Co-activation of mtor and stat3 pathways to promote neuronal survival and regeneration

Abstract

Disclosed herein is a method of promoting sustained survival, sustained regeneration, in a lesioned mature neuron, sustained compensatory outgrowth in a neuron, or combinations thereof. The method comprises contacting the lesioned mature neuron with an effective amount of an inhibitor of PTEN and an effective amount of an inhibitor of SOCS3 to thereby promote survival and/or regeneration and/or compensatory outgrowth of the neuron. Therapeutic methods of treatment of a subject with a neuronal lesion by administration of a therapeutically effective amount of an inhibitor of PTEN and a therapeutically effective amount of an inhibitor of SOCS3, are also disclosed, as are pharmaceutical compositions and devices for use in the methods.

What is claimed: 
     
         1 . A method of promoting sustained survival in a lesioned mature neuron, sustained regeneration in a lesioned mature neuron, sustained compensatory outgrowth in a mature neuron, or a combination thereof, comprising:
 contacting the neuron with an effective amount of an inhibitor of PTEN and an effective amount of an inhibitor of SOCS3 to thereby promote sustained survival, sustained regeneration, and/or sustained compensatory outgrowth of the neuron.   
     
     
         2 . The method of  claim 1 , wherein the lesioned mature neuron is the result of an acute injury. 
     
     
         3 . The method of  claim 2 , wherein the acute injury is selected from the group consisting of crush, severing, and acute ischemia. 
     
     
         4 . The method of  claim 1 , wherein the lesioned mature neuron is the result of chronic neurodegeneration. 
     
     
         5 . The method of  claim 1 , wherein contacting first occurs within 24 hours of the injury 
     
     
         6 . The method of  claim 1 , wherein contacting first occurs within 3 days of the injury. 
     
     
         7 . The method of  claim 1 , wherein contacting first occurs within 6 days of the injury. 
     
     
         8 . The method of  claim 1 , wherein contacting is continued for a period of time selected from the group consisting of 1 week after initiation, 2 weeks after initiation 3 weeks after initiation, 4 weeks after initiation, 5 weeks after initiation, 6 weeks after initiation, 7 weeks after initiation, and 8 weeks after initiation. 
     
     
         9 . The method of  claim 1 , wherein contacting occurs in vivo. 
     
     
         10 . The method of  claim 1 , wherein contacting occurs in vitro. 
     
     
         11 . The method of  claim 1 , wherein the neuron is human. 
     
     
         12 . A method of treating a subject for a CNS lesion, comprising:
 administering to the subject a therapeutically effective amount of an inhibitor of PTEN and a therapeutically effective amount of an inhibitor of SOCS3, wherein administering results in contacting one or more target CNS neurons of the subject with the inhibitor of PTEN and the inhibitor of SOCS3, to thereby promote sustained survival, sustained regeneration, sustained compensatory outgrowth, or a combination thereof in the CNS neurons.   
     
     
         13 . The method of  claim 12 , wherein the subject is a human. 
     
     
         14 . The method of  claim 1 , wherein the inhibitor of PTEN is selected from the group consisting of:
 (a) potassium bisperoxo(bipyridine)oxovanadate (V) (bpV(bipy));   (b) dipotassium bisperoxo(5-hydroxypyridine-2-carboxyl)oxovanadate (V) (bpV(HOpic));   (c) potassium bisperoxo(1,10-phenanthroline)oxovanadate (V), (bpV(phen));   (d) dipotassium bisperoxo(picolinato)oxovanadate (V), (bpV(pic)); and   (e) combinations thereof.   
     
     
         15 . The method of  claim 1 , wherein the inhibitor of SOCS3 is selected from the group consisting of SOCS3-specific hpRNA, siRNA, antisense SOCS3, dominant negative SOCS3, and combinations thereof. 
     
     
         16 . The method of  claim 12 , wherein the CNS lesion results from an acute injury. 
     
     
         17 . The method of  claim 16 , wherein the acute injury is selected from the group consisting of crush, severing, and acute ischemia. 
     
     
         18 . The method of  claim 16  wherein administration first occurs within 24 hours of the injury 
     
     
         19 . The method of  claim 16 , wherein administration first occurs within 3 days of the injury. 
     
     
         20 . The method of  claim 16 , wherein administration first occurs within 6 days of the injury.