METHODS FOR DELIVERY OF siRNA TO THE SPINAL CORD AND THERAPIES ARISING THEREFROM

Abstract

The present application relates at least in part to methods for the administration of small interfering RNAs (siRNAs) to the spinal cord of a human or animal patient and also to a method of treatment for spinal cord injury and other diseases and disorders of the CNS. In particular, the application discloses methods to deliver an siRNA compound locally, directly and without the need for transduction vehicles and formulations in effective doses to the injured spinal cord to promote recovery of CNS function and or attenuation of allodynia.

1 . A method of treating or preventing neuropathic pain in a subject, comprising administering to the subject a double stranded RNA compound directed to a target gene selected from RhoA or TLR4, in an amount effective to treat or prevent neuropathic pain in the subject. 
     
     
         2 . The method of  claim 1 , wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         3 . The method of  claim 1  or  2 , wherein the neuropathic pain is associated with spinal cord injury or with peripheral nervous system injury. 
     
     
         4 . The method of  claim 3  wherein the neuropathic pain is associated with spinal cord injury. 
     
     
         5 . The method of  claim 4  wherein the spinal cord injury comprises nerve trauma or ischemic injury. 
     
     
         6 . The method of  claim 3  wherein the neuropathic pain comprises allodynia. 
     
     
         7 . The method of  claim 1  or  2  wherein the double stranded RNA is chemically modified siRNA. 
     
     
         8 . The method of  claim 1  or  2  wherein the subject is a human subject. 
     
     
         9 . The method of  claim 3  wherein the double stranded RNA is administered to the subject between 0 hours to 48 hours post injury. 
     
     
         10 . The method of  claim 9  wherein the double stranded RNA is administered to the subject between 0 hours to 24 hours post injury. 
     
     
         11 . The method of  claim 1 , wherein the neuropathic pain is associated with a condition selected from the group consisting of traumatic nerve injury, post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, sciatica, phantom limb pain, diabetic neuropathy, and cancer chemotherapeutic-induced neuropathic pain. 
     
     
         12 . The method of  claim 1 , wherein the neuropathic pain is caused by a malignant tumor, stroke, postherpetic neuralgia, neuropathy with monoclonal protein, vasculitic neuropathy, neuropathy associated with Guillain-Barre syndrome, neuropathy associated with Fabry's disease, an inflammatory condition, an autoimmune disorder including mulitiple sclerosis, a toxin, a drug, a hereditary abnormality, a mastectomy, or an amputation. 
     
     
         13 . A method of treating a subject suffering from a disease, a disorder or an injury of the CNS associated with expression of a target gene, comprising locally administering to the subject's spine a double stranded RNA compound directed to the target gene in an amount effective to treat the subject, wherein the target gene is selected from a gene set forth in Table A. 
     
     
         14 . The method of  claim 13  wherein the target gene is selected from the group consisting of RhoA and TLR4. 
     
     
         15 . The method of  claim 13  or  14  wherein the double stranded RNA compound is administered intraparenchymally and/or by lumbar injection. 
     
     
         16 . The method of  claim 15  wherein the double stranded RNA compound is administered intraparenchymally. 
     
     
         17 . The method of  claim 15  wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         18 . The method of  claim 13  wherein the double stranded RNA is siRNA 
     
     
         19 . The method of  claim 18 , wherein siRNA compound is administered as naked siRNA. 
     
     
         20 . The method of  claim 13 , wherein the disease, disorder, or injury comprises neurodegeneration. 
     
     
         21 . The method of  claim 13 , wherein the disease, disorder, or injury comprises loss of motor function. 
     
     
         22 . The method of  claim 13 , wherein the disease, disorder, or injury comprises loss of white matter. 
     
     
         23 . The method of  claim 13  or  14 , wherein the subject is suffering from pain. 
     
     
         24 . The method of  claim 23 , wherein the pain is neuropathic pain. 
     
     
         25 . The method of  claim 13  or  14 , wherein the subject is a human subject. 
     
     
         26 . The method of  claim 1  or  13 , wherein the method comprises administering to the subject a further pharmacological agent selected from a non-steroidal anti-inflammatory drug (NSAID), a steroidal anti-inflammatory drug, anti-inflammatory agent, an antibiotic, an anti-viral agent, a free radical scavenger, an anti-cancer agent and a chemotherapeutic agent or any combination thereof, for simultaneous, concurrent, separate or sequential use in treating the subject. 
     
     
         27 . A method for restoring motor function in a subject, comprising locally administering to subject's spine a double stranded RNA compound directed to a target gene associated with a loss of motor function in the subject, in an amount effective to restore motor function in the subject 
     
     
         28 . The method according to  claim 27 , wherein restoring of motor function is partial or full restoration of motor function. 
     
     
         29 . The method according to  claim 27 , wherein the subject is suffering from injury of the CNS. 
     
     
         30 . The method according to  claim 27 , wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         31 . A method of attenuating pain associated with expression of a target gene in a CNS in a subject suffering from injury of the CNS, comprising administering to the subject a double stranded RNA compound directed to the target gene, in an amount effective to attenuate pain in the subject, wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         32 . The method of  claim 31  wherein the target gene is RhoA or TLR4. 
     
     
         32 . A method of preserving white matter in the spinal cord of a subject suffering from injury of the CNS, comprising administering to the subject a double stranded RNA compound directed to a target gene in the CNS, in an amount effective to preserve white matter in the subject, wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         33 . A method of preventing allodynia in a subject suffering from injury of the CNS, comprising administering to the subject a double stranded RNA compound directed to a target gene in the CNS, in an amount effective to prevent allodynia in the subject, wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         34 . The method of  claim 33  wherein the target gene is RhoA or TLR4. 
     
     
         35 . A method of promoting serotonergic fiber growth in a subject suffering from injury of the CNS, comprising administering to the subject a double stranded RNA compound directed to a target gene in the CNS, in an amount effective to prevent allodynia in the subject, wherein the double stranded RNA compound is administered by lumbar injection. 
     
     
         36 . The method of  claim 35  wherein the target gene is RhoA or TLR4.