A combinatorial approach to target age related decline of the axonal growth capacity
Funded in: 2012, 2013, 2014, 2015
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Axons in the central nervous system (CNS) fail to regenerate following spinal cord injury (SCI), which leads to a permanent interruption of “communication” between the brain and its targets and finally results in a devastating paralysis. The cause of this failure is multi-factorial, and due to
(1) a diminished intrinsic capacity of CNS neurons to regenerate,
(2) the inhibitory glial environment of the CNS following SCI, and
(3) the absence of sufficient substrates for growth across the lesion site. Additionally age may play a pivotal role in diminishing axon regenerative potential.
Combinatorial treatments that target all of these three factors may be necessary to promote long distance axon growth and achieve re-innervation.
Prof. Tetzlaff’s team will assess the therapeutic potential of a combinatorial approach involving “PTEN inhibition” (antagonist of “mTOR” which is needed for regeneration), transplantation of Skin-Derived Precursors differentiated into Schwann Cells (SKP-SC), and histone deacetylase inhibitor trichostatin A (TSA, which is currently tested in another clinical trial).
This combination was chosen because of published data demonstrating:
PTEN inhibition enhances the intrinsic capacity of CNS neurons to regenerate.
SKP-SCs could bridge the lesion site and attenuate the glial response, both resulting in the enhancing of regenerating neurons, and finally could remyelinate denuded and regenerating neurons and thus restore function of the injured spinal cord.
Trichostatin A is a histone deacetylase inhibitor and previous work has shown that the expression of several regeneration associated genes is decreased by histone deacetylation. By de-repressing this regeneration program through treatment with TSA the age related decline of axon growth capacity will be addressed.