, the formulation is such that only one administration route is possible. In other words, the combination is administered in the same mixture at the same time.

[0158] Suitably, the present disclosure further provides a method of making the composition as described herein, wherein the method comprises formulating a combination of at least two compounds selected from a glutamate antagonist; a JAK inhibitor; a NMDA receptor antagonist or analogues, derivatives or salts thereof and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor. In some examples, the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof; the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof and the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

[0159] The method as described herein may further include formulating a combination that comprises or consists of the combination of baricitinib and memantine, or their analogues, derivatives, or salts. In other examples, the method as described herein may further include formulating a combination that comprises or consists of baricitinib and riluzole or analogues, derivatives or salts thereof. In further examples, the method as described herein may further include formulating a combination that comprises or consists of baricitinib, memantine and riluzole or analogues, derivatives or salts thereof. The compounds described herein may be formulated together in a single dosage form or prepared as separate formulations. In one example, the composition or admixture comprising or consisting of a glutamate antagonist and a JAK inhibitor, or a JAK inhibitor and a NMD A receptor antagonist, which are co-formulated in a single dosage unit, such as a tablet, capsule, or injectable solution, to promote ease of administration and ensure simultaneous delivery to the target site. This coformulation may enhance the efficacy of the treatment by allowing the compounds to interact immediately within the biological system, which can improve therapeutic outcomes through synergistic effects. Alternatively, the composition or admixture comprises or consists of a glutamate antagonist and a JAK inhibitor, or a JAK inhibitor and a NMD A receptor antagonist, are formulated separately, each in an individual dosage unit. It is contemplated that separate formulations may allow for flexible dosing schedules, which can be adjusted according to the pharmacodynamics and pharmacokinetics of each compound. In other examples, the composition or admixture comprises or consists of a glutamate antagonist, a JAK inhibitor and a NMDA receptor antagonist, offering a multi-target approach to treatment. Likewise, this three-compound formulation may be delivered as a single admixture or as individual dosage forms, depending on the therapeutic strategy. When administered together, these compounds may act synergistically to inhibit multiple signaling pathways involved in the progression of the neurological disease as described herein, potentially increasing the overall effectiveness of the treatment.

[0160] The formulations herein preferably comprise a pharmaceutically acceptable carrier or excipient. The selection of pharmaceutically acceptable carriers, diluents, and excipients should be tailored to the administration route (e.g., oral, intravenous, or topical) and stability requirements of each compound, facilitating optimal delivery and absorption in the patient.

[0161] The pharmaceutical compositions of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. For example, the synthesis of riluzole, is detailed in U.S. Patent No. 4,370,338. The patent, which is incorporated herein by reference in its entirety, describes a multi-step process involving specific reagents to form the imidazopyridine structure, followed by purification methods to achieve high yield and purity, suitable for oral formulation. Patent application WO2019108594 further discloses liquid formulations of riluzole suitable for both oral and parenteral administration, this disclosure is also incorporated herein by reference in its entirety.

[0162] The synthesis of baricitinib is detailed in U.S. Patent No. 8,158,616, incorporated herein by reference in its entirety, describes a multi-step process that supports the commercial production of baricitinib for therapeutic use. Further, U.S. Patent No. 10,842,792, also incorporated herein by reference in its entirety, discloses compositions suitable for parenteral administration, including aqueous and non-aqueous sterile injection solutions.

[0163] The synthesis of memantine is detailed in U.S. Patent No. US 3,391,142, hereby incorporated by reference in its entirety, provides a detailed synthetic route for preparing memantine, including the reaction of specific chemical reagents to form the desired structure. Patent application WO2009151498 further discloses pharmaceutical compositions of memantine, including those suitable for parenteral administration.

[0164] Routes of administration

[0165] The present disclosure provides a method of administering to a subject in need thereof a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

[0166] As aforementioned, the compounds described herein may be formulated as separate pharmaceutical compositions or in the same pharmaceutical composition. Such compositions may be administered together, separately or sequentially as described herein.

[0167] Pharmaceutical compositions are typically formulated to be compatible with their intended route of administration. Exemplary routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation or through a feeding tube), transdermal (topical), transmucosal, and rectal administration. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques. In some examples, the combination described herein may be administered via a route selected from the group consisting of parenteral, oral, intranasal, sublingual, rectal, intramuscular, intravenous, subcutaneous, intradermal, intrathecal, intra-arterial, intraperitoneal, and inhalation administration.

[0168] In some examples, the compositions or admixtures as described herein are useful for parenteral administration, such as intravenous administration or administration into a body cavity or lumen of an organ or joint. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The dosage of the compounds in these formulations can vary widely, and may be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient’s needs. Exemplary carriers include water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles such as mixed oils and ethyl oleate may also be used. Liposomes may also be used as carriers. The vehicles may contain minor amounts of additives that enhance isotonicity and chemical stability, e.g., buffers and preservatives.

[0169] In further examples, the compositions or admixtures as described herein can also be orally administered in any orally acceptable dosage form. In solid dosage forms for oral administration (capsules, tablets, pills, powders, granules, and the like), the active ingredients are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like. If desired, certain sweetening and / or flavoring and / or colouring agents may be added.

[0170] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.

[0171] Upon formulation, the compositions or admixtures as described herein will be administered in a manner compatible with the dosage formulation and in such an amount as is therapeutically effective. Formulations can be administered in a variety of dosage forms such as tablets, pills, capsules or liquid forms for oral administration, suppositories, pessaries, nasal solutions or sprays, aerosols, inhalants, LNP forms and the like. Pharmaceutical “slow release” capsules or compositions may also be used. Slow-release formulations are generally designed to give a constant drug level over an extended period.

[0172] Suitable dosages of a composition as described herein will vary depending on the subject being treated. It is within the ability of a skilled physician to determine a suitable dosage, e.g., by commencing with a sub-optimal dosage and incrementally modifying the dosage to determine an optimal or useful dosage. Alternatively, to determine an appropriate dosage for treatment / prophylaxis, data from the cell culture assays or animal studies are used, wherein a suitable dose is within a range of circulating concentrations that include the ED50 of the active compound with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. A therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration or amount of the compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. In some examples, a method of the present invention comprises administering a therapeutically effective amount of the composition or admixture as described herein. The amount to be administered to a subject will depend on the particular characteristics of the condition to be treated, the type and stage of condition being treated, the mode of administration, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, and body weight. A person skilled in the art will be able to determine appropriate dosages depending on these and other factors. Accordingly, this term is not to be construed to limit the present invention to a specific quantity.

[0173] In some examples, the methods described herein include administering a glutamate antagonist to a subject. In particular examples, the glutamate antagonist is riluzole, wherein riluzole is administered at a dosage of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 per day. In other examples, riluzole is administered at a dosage of about between about lOmg to 400 mg per day. In other examples, riluzole is administered at a dosage of about between about 50mg to 350 mg per day. In other examples, riluzole is administered at a dosage of about between about lOOmg to 300 mg per day. In other examples, riluzole is administered at a dosage of about between about 150mg to 250 mg per day. In further examples, riluzole is administered at a dosage of about 200 mg per day.

[0174] In other examples, riluzole is administered at a dosage that achieves a plasma concentration of about 0.125 pM, 0.5 pM, 1 pM, 1.5 pM, 2 pM, 2.5 pM, 3 pM, 3.5 pM, 4 pM, 4.5 pM, 5 pM, 5.5 pM, 6 pM, 6.5 pM, 7 pM, 7.5 pM, 8 pM, 8.5 pM, 9 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM, 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM per day. In other examples, riluzole is administered in a dosage that achieves a plasma concentration of about 0.5 pM, 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM, 5.5 pM, 6.5 pM, 7.5 pM, 8.5 pM, 9.5 pM or 10 pM per day. In further examples, riluzole is administered at a dosage that achieves a plasma concentration of about 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM per day. In some examples, riluzole achieves a plasma concentration of 2.5 pM.

[0175] Suitably, the methods described herein include administering a JAK inhibitor to a subject. In particular examples, the JAK inhibitor is baricitinib, SAR20347 or TCS21311 and is administered at a dosage of about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg per day. In other examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage of between about 0.5 mg to 4 mg per day. In further examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage of about 1 mg to 4 mg per day. In further examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage of about 2 mg to 4 mg per day. In some examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage of 2 mg per day. In other examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage of 4 mg per day.

[0176] In other examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage that achieves a plasma concentration of about 0.0025 pM, 0.04pM, 0.0525 pM, 0.1025 pM, 0.1525 pM, 0.2025 pM, 0.2525 pM, 0.3025 pM, 0.3525 pM, 0.4025 pM, 0.4525 pM, 0.5 pM, 1 pM, 1.5 pM, 2 pM,

[0177] 2.5 pM, 3 pM, 3.5 pM, 4 pM, 4.5 pM, 5 pM, 5.5 pM, 6 pM, 6.5 pM, 7 pM, 7.5 pM, 8 pM, 8.5 pM, 9 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM,

[0178] 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM per day. In other examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage that achieves a plasma concentration of about 0.0025 pM, 0.1525 pM, 0.5 pM, 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM, 5.5 pM, 6.5 pM, 7.5 pM, 8.5 pM, 9.5 pM or 10 pM per day. In further examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage that achieves a plasma concentration of about 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM per day. In some examples, baricitinib, SAR20347 or TCS21311 is administered at a dosage that achieves a plasma concentration of 2.5 pM.

[0179] In other examples, the methods described herein include administering a NMDA receptor antagonist to a subject. In particular examples, the NMDA receptor antagonist is memantine, wherein memantine is administered at a dosage of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg or 80 mg per day. In other examples, memantine is administered at a dosage of between about 5 mg to 80 mg about per day. In further examples, memantine is administered at a dosage of between about 10 mg to 70 mg about per day. In further examples, memantine is administered at a dosage of between about 15 mg to 65 mg about per day. In further examples, memantine is administered at a dosage of between about 20 mg to 60 mg about per day. In further examples, memantine is administered at a dosage of between about 25 mg to 55 mg about per day. In further examples, memantine is administered at a dosage of between about 30 mg to 50 mg about per day. In further examples, memantine is administered at a dosage of between about 35 mg to 45 mg about per day. In some examples, memantine is administered at a dosage of 40 mg per day. In further examples, memantine is administered at a dosage that achieves a plasma concentration of about 0.15 pM, 0.2 M, 0.25 pM, 0.3 pM, 0.35 pM, 0.4 pM, 0.45 pM, 0.5 pM, 1 pM, 1.5 pM, 2 pM, 2.5 pM, 3 pM, 3.5 pM, 4 pM, 4.5 pM, 5 pM, 5.5 pM, 6 pM, 6.5 pM, 7 pM, 7.5 pM, 8 pM, 8.5 pM, 9 pM, 9.5 pM, 10 pM, 10.5 pM, 11 pM, 11.5 pM, 12 pM, 12.5 pM, 13 pM, 13.5 pM, 14 pM, 14.5 pM, 15 pM, 15.5 pM, 16 pM, 16.5 pM, 17 pM, 17.5 pM, 18 pM, 18.5 pM, 19 pM, 19.5 pM or 20 pM per day. In other examples, memantine is administered at a dosage that achieves a plasma concentration of about 0.5 pM, 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM, 5.5 pM, 6.5 pM, 7.5 pM, 8.5 pM, 9.5 pM or 10 pM per day. In further examples, memantine is administered at a dosage that achieves a plasma concentration of about 1.5 pM, 2.5 pM, 3.5 pM, 4.5 pM per day. In some examples, memantine is administered at a dosage of 2.5 pM.

[0180] The regimen of administration (e.g., dose combined with frequency of administration) will generally involve administration in an amount and at a frequency to provide for a desired effect, e.g., administration of an amount effective to provide for improvement in one or more symptoms of a neurological disease such as ALS.

[0181] In one example, the composition or admixture as described herein is administered once daily. In another example, the composition or admixture as described herein is administered twice daily. In another example, the glutamate antagonist, preferably riluzole, and / or the NMDA receptor antagonist, preferably memantine, is / are administered daily or twice daily and the JAK inhibitor, preferably baricitinib, is administered daily. Where riluzole and / or memantine is / are administered twice daily with a particular dosage per day, it is envisaged that the dosage taken a twice a day will equal the total daily dosage. For example, if the daily dosage of riluzole is 200mg per day, one dosage may comprise lOOmg and the other dosage may comprise lOOmg. In another example, if the daily dosage of riluzole is 200mg per day, one dosage may comprise 150mg and the other dosage may comprise 50mg, and so forth.

[0182] In some examples, the compositions or admixtures described herein may be administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, or more consecutive days. In other examples, the composition or admixture is taken continuously for as long as it remains effective and is well-tolerated by the subject.

[0183] The precise time of administration and / or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc. However, the above guidelines can be used as the basis for fine-tuning the treatment, e.g., determining the optimum time and / or amount of administration, which will require no more than routine experimentation consisting of monitoring the patient and adjusting the dosage and / or timing.

[0184] Kits

[0185] The present disclosure also provides a kit for treating a motor neurone disease, the kit comprising: (i) at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and a NMDA receptor antagonist or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor; and optionally (ii) instructions for administering the at least two compounds of (i) according to the method as described herein.

[0186] In some examples, the kit comprises a composition or admixture comprising a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N- methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor.

[0187] In particular examples, the kit comprises a glutamate antagonist, specifically riluzole; a JAK inhibitor, specifically baricitinib, SAR20347 or TCS21311; and an NMDA receptor antagonist, specifically memantine, or analogues, derivatives, or salts of these compounds.

[0188] Optionally, a kit according to the invention includes a container with an associated label or package insert and may further include instructions for using the composition in any method described herein. The instructions, either printed on the packaging or provided as a separate insert, guide the user in applying the composition according to any example provided.

[0189] In some examples, the present disclosure relates to an article of manufacture (such as a kit) containing materials useful for the treatment or prevention of a neurological disorder as described herein. The article of manufacture may comprise a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers can be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating or preventing the condition and may have a sterile access port. The label or package insert indicates that the composition is used for treating the condition of choice. Optionally, the article of manufacture can further comprise a further container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection, phosphate-buffered saline, Ringer’s solution and dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0190] EXAMPLES

[0191] The present invention will now be described with reference to the following examples which should be considered in all respects as illustrative and non-restrictive.

[0192] Example 1: Generation of ALS iPSC library

[0193] A significant hurdle in understanding the aetiology, pathophysiology, and delivering effective therapies for ALS has been the lack of animal or cell models of the predominant sALS. In the absence of appropriate models of sALS, the field relies on systems expressing gene mutations linked to rare forms of fALS, often with non-physiological levels of regulation.

[0194] In view of this, the inventors established a curated iPSC library with over 100 sALS patients to capture the clinical, genetic and biological heterogeneity in the patient population. A rigorously optimised screening protocol using an innovative automated robotics platform was developed to provide powerful and robust longitudinal phenotypic, transcriptional and pathological analyses of sALS.

[0195] Materials and methods

[0196] Patient Recruitment

[0197] Volunteers diagnosed with MND (including ALS and SBMA) and adult-onset SMA were recruited from all states of Australia. Demographic and longitudinal clinical information was collected by the Australian Motor neurone disease Register (AMNDR) and the Sporadic ALS Australian Systems Genomics Consortium (SALSA). Longitudinal blood samples were collected from ALS volunteers enrolled at SALSA participating clinics. Volunteers with no history of neurological disease were recruited from latitude matched locations to act as healthy controls, and with an average age after the typical onset of ALS to reduce the risk of neurological comorbidities. Patient skin biopsies and blood were collected between December 2017 and August 2018 for iPSC generation and pairwise iPSC quality control / genetic analysis respectively. iPS Cell Reprogramming

[0198] Primary fibroblasts were isolated from skin biopsies and reprogrammed using non-integrating vectors in feeder-free conditions using automated cell handling robotics (Tecan). Skin punch biopsy of 3-4mm were collected into DMEM with 100 U / mL penicillin, 100 pg / mL 678 streptomycin and 250 ng / L fungizone (Life Technologies). The tissue was treated with 1.8 U / ml dispase in HBSS (Life Technologies) at 4°C overnight, epidermis and subcutaneous fat was removed, and the dermis cut into small pieces. Dermis pieces were cultured at 37°C, 5% CO2 in DMEM medium supplemented with 10% fetal bovine serum (Sigma), 2mM GlutaMAX, 100 U / mL penicillin and 100 pg / mL streptomycin (Life Technologies). Fibroblasts were passaged with 0.05% Trypsin-EDTA (Life Technologies) at 60-80% confluency and frozen for reprogramming at passage 2.

[0199] Cryopreserved fibroblasts (0.5 xlO6) were thawed and reprogrammed in batches of 20-60 using an automated platform (Tecan) under feeder-free conditions. Fibroblasts were plated on vitronectin XF (Stem Cell Technologies) using the media described above. Reprogramming was conducted by episomal nucleofection using a Basic Fibroblasts Nucleofector Kit (Lonza) with OCT4, SOX2, KLF4, L-688 MYC, LIN28 vectors and p53 shRNA. Nucleofected fibroblasts were cultured in E7 media (Stem Cell Technologies), and pluripotent stem cells selected by magnetic sorting using anti-human TRA-1-60 microbeads (Miltenyi Biotec). Reprogrammed iPSCs were cultured in StemFlex (Life Technologies) and passaged using ReLeSR (Stem Cell Technologies) weekly for 8 weeks and confirmed mycoplasma negative using a MycoAlert Mycoplasma Detection Kit (Lonza). Reprogramming and karyotypic analysis for single donor (ID 797, harbouring a UBQLN2 variant) was performed separately using a donor blood sample. PBMC’s were isolated using BD Vacutainer CPT (BD Biosciences) and reprogrammed using a Cytotune-iPS 2.0 Sendai Reprograming kit.

[0200] Spinal Motor Neuron Differentiation

[0201] Differentiation into spinal motor neurons was conducted using the Du et al. differentiation protocol1to take advantage of the highly pure motor neuron cultures generated. The protocol was modified to mimic the environment in the CNS (stage 1-5), optimise the health and maturation of the motor neurons (stage 4), and to provide long term culturing conditions for a disease phenotype to develop (stage 5).

[0202] The terminal differentiation to spinal motor neurons was conducted using small molecules as previously described1with the following modifications: human laminin 521 substrate (Biolamina), hypoxic conditions (37°C, 95% humidity, 5% 02 and C02). At Day 19 motor neuron progenitors were dissociated to a single cell-suspension with Accutase (StemCell Technologies) and seeded onto optically clear 384 well plates (Greiner) coated with human laminin 521 substrate (Biolamina). Motor neurons were matured in Brainphys and NeuroCult™ SMI Without Antioxidants (ThermoFisher) containing 0.5 pM all-trans retinoic acid (StemCell Technologies), 0.1 pM Purmorphamine (StemCell Technologies), 0.1 pM StemSelect Compound E (Calbiochem) and 20 ng / mL rh IGF-1, rh CNTF 1 and rh BDNF (R&D systems) until Day 26 (Stage 4). On Day 25 cultures were treated with 5 pM Cytosine P-D-arabinofuranoside (ARAC) (Sigma-Aldrich) to prevent proliferation of non-neuronal cells. From Day 26 rh IGF-1, rh CNTF 1 and rh BDNF were omitted from the media and from Day 32 Purmorphamine was also omitted to avoid suppressing the disease phenotype (Stage 5). Media changes of 50% were conducted every 3-4 days for stage 4 and 5 of the protocol.

[0203] Motor neuron cell characterisation

[0204] Motor neurons were washed with PBS and immersion-fixed in 4% (wt / vol) paraformaldehyde for 2 hours and immunohistochemistry performed using the several antibody markers such as pancreas homeobox 1 (MNX1 / HB9), choline acetyltransferase (ChAT) and beta-tubulin III (Tuj l). Z-stack images were captured on an Opera Phenix High-Content Screening System (Perkin Elmer) and cell numbers quantified from four 20x fields in 4 wells per donor culture. Other parameters including neurite innervation and transcriptional profiling were also conducted to characterize the motor neurons.

[0205] Results

[0206] To facilitate large-scale ALS disease mapping and drug discovery across the heterogeneous patient population, an iPSC library was generated derived from 111 patients and 25 healthy donors with no history of neurodegenerative disease as controls (Figure 1A). Patient donors were clinically assessed by a specialist ALS clinician and designated an ALS subtype classification based on upper and lower motor neuron involvement. Thirteen donors were classified with lower motor neuron (LMN) predominant ALS inclusive of flail limb syndrome, 76 as classic ALS, 3 as upper motor neuron (UMN) predominant ALS and 5 donors as primary lateral sclerosis (PLS) (Figure IB). The key measures of disease course; site of onset (Figure 1C), onset age (Figure ID), disease progression measured by median ALS functional rating score-revised (ALSFRS-R) rate of decline (Figure 1E-F) and survival time (Figure 1G) confirmed a clinically heterogeneous donor population consistent with the general ALS patient population. Whole genome DNA sequencing in control and ALS established a predominant European ancestry for 95% the donors and identified pathogenic / likely pathogenic variants or expansions in causal ALS genes in 10 ALS donors (Figure 1H). Disease causing expansions / variants in 2 related diseases (SBMA or SMA-PME) were also identified in 3 ALS donors and the presence of C9ORF72 and AR expansion repeats confirmed in both donor blood and iPSC lines. ALS donors with no family history or causal variants identified were classified as SALS.

[0207] Without a genuine pathological phenotype reflecting the clinical vulnerability of patients in-life, iPSC libraries hold little value for ALS research. Accordingly, the inventors developed a robust motor neuron differentiation and phenotyping pipeline capable of modelling motor neuron degeneration, the pathological hallmark of ALS and the most important readout to identify effective therapeutics. A protocol was adapted from a well-established spinal motor neuron differentiation protocol1with extensively optimised maturation and screening conditions capable of discriminating between healthy control and disease motor neurons (Figure II). Using this, the inventors generated consistently highly pure cultures of mature motor neurons displaying extensive neurite networks (Figure 1J-K). Implementing highly stringent quantification criteria2, 92.44% ± 1.66 (mean ± SEM) of cells were defined as motor neurons, co-expressing motor neuron and pancreas homeobox 1 (MNX1 / HB9), choline acetyltransferase (ChAT) and beta-tubulin III (Tuj l) (Figure IL). Additionally the cultures contained 97.66% ± 0.99 Tuj l+ cells (neurons), 0.12% ± 0.01 GFAP+ cells (astrocytes) and 0.04% ± 0.02 CDllb+ cells (microglia) (Figure IL). To assess motor neuron health, cultures were monitored daily using live-cell imaging in conjunction with a virally delivered non-integrating motor neuron-specific reporter HB9- turboGFP (Figure IM).

[0208] In short, the inventors have generated a highly curated ALS iPSC library using non-integrating reprogramming, a single reprogramming protocol, and an automated reprogramming platform to maximise uniformity. These patient-derived iPSC motor neurons were shown to successfully recapitulate the clinical phenotype of ALS. Accordingly, this approach enables the high-throughput phenotyping and drug screening of the ALS iPSC library.

[0209] Example 2: Drug screen of clinically tested ALS drugs

[0210] In a first for ALS drug screening, the inventors sought to re-define drug screening in ALS. Using the sALS patient-derived iPSC motor neurons, the inventors re-assessed over 100 drugs that have undergone clinical trials for ALS. This drug screen was implemented across an unprecedented 16 sALS donors in a paradigm shifting experiment for ALS (and all sporadic neurodegenerative disease). The failure of 95% of the drugs to show efficacy on sALS motor neurons in vitro closely mirrors the clinical trial outcomes for these drugs. The result also contrasts strongly with pre- clinical testing of the drugs using existing models based on individual mouse lines harbouring rare genetic variants that incorrectly predicted the drugs increased motor neuron survival.

[0211] Materials and methods

[0212] Motor neurons were labelled with an adenovirus expressing turboGFP driven by a Mouse Hb9 enhancer fused to mouse Hsp68 minimal promoter (VectorBuilder) at 10 MOI and delivered on Day 21. Images of turbo-GFP labelled motor neurons were acquired every 24 hours on a Cell Discoverer 7 (Zeiss) or Opera Phenix High-Content Screening System (Perkin Elmer) live cell imaging microscope at 20x magnification under hypoxic conditions. Images of motor neurons expressing turboGFP were batch processed and analysed using a custom pre-processing, segmentation and quantification pipeline developed in Knime v4.6.3. Total neurite length was calculated per image and averaged over 3 images captured per well. Wells with less than 12,500 um total neurite length at all timepoints, failed neurite quantification in >25% of time points (excluding day 50-60 where failed quantification may result from degeneration), or LD50 occurring prior to maturation of the neurons (< day 39) were excluded from analysis. To account for the differential growth characteristics between donors and simplify visualisation of the data, motor neuron neurite length was expressed as a percentage of the maximum neurite length across timepoints for each well (i.e. plots displayed with peak neurite innervation standardised to 100% for each well).

[0213] Drug screening was conducted in duplicate wells from three 20x fields of view in 2 wells per donor culture. Wells were treated with DMSO, or drugs (MedchemExpress) at Day 36 to a final concentration of 2.5 pM. Media changes of 50% were conducted every 3-4 days containing DMSO / drug at the specified GFP-positive neurite length was quantified using the average of duplicate wells with 3 images / fields of view per well. Drug efficacy was estimated by calculating the LD50 of the DMSO treatment group for each well, and motor neurite length assessed 5 days later (LD50 +5). Data for each treatment / drug was expressed as percentage of pre-treated neurite length (day 35) to represent percent motor neuron survival. Cumulative effect was calculated using the change in neurite length compared to DMSO treatment (treatment - DMSO) per day calculated over 10 days (LD50 ± 5 days) per well and summed to capture both positive (rescue) and negative (toxicity) longitudinal effects on motor neuron health. Results

[0214] To capture heterogeneity in the SALS patient population, drug efficacy was screened on motor neurons derived from 16 SALS donors (Figure 2 A). The screen aimed to re-assess the efficacy all drugs that have previously undergone evaluation in Phase 1-3 clinical trials as disease modifying treatments for ALS. Using clinical trial databases, 169 interventions to modify disease progression were identified in ALS trials (excluding nutritional and biological therapies). 107 drugs compatible with drug screening and commercially available were sourced, and their efficacy assessed on motor neurons from SALS donors with established survival deficits (LD50 <46). Strikingly, a majority of the drugs tested (black lines) did not rescue motor neuron health, with only three drugs (riluzole, baricitinib and memantine) showing evidence of efficacy over the time course (Figure 2B-C). Drug efficacy across the SALS population was assessed by quantifying the percent motor neuron survival at the screen endpoint (5 days after the LD50 for each donor) and expressed relative to the day before treatment (Figure 2D, each dot represents an individual). Baricitinib (p<0.0001), riluzole (p<0.0001), memantine (p=0.0008), trazodone (p=0.0046) and icerguastat (p=0.0178) produced significant rescue of motor neuron health. Baricitinib produced the strongest rescue across the sporadic patient population with motor neuron health at 59% of pre-treatment levels, followed by riluzole at 46%, memantine at 35%, trazodone at 21% and icerguastat at 15% of pre-treatment. The cumulative change in motor neuron health was also quantified to assess the longitudinal rescue or toxicity of each drug over 10 days (LD50 ± 5 days). Baricitinib (p<0.0001), riluzole (p<0.0001) and memantine (p=0.0009), significantly improved motor neuron health, with an average cumulative 245-375% improvement in motor neuron heath compared to DMSO (Figure 2E, each dot represents an individual). Nine drugs (colchicine, bosutinib, methylcobalamin, fmgolimod, icapamespib, febuxostat, masitinib, biotin and pimozide) significantly reduced longitudinal survival.

[0215] Example 3: iPSC pre-clinical trial of clinically tested ALS drugs

[0216] To test the therapeutic potential of the drugs identified in Example 2, an iPSC pre-clinical trial was conducted on 15 sALS donors to test the efficacy of riluzole, baricitinib and memantine across the sALS population.

[0217] Materials and methods

[0218] Pre-clinical testing was conducted as described above for drug screening, with the following modifications. Wells were treated with DMSO, riluzole, baricitinib (all MedchemExpress) or memantine (Tocris Bioscience) at Day 36. Wells with single and 2-drug combinations were treated with DMSO in lieu of drug to maintain 7.5 pM DMSO concentration in all wells. Media changes of 50% were conducted every 3-4 days containing DMSO / drug and GFP-positive neurite length quantified using the average of 4 replicate wells per control / treatment group with 3 images / fields of view per well. Lethal day 50% (LD50) was defined as the day neurite innervation dropped to 50% of its peak value in each well. Data was expressed as the LD50 survival, or days of rescue (treatment group LD50-DMSO group LD50).

[0219] Results

[0220] Riluzole, baricitinib and memantine were tested as either monotherapies, in a 2-drug combination, or as a 3-drug combination at 2.5pM each. Pre-clinical testing assessed each drug / drug combination over a prolonged time course to model the LD50 survival for each treatment (Figure 3 A-B). Quantification of the LD50 survival for the sALS population (Figure 3C, each dot represents an individual) resulted in a significantly rescue following treatment with riluzole (+4.7 days, P=0.0257) and baricitinib (+13 days, P= 0.0014), but not memantine as monotherapies. In combination, treatment with memantine and riluzole (+12.5 days, P=0.0109), baricitinib and memantine (+23.5 days, P<0.0001), baricitinib and riluzole (+24.5 days, P<0.0001), or riluzole, memantine and baricitinib (+30.3 days, P<0.0001) significantly increased the LD50 survival of the SALS population. Assessing the response of individual donors within the treated donor population, combinations of memantine and baricitinib or riluzole and baricitinib resulted in strong rescue in 87% of donors to greater than 10 days. Notably, the number of responding donors increased to 100% following treatment with riluzole, memantine and baricitinib, with the minimum rescue for an individual donor over 16 days. This result indicated that the triple drug combination may act not only increase the average benefit over the SALS population, but also provided benefit to donors who failed to respond to other combinations (Figure 3D). Rescue of motor neuron health was also observed in fALS donors harbouring variants in SOD1 or repeat expansions in C9ORF72 (Figure 3E-F). Quantification of ChAT immunolabeled cultures at day 49 confirmed a significant increase in sALS motor neuron survival following treatment with baricitinib and memantine (P=0.0060), baricitinib and riluzole (P=0.0242), or riluzole, memantine and baricitinib (P=0.0031, data not shown). With each drug acting through different mechanisms, the synergistic benefit afforded by combining the therapies here strongly support the use of combinatorial therapies in ALS and other complex neurodegenerative disease.

[0221] Example 4: Synergistic rescue of motor neuron health using JAK inhibition in combination with riluzole and memantine

[0222] To determine whether the beneficial effects observed with baricitinib were attributable to broader modulation of the JAK-STAT pathway rather than baricitinib alone, additional JAK -targeting compounds were assessed fortheir capacity to rescue motor neuron health in sALS donor cultures. In particular, a selective JAK3 inhibitor (TCS-21311) and a pan-JAK inhibitor with activity against JAK1, JAK2, JAK3 and TYK2 (SAR-20347) were tested as monotherapies and in combination with riluzole and memantine to evaluate whether alternative JAK -pathway inhibition similarly enhances motor neuron survival.

[0223] Materials and methods

[0224] Pre-clinical testing was conducted as described in Example 3 for drug screening, using the established iPSC-derived motor neuron assay and LD50 survival modelling. Cells were treated with DMSO or with one of the following: TCS-21311 (MedChemExpress), a selective JAK3 inhibitor (ICso = 8 nM), at 1 pM; or SAR-20347 (MedChemExpress), a pan-JAK inhibitor (ICso values: TYK2 = 0.6 nM, JAK1 = 23 nM, JAK2 = 26 nM, JAK3 = 41 nM), at 0.04 pM. For combination treatments, wells were additionally treated with riluzole and memantine (both at 2.5 pM). Each drug and drug combination was assessed over an extended time course to determine LD50 survival.

[0225] Results

[0226] TCS-21311 and SAR-20347 were evaluated as monotherapies or in 3-drug combinations with riluzole and memantine. Time-course analysis demonstrated that modulation of the JAK-STAT pathway provided additional rescue of motor neuron health when combined with riluzole and memantine. For cultures treated with TCS-21311, quantification of LD50 survival (Figure 4A, each dot represents an individual donor) showed a modest increase following TCS-21311 alone (+1.5 days, p>0.999) as compared to untreated. Treatment with memantine and riluzole increased survival (+3.5 days, p=0.011), while the triple combination of riluzole, memantine and TCS-21311 produced a greater rescue (+8.2 days, p=0.016). For cultures treated with SAR-20347, a similar trend was observed. Quantification of the LD50 survival (Figure 4B) showed minimal rescue with SAR-20347 alone (+0.5 days, p>0.999), increased survival with riluzole and memantine (+3.5 days, p=0.045), and a substantially enhanced response with the triple combination (+6.9 days, p=0.005).

[0227] Taken together, these results indicate that inhibition of JAK family kinases (JAK1 / 2 / 3 and TYK2) can synergise with riluzole and memantine to prolong motor neuron survival in sALS donor cultures. The increased LD50 survival observed with the triple-drug combinations supports a potential therapeutic role for JAK signalling modulation in combination therapy for ALS. Example 5: Dose-response analysis of riluzole, memantine and baricitinib combinations

[0228] To further evaluate the combinatorial effects of riluzole, memantine and baricitinib identified in Example 3, a dose-response matrix was generated to assess how varying concentrations of each drug influence motor neuron rescue in sALS donor cultures. Motor neurons were treated across a range of concentrations of riluzole (R), memantine (M) and baricitinib (B), in which the concentration of riluzole was varied across panels and the concentrations of memantine and baricitinib were varied within each matrix. LD50 survival was modelled over the treatment period as described above, and the number of days of rescue relative to DMSO control was quantified.

[0229] A heatmap summarising the resulting dose-response interactions is shown in Figure 5. The heatmaps depict the rescue values observed for each combination of riluzole, memantine and baricitinib concentrations, with each grid cell representing the measured days of rescue for that specific three-drug concentration set. These data provide further evidence supporting the use of multi-drug combinations for the treatment of ALS and demonstrate that optimal rescue can be achieved through specific concentration-dependent interactions between riluzole, memantine and baricitinib.

[0230] References

[0231] 1. Du, Z.-W. et al. Generation and expansion of highly pure motor neuron progenitors from human 951 pluripotent stem cells. Nature communications 6, 6626; 10.1038 / ncomms7626 (2015).

[0232] 2. Sances, S. et al. Modeling ALS with motor neurons derived from human induced pluripotent stem cells. 915 Nature neuroscience 19, 542-553; 10.1038 / nn.4273 (2016).

Claims

Claims1. A method of treating a motor neurone disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

2. The method of claim 1, wherein the motor neurone disease is selected from the group consisting of spinal muscular atrophy (SMA), pseudobulbar palsy, spinal and bulbar muscular atrophy (SBMA), progressive bulbar palsy (PBP), flail limb syndrome, primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS), optionally wherein the ALS is sporadic ALS.

3. A method of improving motor neuron survival in a subject, the method comprising administering to the subject a therapeutically effective amount of a combination comprising at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

4. A method of inhibiting (i) Janus kinase (JAK), (ii) an N-methyl-D-aspartate (NMDA) receptor and / or (iii) neuronal release of glutamate in neurons of a subject, the method comprising administering to the subject a combination comprising at least two compounds selected from a glutamate antagonist; a JAK inhibitor; and an NMDA receptor antagonist, or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor.

5. The method of any one of claims 1-4, wherein the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof.

6. The method of any one of claims 1-5, wherein the JAK inhibitor is one or more or all of a JAK1 inhibitor, a JAK2 inhibitor and a JAK3 inhibitor.

7. The method of any one of claims 1-6, wherein the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof.

8. The method of any one of claims 1-7, wherein the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

9. The method of any one of claims 1-8, wherein the combination comprises or consists of baricitinib and memantine, or analogues, derivatives or salts thereof.

10. The method of any one of claims 1-8, wherein the combination comprises or consists of riluzole and baricitinib, or analogues, derivatives or salts thereof.

11. The method of any one of claims 1-8, wherein the combination comprises or consists of riluzole, baricitinib and memantine, or analogues, derivatives or salts thereof.

12. The method of any one of claims 1-10, wherein the combination further comprises a sodium channel blocker, optionally wherein the sodium channel blocker is selected from the group consisting of lamotrigine, phenytoin, carbamazepine, topiramate, valproate (valproic acid), mexiletine, and lacosamide.

13. The method of any one of claims 5, 10 or 11, wherein riluzole is administered at a dosage of about 200 mg per day.

14. The method of any one of claims 7 or 9-11, wherein baricitinib is administered at a dosage of about 4mg per day.

15. The method of any one of claims 8, 9 or 11, wherein memantine is administered at a dosage of about 40mg per day.

16. The method of any one of claims 6, 7-11 or 13-15, wherein riluzole and / or memantine are administered daily or twice daily and baricitinib is administered daily.

17. The method of any one of claims 1-16, wherein the administration is oral or parental administration.

18. A composition comprising a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N-methyl-D-aspartate (NMDA) receptor antagonist and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor, preferably wherein the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof; the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof and the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

19. A method of making the composition of claim 18, wherein the method comprises formulating a combination of at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; an N-methyl-D-aspartate (NMDA) receptor antagonist and a pharmaceutically acceptable carrier or excipient, wherein at least one of the compounds is a JAK inhibitor, preferably wherein the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof; the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof and the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

20. A kit for treating a motor neurone disease, the kit comprising:(i) at least two compounds selected from a glutamate antagonist; a Janus kinase (JAK) inhibitor; and an N-methyl-D-aspartate (NMDA) receptor antagonist or analogues, derivatives or salts thereof, wherein at least one of the compounds is a JAK inhibitor; and(ii) instructions for administering the at least two compounds of (i) according to the method of any one of claims 1-17, preferably wherein the glutamate antagonist is riluzole, or analogues, derivatives or salts thereof; the JAK inhibitor is baricitinib, or analogues, derivatives or salts thereof and the NMDA receptor antagonist is memantine, or analogues, derivatives or salts thereof.

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