Modulation of axon degeneration

Abstract

The invention relates generally to treatment of neurological disorders and nervous system injuries. The invention specifically provides methods of using modulators of particular target proteins to modulate degeneration of neurons or portions thereof, such as axons.

What is claimed is: 
     
         1 . A method for inhibiting degeneration of a neuron or a portion thereof, the method comprising administering to the neuron or portion thereof an agent that modulates: (i) the activity or expression of a target protein in the neuron or portion thereof, or (ii) a process in the neuron or portion thereof. 
     
     
         2 . The method of  claim 1 , wherein the inhibited degeneration is in the axon or the cell body of the neuron. 
     
     
         3 . The method of  claim 1 , wherein the neuron or portion thereof is or is comprised within a neuron selected from the group consisting of a cerebellar granule neuron, a dorsal root ganglion neuron, a cortical neuron, a sympathetic neuron, and a hippocampal neuron. 
     
     
         4 . The method of  claim 1 , wherein said administering results in at least a 10% decrease in the degeneration of a population of neurons or at least a 10% decrease in the degeneration of axons or cell bodies in a population of neurons as compared to a control population of neurons. 
     
     
         5 . The method of  claim 1 , wherein the target protein is selected from the group consisting of dual leucine zipper-bearing kinase (DLK), glycogen synthase kinase 3β (GSK3β), p38 mitogen-activated protein kinase (p38 MAPK), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), cyclin-dependent kinase 5 (cdk5), adenylyl cyclase, c-Jun N-terminal kinase (JNK), BCL2-associated X protein (Bax), Ih channel, calcium/calmodulin-dependent protein kinase kinase (CaMKK), a G-protein, a G-protein coupled receptor, transcription factor 4 (TCF4), and β-catenin; or
 the process is transcription or protein synthesis. 
 
     
     
         6 . The method of  claim 1 , wherein the agent is an inhibitor of the target protein or process. 
     
     
         7 . The method of  claim 1 , wherein the agent is selected from the group consisting of an antibody, polypeptide, peptide, peptibody, nucleic acid molecule, short interfering RNA (siRNA), polynucleotide, aptamer, small molecule, and polysaccharide. 
     
     
         8 . The method of  claim 7 , wherein the antibody is selected from the group consisting of a polyclonal antibody, monoclonal antibody, chimeric antibody, humanized antibody, Fv fragment, Fab fragment, Fab′ fragment, and F(ab′) 2  fragment; or
 the small molecule is selected from the group consisting of GSK3β inhibitor I, GSK3β inhibitor VII, GSK3β inhibitor VIII, GSK3β inhibitor XII, Lithium Chloride, Tyrphostin B44, Tyrphostin B42 (AG 490), Anisomycin, Cycloheximide, Roscovitine, Forskolin, Actinomycin D, Bax Channel Blocker, bortezomid, disulfiram, pamapimod, gefitinib, erlotinib, lapatinib ditosylate, demeclocycline hydrochloride, gentamicin sulfate, neomycin sulfate, paromomycin sulfate, and a pharmaceutically acceptable salt thereof. 
 
     
     
         9 . The method of  claim 6 , wherein the inhibitor is a DLK signaling inhibitor, a GSK3β inhibitor, an EGFR pathway inhibitor, or a G-protein inhibitor. 
     
     
         10 . The method of  claim 9 , wherein the inhibitor is:
 (i) a DLK signaling inhibitor selected from the group consisting of an siRNA molecule targeting DLK, an siRNA molecule targeting JNK1, an siRNA molecule targeting JNK2, an siRNA molecule targeting JNK3, a small molecule, T278A DLK, S281A DLK, K152A DLK, and the leucine zipper domain of DLK;   (ii) a GSK3β inhibitor selected from the group consisting of GSK3β inhibitor I, GSK3β inhibitor VII, GSK3β inhibitor VIII, GSK3β inhibitor XII, and lithium chloride;   (iii) an EGFR pathway inhibitor selected from the group consisting of erlotinib, tyrphostin B44, tyrphostin B42/AG 490, and a small molecule; or   (iv) the G-protein inhibitor is pertussis toxin or a small molecule.   
     
     
         11 . The method of  claim 1 , wherein the neuron or portion thereof is present in a human subject, in a nerve graft or a nerve transplant, or is ex vivo or in vitro. 
     
     
         12 . The method of  claim 11 , wherein said subject, or a subject into whom the nerve graft or nerve transplant is to be introduced, has or is at risk of developing a disease or condition selected from the group consisting of (i) disorders of the nervous system, (ii) conditions of the nervous system that are secondary to a disease, condition, or therapy having a primary effect outside of the nervous system, (iii) injuries to the nervous system caused by physical, mechanical, or chemical trauma, (iv) pain, (v) ocular-related neurodegeneration, (vi) memory loss, and (vii) psychiatric disorders. 
     
     
         13 . The method of  claim 12 , wherein said administering results in at least a 10% decrease in one or more symptoms of, or the likelihood of developing, said disorder of the nervous system; condition of the nervous system that is secondary to a disease, condition, or therapy having a primary effect outside of the nervous system; injury to the nervous system caused by physical, mechanical, or chemical trauma; pain; ocular-related neurodegeneration; memory loss; or psychiatric disorder. 
     
     
         14 . The method of  claim 13 , wherein said one or more symptoms are selected from the group consisting of tremors, slowness of movement, ataxia, loss of balance, depression, decreased cognitive function, short-term memory loss, long-term memory loss, confusion, changes in personality, language difficulties, loss of sensory perception, sensitivity to touch, numbness in extremities, muscle weakness, muscle paralysis, muscle cramps, muscle spasms, significant changes in eating habits, excessive fear or worry, insomnia, delusions, hallucinations, fatigue, back pain, chest pain, digestive problems, headache, rapid heart rate, dizziness, blurred vision, shadows or missing areas of vision, metamorphopsia, impairment in color vision, decreased recovery of visual function after exposure to bright light, and loss in visual contrast sensitivity. 
     
     
         15 . The method of  claim 12 , wherein the disease or condition is:
 (i) a disorder of the nervous system selected from the group consisting of amyotrophic lateral sclerosis (ALS), trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, invertebrate disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, prophyria, Alzheimer's disease, Huntington's disease, Parkinson's disease, Parkinson's-plus diseases, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, frontotemporal dementia, demyelinating diseases, Guillain-Barré syndrome, multiple sclerosis, Charcot-Marie-Tooth disease, prion disease, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, and AIDS demential complex;   (ii) pain associated with a condition selected from the group consisting of chronic pain, fibromyalgia, spinal pain, carpel tunnel syndrome, pain from cancer, arthritis, sciatica, headaches, pain from surgery, muscle spasms, back pain, visceral pain, pain from injury, dental pain, neuralgia, such as neuogenic or neuropathic pain, nerve inflammation or damage, shingles, herniated disc, torn ligament, and diabetes;   (iii) peripheral neuropathy or neuralgia caused by diabetes, cancer, AIDS, hepatitis, kidney dysfunction, Colorado tick fever, diphtheria, HIV infection, leprosy, lyme disease, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, Sjogren syndrome, syphilis, systemic lupus erythematosus, or oramyloidosis;   (iv) nerve damage caused by exposure to toxic compounds, heavy metals, industrial solvents, drugs, chemotherapeutic agents, dapsone, HIV medications, cholesterol lowering drugs, heart or blood pressure medications, or ormetronidazole;   (v) injury to the nervous system caused by physical, mechanical, or chemical trauma;   (vi) a psychiatric disorder selected from the group consisting of schizophrenia, delusional disorder, schizoaffective disorder, schizopheniform, shared psychotic disorder, psychosis, paranoid personality disorder, schizoid personality disorder, borderline personality disorder, anti-social personality disorder, narcissistic personality disorder, obsessive-compulsive disorder, delirium, dementia, mood disorders, bipolar disorder, depression, stress disorder, panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, anxiety disorder, and impulse control disorders; or   (vii) ocular-related neurodegeneration selected from the group consisting of glaucoma, lattice dystrophy, retinitis pigmentosa, age-related macular degeneration (AMD), photoreceptor degeneration associated with wet or dry AMD, other retinal degeneration, optic nerve drusen, optic neuropathy, and optic neuritis.   
     
     
         16 . The method of  claim 15 , wherein the injury to the nervous system is selected from the group consisting of burn, wound, surgery, accidents, ischemia, prolonged exposure to cold temperature, stroke, intracranial hemorrhage, and cerebral hemorrhage, or
 the glaucoma is selected from the group consisting of primary glaucoma, low-tension glaucoma, primary angle-closure glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, intermittent angle-closure glaucoma, chronic open-angle closure glaucoma, pigmentary glaucoma, exfoliation glaucoma, developmental glaucoma, secondary glaucoma, phacogenic glaucoma, glaucoma secondary to intraocular hemorrhage, traumatic glaucoma, neovascular glaucoma, drug-induced glaucoma, toxic glaucoma, and glaucoma associated with intraocular tumors, retinal deatchments, severe chemical burns of the eye, and iris atrophy.   
     
     
         17 . The method of  claim 12 , wherein the contacting of the neuron or portion thereof with the agent comprises administering to the subject a pharmaceutical composition comprising the agent. 
     
     
         18 . The method of  claim 17 , wherein the administering is carried out by intravenous infusion; injection by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes; or topical or ocular application. 
     
     
         19 . The method of  claim 17 , further comprising administering to the subject one or more additional pharmaceutical agents. 
     
     
         20 . A method of identifying an agent for use in inhibiting degeneration of a neuron or portion thereof, the method comprising contacting a neuron or portion thereof with a candidate agent in an assay of axon or neuron degeneration, wherein detection of reduced degeneration of the neuron or portion thereof in the presence of the candidate agent, relative to a control, indicates the identification of an agent for use in inhibiting degeneration of a neuron or portion thereof. 
     
     
         21 . The method of  claim 20 , wherein the assay of axon or neuron degeneration is selected from the group consisting of anti-nerve growth factor (NGF) antibodies, serum deprivation/KCl reduction, and rotenone treatment. 
     
     
         22 . The method of  claim 20 , wherein the candidate agent is selected from the group consisting of an antibody, polypeptide, peptide, peptibody, nucleic acid molecule, short interfering RNA (siRNA), polynucleotide, aptamer, small molecule, and polysaccharide. 
     
     
         23 . A pharmaceutical composition or kit comprising one or more agent that can be used to inhibit degeneration of a neuron or portion thereof. 
     
     
         24 . The pharmaceutical composition or kit of  claim 23 , wherein the one or more agent is a DLK signaling inhibitor, a GSK3β inhibitor, an EGFR pathway inhibitor, or a G-protein inhibitor. 
     
     
         25 . The pharmaceutical composition or kit of  claim 23 , wherein the one or more agent is selected from the group consisting of GSK3β inhibitor I, GSK3β inhibitor VII, GSK3β inhibitor VIII, GSK3β inhibitor XII, Lithium Chloride, Tyrphostin B44, Tyrphostin B42 (AG 490), Anisomycin, Cycloheximide, Roscovitine, Forskolin, Actinomycin D, Bax Channel Blocker, bortezomid, disulfiram, pamapimod, gefitinib, erlotinib, lapatinib ditosylate, demeclocycline hydrochloride, gentamicin sulfate, neomycin sulfate, paromomycin sulfate, and pharmaceutically acceptable salts thereof. 
     
     
         26 . The pharmaceutical composition or kit of  claim 24 , wherein the one or more agent is:
 (i) a DLK signaling inhibitor selected from the group consisting of an siRNA molecule targeting DLK, an siRNA molecule targeting JNK1, an siRNA molecule targeting JNK2, an siRNA molecule targeting JNK3, a small molecule, T278A DLK, S281A DLK, K152A DLK, and the leucine zipper domain of DLK;   (ii) a GSK3β inhibitor selected from the group consisting of GSK3β inhibitor I, GSK3β inhibitor VII, GSK3β inhibitor VIII, GSK3β inhibitor XII, and lithium chloride;   (iii) an EGFR pathway inhibitor selected from the group consisting of erlotinib, tyrphostin B44, tyrphostin B42/AG 490, and a small molecule; or   (iv) the G-protein inhibitor is pertussis toxin or a small molecule.   
     
     
         27 . The pharmaceutical composition or kit of  claim 23 , further comprising one or more pharmaceutically acceptable excipients or instructions for use of the composition or kit in a method for inhibiting degeneration of a neuron or portion thereof. 
     
     
         28 . A method for activating degeneration of a neuron or a portion thereof, the method comprising administering to a neuron or portion thereof an agent that modulates: (i) the activity or expression of a target protein in the neuron or portion thereof, or (ii) a process in the neuron or portion thereof. 
     
     
         29 . The method of  claim 28 , wherein the target protein is selected from the group consisting of dual leucine zipper-bearing kinase (DLK), glycogen synthase kinase 3β (GSK3β), p38 mitogen-activated protein kinase (p38 MAPK), epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), cyclin-dependent kinase 5 (cdk5), adenylyl cyclase, c-Jun N-terminal kinase (JNK), BCL2-associated X protein (Bax), Ih channel, calcium/calmodulin-dependent protein kinase kinase (CaMKK), a G-protein, a G-protein coupled receptor, transcription factor 4 (TCF4), and β-catenin; or
 the process is transcription or protein synthesis. 
 
     
     
         30 . The method of  claim 28 , wherein the agent is an activator of the target protein or process. 
     
     
         31 . The method of  claim 28 , wherein said modulation of a target protein is an increase in the activity or expression of GSK3β, a decrease in the activity or expression of β-catenin, and/or a decrease in the activity or expression of TCF4.