Methods of modulating inflammasome activity to treat inflammatory conditions

Abstract

Compositions and methods for reducing inflammation in the central nervous system (CNS) of a mammal that has been subjected to a stroke, traumatic injury to the CNS such as traumatic brain injury (TBI), spinal cord injury (SCI), or having an autoimmune or CNS disease have been developed. The compositions and methods described herein include antibodies that specifically bind to at least one component (e.g., ASC, NALP1) in a mammalian inflammasome (e.g., the NALP1 inflammasome) and have use as treatments for SCI, TBI, stroke, and autoimmune and CNS diseases in a mammal. In a rodent model of SCI, therapeutic neutralization of ASC using a polyclonal antibody that specifically binds to ASC inhibited the inflammasome, reduced caspase-1 activation, XIAP cleavage, and interleukin processing, resulting in significant tissue sparing and functional improvement. Additionally, in a rodent model of TBI, neutralization of ASC after TBI reduced caspase-1 activation and XIAP cleavage. Further, in a rodent thromboembolic stroke model, neutralization of NLRP1 resulted in reduced histopathological damage in mice and reduced cytokine activation, suggesting that the inflammasome complex forms in the brain after stroke and is a therapeutic target for reducing the detrimental consequences of post-stroke inflammation.

What is claimed is: 
     
         1 . A method of reducing inflammation in the central nervous system (CNS) of a mammal having a CNS injury or disease, the method comprising the steps of:
 providing a therapeutically effective amount of a composition comprising an antibody that specifically binds to at least one component of a mammalian inflammasome; and   administering the composition to the mammal,   wherein administering the composition to the mammal results in a reduction of caspase-1 activation in the CNS of the mammal.   
     
     
         2 . The method of  claim 1 , wherein the composition is administered intravenously, intraperitoneally, or intracerebroventicularly. 
     
     
         3 . The method of  claim 1 , wherein the composition further comprises at least one pharmaceutically acceptable carrier or diluent. 
     
     
         4 . The method of  claim 1 , wherein the CNS injury or disease is selected from the group consisting of: traumatic brain injury, traumatic spinal cord injury, ischemic stroke, and autoimmune disease. 
     
     
         5 . The method of  claim 1 , wherein the CNS injury or disease is selected from the group consisting of: amyotropic lateral sclerosis (ALS), Lou Gehrig's, multiple sclerosis (MS), immune dysfunction muscular central nervous system breakdown, muscular dystrophy (MD), Alzheimer' disease (AD), and Parkinson's disease (PD). 
     
     
         6 . The method of  claim 1 , wherein the mammalian inflammasome is a NALP1 inflammasome. 
     
     
         7 . The method of  claim 6 , wherein the CNS injury or disease is spinal cord injury and the at least one component of the NALP1 inflammasome is Apoptosis-associated Speck-like protein containing a Caspase Activating Recruitment Domain protein (ASC) or NAcht Leucine-Rich-Repeat Protein 1 (NALP1). 
     
     
         8 . The method of  claim 7 , wherein administering the composition to the mammal results in an improvement in motor skills and locomotor function in the mammal. 
     
     
         9 . The method of  claim 7 , wherein administering the composition to the mammal results in a decreased spinal cord lesion volume in the mammal. 
     
     
         10 . The method of  claim 7 , wherein the antibody binds to an amino acid sequence having at least 85% sequence identity with an amino acid sequence selected from the group consisting of: SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO: 4. 
     
     
         11 . The method of  claim 7 , wherein said antibody inhibits ASC activity in cells of the CNS in the mammal. 
     
     
         12 . The method of  claim 6 , wherein the CNS injury or disease is ischemic stroke and the at least one component of the NALP1 inflammasome is ASC or NLRP1. 
     
     
         13 . The method of  claim 12 , wherein the composition is administered intracerebroventricularly, intraperitoneally or intravenously. 
     
     
         14 . The method of  claim 12 , wherein administration of the composition results in a reduced infarct size in the mammal. 
     
     
         15 . The method of  claim 6 , wherein the CNS injury or disease is a traumatic brain injury and the at least one component of the NALP1 inflammasome is ASC or NALP1. 
     
     
         16 . A method of reducing inflammation in the brain of a mammal that has been subjected to a traumatic brain injury, the method comprising the steps of:
 providing a therapeutically effective amount of a composition comprising an antibody that specifically binds to ASC or NALP1; and   administering the composition to the mammal such that the antibody is taken up by cells in the brain,   wherein administering the composition to the mammal results in a reduction of caspase-1 activation and XIAP cleavage in the brain of the mammal.   
     
     
         17 . The method of  claim 16 , wherein the composition comprises at least one pharmaceutically acceptable carrier or diluent and is administered intracerebroventricularly, intravenously or intraperitoneally. 
     
     
         18 . A method of treating a spinal cord injury in a mammal, the method comprising the steps of:
 providing a therapeutically effective amount of a composition comprising an antibody that specifically binds to ASC or NALP1; and   administering the composition to the mammal such that the antibody is taken up by neurons in the CNS,   wherein administering the composition to the mammal results in an improvement in motor skills and locomotor function or cognition in the mammal.   
     
     
         19 . The method of  claim 18 , wherein administering the composition to the mammal results in a decreased spinal cord lesion volume in the mammal. 
     
     
         20 . The method of  claim 18 , wherein the composition comprises at least one pharmaceutically acceptable carrier or diluent and is administered intravenously.