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

Regulatable chondroitinase gene delivery for acute and chronic SCI

Funded in: 2020, 2021, 2022


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Problem: Advance the clinical translation of a vector-based chondroitinase gene therapy
Target: Chondroitinase is a promising preclinical regenerative therapy
Goal: Generate vectors also available for studies on other genes with potential therapeutic benefit in SCI.

Gene therapy can be defined as the use of a gene to treat a disease. In recent years there has been remarkable progress toward realizing the potential of gene therapy for several neurological diseases. These advances are directly relevant to translational research on gene therapy for spinal cord injury. In this twin project with the research group of Elizabeth Bradbury (King’s College, London) the researchers propose to further advance the clinical translation of a vector-based chondroitinase (ChABC) gene therapy. ChABC is a promising preclinical regenerative therapy that promotes regeneration by degrading the extracellular matrix and removing inhibitory cues from the injured spinal cord.
In previous collaborative work between the Bradbury and Verhaagen laboratories they developed a gene therapy strategy whereby ChABC was delivered to the spinal cord with a regulatable immune-evasive – stealth – lentiviral vector. Lentiviral vectors have been used in clinical trials for neurological diseases and are well tolerated by patients but these vectors do insert their genetic material in the genome of the host cells. AAV vectors are efficient, versatile vectors with an impressive safety profile that are gaining increasing acceptance as a clinical gene delivery platform. The aim of this project is therefore to develop and test the performance of a regulatable AAV vector encoding chondroitinase. The project in the Bradbury laboratory will apply the gold-standard inducible – stealth – lentiviral vectors generated in the Verhaagen laboratory to deter-mine the optimal therapeutic window and rehabilitation regime for recovery of hand function and will test the efficacy of the novel AAV vectors following acute and chronic spinal cord injury. The combined results obtained in the Bradbury and Verhaagen laboratories are essential to facilitate translation of a ChABC gene therapy to the clinic. The inducible AAV vectors generated here will also be an asset for the broader SCI-community because they will be available for studies on other genes with potential therapeutic benefit in SCI.