Myelin repair by neural stem cells genetically modified to secrete growth factors TGFbeta or IGF-1

Funded Activity Summary

The goal is to locally modify the environment in demyelinating lesions to enhance repair and recovery of function. We will use undifferentiated neural stem (progenitor) cells (NSC) as gene delivery vehicles to supply therapeutic growth factors to areas of damage. Implanted NSC integrate readily into the brain, restoring lost functions, without causing damage. They respond to tissue damage by differentiating into appropriate cells to repair defects, features which are particularly valuable where endogenous myelin repair mechanisms have failed. The first approach will determine whether NSC engineered to secrete Insulin Like Growth Factor-1 (IGF1) promote myelin repair. IGF-1 is a potent stimulator of oligodendrocytes, the myelinating cells in the brain. Itstimulates oligodendrocyte proliferation, differentiation and myelin formation so it may reverse the demyelination and oligodendrocyte loss which are hallmarks of disease. The second strategy is to use NSC to deliver TGF-beta directly to demyelinated areas. TGF-beta suppresses autoimmune responses and is central to recovery from episodes of demyelination in multiple sclerosis and mouse models of immune demyelination. Two mouse models of demyelination will be used to determine the effect of implanted genetically modified NSC; inherited Krabbe disease in which a biochemical defect produces progressive toxic damage to myelinating cells, and injection of an antibody to myelin oligodendrocyte glycoprotein, which induces immune-mediated myelin damage. The behaviour and survival of IGF-1 or TGF-beta secreting NSC, the impact on the quantity of myelin, number of oligodendrocytes and nature of the cellular response to therapy will be quantified. The need for effective therapy of demyelination is urgent. Successful delivery of growth factors to support myelin repair combined with oligodendrocyte replacement would be a significant advance towards treatment for MS, Krabbe disease and other severe neurological disorders.

Funded Activity Details

Start Date: 01-01-2000

End Date: 01-01-2002

Funding Scheme: NHMRC Project Grants

Funding Amount: $199,165.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Gene Therapy

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Demyelinating disease | Growth factor delivery by gene transfer | Leukodystrophy | Lysosomal storage disease | Multiple Sclerosis | Myelin repair | Neural stem cell transplantation | Neurological disease | Oligodendrocyte differentiation

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