Methods for treating amyotrophic lateral sclerosis
Provided herein are methods for treating, delaying progression of, or reducing the severity of amyotrophic lateral sclerosis (ALS) in a subject through administration of therapeutically effective amounts of agents (e.g., JAK kinase inhibitors (e.g., tofacitinib)) capable of interfering with central nervous system related natural killer cell (NK) levels and function.
1. A method of treating, delaying progression of, or reducing the severity of amyotrophic lateral sclerosis (ALS) in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of an agent, wherein the therapeutically effective amount is sufficient to interfere with central nervous system related natural killer cell (NK) levels and function.
2. The method of claim 1 , wherein the agent is selected from the group consisting of AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), and XL019.
3. The method of claim 1 wherein the agent is a JAK kinase inhibitor, wherein the JAK kinase inhibitor is a JAK1 kinase inhibitor, a JAK2 kinase inhibitor, and/or a JAK3 kinase inhibitor.
4. The method of claim 1 , wherein the therapeutically effective amount is an amount sufficient to detectably reduce or ameliorate one or more symptoms of the ALS, wherein the one or more symptoms comprise difficulty lifting the front part of the foot; difficulty lifting the toes; weakness in one or both legs; weakness in one or both feet; weakness in one or both ankles; hand weakness; hand clumsiness; slurring of speech; trouble swallowing; muscle cramps; twitching in one or both arms; twitching in one or both shoulders and/or twitching of the tongue.
5. The method of claim 1 , wherein the administering attenuates CNS inflammation and/or attenuates motor neuron vulnerability to NK cell activity.
6. The method of claim 1 , wherein the administering results in hindering and/or inhibiting NK cell maintenance, expansion and cytotoxicity against motor neuron cells through one or more of hindering and/or inhibiting IL-15 signaling, hindering and/or inhibiting IL-10 expression, hindering and/or inhibiting IFN-γ expression, reducing perforin levels, and hindering and/or inhibiting NK cell migration.
7. The method of claim 1 , wherein the subject is a mammalian subject.
8. The method of claim 1 , wherein the subject is a human patient suffering from or at risk of suffering from ALS.
9. The method of claim 1 , further comprising administering to the patient one or more of riluzole, ceftriaxone, dexpramipexole, creatine+tamoxifen, rasagiline, pioglitazone, arimoclomol, pyrimethamine, trantinoin+pioglitazone, edaravone, and an antisense molecule or interfering RNA directed against an RNA encoding superoxide dismutase.
10. The method of claim 1 , wherein the agent is formulated to be administered systemically, intravenously, intraarterially, subcutaneously, or intrathecally.
11. The method of claim 1 , wherein the administering of the agent is specifically targeted to one or more of
the central nervous system of the subject,
ALS motor neurons,
ALS motor neurons having reduced levels of MHC-1 in comparison with normal levels of MHC-1, and
spinal cord cells.