Compositions and methods for promoting nerve regeneration

Abstract

FK506 and geldanamycin promote nerve regeneration by a common mechanism that involves the binding of these compounds to polypeptide components of steroid receptor complexes other than the steroid hormone binding portion of the complex (FKBP52 and hsp90, respectively). These and other agents cause hsp90 dissociation from steroid receptor complexes or block association of hsp90 with steroid receptor complexes.

1 . A pharmaceutical composition comprising a nerve growth stimulating amount of a non-FKBP12-binding agent that binds to a polypeptide component of a steroid receptor complex other than a steroid hormone binding portion of the complex and a pharmaceutically acceptable excipient.  
     
     
         2 . The composition of  claim 1  wherein binding of the agent to the polypeptide component causes hsp90 dissociation from the complex or prevents hsp90 association with the complex.  
     
     
         3 . The composition of  claim 1  wherein the agent is selected from the group consisting of a non-FKBP12-binding FK506 analog, a benzoquinone ansamycin, a peptide comprising a sequence of a selected polypeptide component of the complex at a site of interaction between the selected component and another polypeptide component of the complex, an antibody that binds to a polypeptide component of the complex, and combinations thereof.  
     
     
         4 . The composition of  claim 3  wherein the benzoquinone ansamycin is geldanamycin or a derivative thereof.  
     
     
         5 . The composition of  claim 1  wherein the agent binds to hsp90 or FKBP52.  
     
     
         6 . The composition of  claim 1  wherein the composition further comprises a neurotrophic factor other than the agent.  
     
     
         7 . The composition of  claim 6  wherein the neurotrophic factor is selected from the group consisting of NGF, IGF-1, aFGF, bFGF, PDGF, BDNF, CNTF, GDNF, NT-3, NT 4/5, and mixtures thereof.  
     
     
         8 . The composition of  claim 1  wherein the composition further comprises a steroid hormone that is a ligand of the steroid receptor complex.  
     
     
         9 - 13 . (canceled)  
     
     
         14 . A method of stimulating nerve cell growth in a mammal comprising administering to a mammal the pharmaceutical composition according to  claim 1 .  
     
     
         15 . A method of stimulating nerve cell growth in a mammal comprising administering to a mammal the pharmaceutical composition of claim  9 .  
     
     
         16 . A method of stimulating nerve cell growth in a mammal comprising administering to a mammal the pharmaceutical composition of claim  12 .  
     
     
         17 . A method of stimulating nerve cell growth in a mammal comprising administering to a mammal the pharmaceutical composition of claim  13 .  
     
     
         18 . A method for stimulating growth of a nerve cell comprising contacting the nerve cell with a non-FKBP 12-binding agent that binds to a polypeptide component of a steroid receptor complex other than a steroid hormone binding portion of the complex and causes hsp90 dissociation from the complex or blocks association of hsp90 with the complex.  
     
     
         19 . A method of treating a mammal having a transected peripheral nerve or injured spinal cord, the method comprising: 
 administering to the mammal a pharmaceutical composition comprising a nerve growth stimulating amount of a non-FKBP 12-binding agent that binds to a polypeptide component of a Page 4 of 6 steroid receptor complex other than a steroid hormone binding portion of the complex and a pharmaceutically acceptable excipient; and    grafting to the peripheral nerve or spinal cord an allograft or an artificial nerve graft.    
     
     
         20 . The method of  claim 19  wherein grafting the allograft or artificial nerve graft to the peripheral nerve or spinal cord of the mammal produces a gap between transected ends of the peripheral nerve or spinal cord, wherein the non-FKBP 12-binding agent is administered by filling the gap with a gap-filling composition comprising the non-FKBP-12-binding agent.  
     
     
         21 . A method of identifying a compound that stimulates nerve cell growth comprising: 
 assaying a plurality of test compounds for binding to a polypeptide component of a steroid receptor complex other than a steroid hormone binding portion of the complex, thereby identifying binding compounds;    assaying the binding compounds for stimulation of nerve cell growth.    
     
     
         22 . The method of  claim 19  further comprising assaying the binding compounds for dissociation of hsp90 from the complex or blocking association of hsp90 with the complex.