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.

1 - 20 . (canceled) 
     
     
         21 . A method for treating inflammation associated with a central nervous system (CNS) injury, an autoimmune or neurodegenerative disease in a subject in need thereof comprising administering to the subject an antibody that specifically binds to Apoptosis-associated Spec-like protein containing a Caspase Activating Recruitment Domain (ASC), wherein the administering the antibody reduces the levels of at least one inflammatory cytokine, thereby treating the inflammation in the patient. 
     
     
         22 . The method of  claim 21 , wherein the autoimmune or neurodegenerative disease is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, muscular dystrophy or multiple sclerosis. 
     
     
         23 . The method of  claim 21 , wherein the inflammation in the central nervous system (CNS) of the subject is reduced following administration of the antibody. 
     
     
         24 . The method of  claim 21 , wherein the antibody is administered by a parenteral route of administration. 
     
     
         25 . The method of  claim 24 , wherein the parenteral route of administration is intravenous, subcutaneous, intramuscular, intraperitoneal, or intrathecal. 
     
     
         26 . The method of  claim 21 , wherein the antibody is administered intracerebroventricularly. 
     
     
         27 . The method of  claim 21 , wherein administering the antibody results in improvement in motor skills and locomotor function or cognition in the subject. 
     
     
         28 . The method of  claim 21 , wherein the antibody binds to a region of a mammalian ASC, wherein the mammalian ASC is selected from accession number BAC43754 or Q9ULZ3. 
     
     
         29 . The method of  claim 21 , wherein the antibody binds to the CARD domain of a mammalian ASC. 
     
     
         30 . The method of  claim 21 , wherein the antibody binds to an amino acid sequence having at least 85% sequence identity with an amino acid sequence that is SEQ ID NO: 1. 
     
     
         31 . The method of  claim 21 , wherein the antibody binds to an amino acid sequence having at least 85% sequence identity with an amino acid sequence that is SEQ ID NO: 2. 
     
     
         32 . The method of  claim 21 , wherein the antibody is a monoclonal antibody. 
     
     
         33 . The method of  claim 21 , wherein the antibody is a polyclonal antibody. 
     
     
         34 . The method of  claim 21 , wherein said antibody is taken up by cells in the CNS. 
     
     
         35 . The method of  claim 21 , wherein administering the antibody results in inhibition of inflammasome activation in the subject. 
     
     
         36 . The method of  claim 21 , wherein administering the antibody results in a reduction of caspase-1 activation and X-Linked Inhibitor of Apoptosis (XIAP) cleavage in the CNS of the subject. 
     
     
         37 . The method of  claim 21 , wherein said antibody is formulated with a pharmaceutically acceptable carrier or diluent. 
     
     
         38 . The method of  claim 21 , wherein the CNS injury is traumatic brain injury (TBI), stroke, or spinal cord injury (SCI). 
     
     
         39 . The method of  claim 21 , wherein the at least one inflammatory cytokine is interleukin-1β (IL-1β) or interleukin-18.