Joost Verhaagen, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

Promoting long-distance regeneration of lumbar spinal motor neurons by gene therapy using a novel immune-evasive gene switch

Funded in: 2016, 2017, 2018

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Problem: After spinal cord injury, axons are injured resulting in denervation of peripheral targets

Target: Apply a novel immune-evasive inducible gene therapy strategy to promote axon outgrowth

Goal: Achieve sustained axon regeneration over a centimeters long nerve pathway


Problem: In patients longitudinal spinal cord lesions due to traction to the brachial plexus often cause complete and permanent loss of motor and sensory function. Until fairly recent, such lesions were considered impossible to repair. The aim of this Wings for Life proposal is to develop a gene-based treatment strategy that has the potential to promote long-distance motor neuron regeneration following ventral spinal root avulsion lesions.

Approach: We will employ a novel immune-evasive gene switch to direct temporally and spatially controlled combinatorial expression of the potent motor neuron survival and axon growth factor glia-cell line derived neurotrophic factor (GDNF) and ChondroitinaseABC (CHABC), an enzyme which digests the inhibitory extracellular matrix in chronically denervated peripheral nerves.

Expected results: This gene therapeutic strategy offers the unique advantage of temporal and spatial control over the expression of GDNF and CHABC in the Schwann cells present along the centimeters long nerve pathway. We expect that our approach will result in functional reinnervation of denervated hind paw muscles. Although the current project is fundamental in nature we also aim to make an important contribution towards future clinical translation of gene therapy as a way to promote spinal cord regeneration.