AAV-based gene therapy for axonal regeneration in a rat model of rubrospinal tract lesion

by Malleswari Challagundla
Doctoral thesis
Date of Examination:2014-05-07
Date of issue:2015-04-29
Advisor:Prof. Dr. Mathias Bähr
Referee:Prof. Dr. Mathias Bähr
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Wolfgang Brück
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Ph.D. Camin Dean
Referee:Prof. Dr. Ralf Heinrich
Persistent Address: http://dx.doi.org/10.53846/goediss-5040

 

 

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Abstract

English

Spinal cord injury (SCI) is a devastating and largely irreversible clinical condition, which can lead to permanent sensory and motor functional disabilities. Worldwide, an estimated 2.5 million people suffer from SCI and more than 130,000 new injuries are reported annually.The mammalian adult CNS is extremely limited in axonal regeneration.Activation of growth impairing pathways by inhibitory extrinsic substrates, scar tissue and a markedly reduced intrinsic growth capacity of adult neurons lead to a severely impaired axonal regeneration, sprouting and functional recovery after spinal cord injury (SCI). The current study was designed to evaluate the potential of AAV-based gene therapy by overexpression of BAG1, reggie1, miRNA-134, or shRNA-mediated downregulation of ROCK2 alone and in combination with an anti-scarring treatment (AST) in an established CNS lesion model, the dorsal spinal cord hemisection. The target molecules were chosen to combine both neuroprotective and pro-regenerative properties and the AST with the iron-chelating agent BPY-DCA was chosen to ameliorate the scar formation further improving axonal regeneration. this study implies that AAV-mediated gene therapy is a highly interesting future therapeutic tool for the treatment of traumatic CNS injuries. BAG1 represents a valuable target, stimulating neuronal survival and collateral sprouting.
Keywords: spinal cord injury; rubrospinal tract; BAG1; ROCK2; Adeno associated virus; gene therapy; antiscarring treatment; red nucleus; axonal regeneration; ladder rung test; Catwalk; motor behavioral test; open field test
 
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