Therapy for subarachnoid hemorrhage and ischemia

Abstract

The application provides data from a clinical trial of a PSD-95 inhibitor in subjects undergoing endovascular repair of an aneurysm in or otherwise affecting the CNS. The subjects were stratified by whether the aneurysm ruptured before performing the endovascular surgery. Rupture is associated with higher mortality or increased debilitation if a subject survives. The trial provided evidence of significant benefit in subjects with and without aneurysm rupture before endovascular was surgery performed. Surprisingly, the subjects benefitting most from treatment as judged both by pathology and neurocognitive outcome were those in which the aneurysm had ruptured causing a subarachnoid hemorrhage. These data constitute evidence that a PSD-95 inhibitor is beneficial not only in ischemic and hemorrhagic stroke but in forms of hemorrhage in or affecting the CNS, particularly, subarachnoid hemorrhage.

1 - 30 . (canceled) 
     
     
         31 . A method of treating a damaging effect of ischemia or hemorrhage on the central nervous system, comprising administering an agent, which agent inhibits binding of PSD-95 to an NMDAR2 subunit or nNos, to a subject having or at risk of ischemia or hemorrhage, wherein the agent is administered on any or all of days 1-4 and on any or all of days 5-12, day 1 being a day of onset of the ischemia or hemorrhage. 
     
     
         32 . The method of  claim 31 , wherein the agent is administered in conjunction with reperfusion therapy, wherein the agent and reperfusion therapy treat a damaging effect of the ischemia on the central nervous system. 
     
     
         33 . The method of  claim 31 , wherein the subject has or is at risk of ischemia of the central nervous system. 
     
     
         34 . The method of  claim 31 , wherein the method treats a damaging effect of hemorrhagic stroke. 
     
     
         35 . The method of  claim 34 , wherein the agent is administered before, during or after endovascular repair of the hemorrhage. 
     
     
         36 . The method of  claim 34 , wherein the agent is administered before, during or after treatment with other drugs for the treatment of hemorrhage affecting the central nervous system. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 31 , wherein the agent is a peptide having an amino acid sequence consisting or comprising of X1tSX2V (SEQ ID NO:7), wherein t and S are alternative amino acids, X1 is selected from among E, Q, and A, X2 is selected from among A, Q, D, N, (N-Methyl)-A, (N-methyl)-Q, (N-methyl)-D, and (N-methyl)-N, or the peptide is an agent according to a formula shown below. 
       
         
           
           
               
               
           
         
       
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 31 , wherein the agent is a peptide having an amino acid sequence consisting or comprising of YGRKKRRQRRRKLSSIESDV, SEQ ID NO:6 or YGRKKRRQRRRKLSSIETDV (SEQ ID NO:37). 
     
     
         41 . The method of  claim 31 , wherein the agent is a myristoylated peptide. 
     
     
         42 . The method or agent of  claim 41 , wherein peptide has an amino acid sequence consisting or comprising of KLSSIESDV or KLSSIETDV. 
     
     
         43 . The method of  claim 41 , wherein the myristoylation is at the N-terminus of the peptide. 
     
     
         44 - 52 . (canceled) 
     
     
         53 . The method of  claim 31 , wherein the agent is administered on each of days 1-12. 
     
     
         54 . The method of claim  534 , wherein the agent is administered one or twice a day for each of days 1-12.