Development of self-delivering RNAi targeted to PTEN for treatment of spinal cord injury

Studies on axon regeneration and recovery in rodents have revealed that the spinal cord is not hard wired andlearningcan occur in spinal cord circuitsCompounds that elicit axonal regeneration and sprouting help plasticity in the spinal cord and dramatically improve recovery from traumatic injuryat least in rodentsIntrinsic signals that progress with normal neuronal differentiation play a significant role in preventing axon regenerationSeveral intrinsic negative regulators of regeneration have been identified through studies of knock out miceSuppression of synthesis of PTEN protein can promote axon regeneration and recovery of motor function in adult rodentsThere has been a concerning lack of translation in SCI research for the most promising targetsand therefore we decided to create a compound with potential for therapeutic developmentWe chose the technology of self deliverable RNA interferencesd rxRNAibecause of the simplicity and proven efficacy of in vivo delivery to the central nervous systemBAas a novel sd rxRNA that targets mRNA encoding PTEN and suppress the expression of PTEN proteinIt has sequence homology to ratpig and humanand was selected fromthat we screenedWe propose to further development of BAand carry out IND enabling safety and efficacy experiments to translate these findings to clinical studyWe will optimize stability of BAand dose and efficacy in spinal cord injury modelsWe will also confirm appropriate drug delivery in pig spinal cord because the size of pig spinal cord better approximates the size of human spinal cordThe proposed research will form the basis of non GLP safety and efficacy studies in support of an IND application