Naveen Jayaprakash , Marquette University, Milwaukee, USA

Augmentation of a Pro-Regenerative Gene Therapy for SCI Using Stem Cell Transplants and Electrical Stimulation

Funded in: 2017, 2018, 2019


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Problem: Spinal cord injury (SCI) is a multi-faceted problem: minor capacity of regeneration, hostile growth environment and need for direction of the growing axons

Target: Combinatorial approach to the three problems

Goal: Development of clinically oriented combinatorial treatment

 

Introduction: Spinal cord injury (SCI) is a multi-faceted problem that requires multi-faceted solutions. First, injured neurons must be stimulated to reactivate internal programs of cellular growth that will allow them to regenerate lost axons. Second, the hostile growth environment of the injured spinal cord must be improved, in order to provide these axons with a suitable tissue bridge. Finally, once axons succeed in regenerating across the injury site, this growth must be directed to appropriate target cells that can help restore controlled movement. This project brings together leading-edge solutions to all three problems.

Problem Statement: We hypothesize that simultaneously boosting the cells-intrinsic growth capacity of an injured axon tract by gene therapy, while also providing cut axons with growth-permissive stem cell grafts, will maximize axon regeneration after SCI. We also hypothesize that the functional benefits of this combined treatment will be further improved by elevating neural activity with mild electrical stimulation, particularly when this stimulation is synchronized with muscle activity.

Methods: Using a murine model of spinal injury, gene therapy vectors will be delivered to injured neurons to increase production of a growth-promoting gene called KLF6, and stem cell grafts will be transplanted into the injured spinal cord. Finally, non-penetrating electrodes will deliver electrical stimulus to injured neurons as animals move freely. Behavioral testing, microscopy, and electrical recordings will measure improvements in axon growth, synaptic connectivity, and forelimb movement.

Expected Results: We expect that our combinatorial treatment approach will substantially improve both axon growth and behavioral recovery following SCI.

Potential application: This experimental treatment strategy will direct development of a more clinically oriented combinatorial treatment comprising gene therapy, stem cells and electrical stimulus for the treatment of chronic SCI.