Evaluation of Neural Stem Cell Therapy for Glycosphingolipid Storage Diseases: Stem Cell Tropism and Therapeutic Outcome

Lead Research Organisation: University of Oxford
Department Name: Biochemistry


The glycosphingolipid (GSL) storage diseases are inherited diseases and are one of the commonest causes of neurodegeneration in children. We have been evaluating a therapeutic approach called substrate reduction therapy (SRT) that in principle could be effective in all GSL storage diseases that involve the storage of GSLs. SRT utilises a small molecule drug (Zavesca‚ / miglustat) and has been approved for the treatment of type 1 Gaucher disease. Although SRT may slow the course of the disease in storage diseases with brain pathology, it is likely that other additional therapies will be required in combination with SRT to achieve maximal benefit. Our hypothesis is that combining substrate-lowering drugs and neural stem cells (as a source of enzyme and to help repair the brain) may be synergistic and provide significant therapeutic benefit. We aim to determine whether stem cell therapy will improve the clinical outcome in mouse models of these diseases.

Technical Summary

Studies evaluating stem cell-mediated brain repair will be conducted in mouse models of the gangliosidoses, a group of inherited neurodegenerative diseases. A well characterised murine multi-potent neural stem cell clone C17.2 will be grafted into two mouse models: Hexb-/- (human infantile Sandhoff disease model), and betaGal-/- (human infantile/juvenile GM1 gangliosidosis model). Preliminary experiments in Hexb-/- mice shows efficacy, with tropism to sites of pathology.
An approach to over express the wild type lysosomal enzyme(s) (deficient in these disorders) in the C17.2 clone will also be examined in vitro, prior to grafting. Enzyme secretion in vivo, after grafting into the brain, will then be measured. We will determine whether increased enzyme secretion increases clinical benefit. We will evaluate the phenotypes adopted by the neural stem cell clone, host responses to the graft, graft integration, survival, function (including appropriate projections, synapses, enzyme content and release), and neurological status of the animal, will be evaluated. The project will also seek to address whether combining substrate-lowering drugs and stem cell therapy synergise to achieve significant therapeutic benefit. In these diseases even very slight increases in functional enzyme can make major differences to the clinical presentation of the disease. For this reason, these disorders also serve as prototypes in which initial attempts at experimental therapies can realistically be evaluated.


10 25 50
Description New therapies for storage disorders 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact Scientists interested in the blood-brain barrier and storage diseases. stem cell expert present. Head of one of UK storage disease charities present.

Well received and good discussion. Practicalities/obstacles of translation also discussed.
Year(s) Of Engagement Activity 2008
Description Seminar 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact Talk

Year(s) Of Engagement Activity 2007
Description Understanding and treating lysosomal disorders of the brain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact Scientists, clinicians and patients families 25 min talk Good feedback from questions Positively received

Publication picked up by press
Year(s) Of Engagement Activity 2007