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Novel strategies for the cell therapy of muscular dystrophies

Objective

This project aims to develop an effective cell therapy for Duchenne Muscular Dystrophy (DMD). To reach this goal we plan to transfer a human artificial chromosome containing the whole dystrophin locus into dystrophic mesoangioblasts. As the transfer is inefficient and requires selection, it is impossible to use primary cells that would undergo senescence during selection. Therefore we need to reversibly immortalize DMD patient mesoangioblasts by the combined use of lentiviral vectors expressing either floxed human telomerase (h-Tert) or floxed Bmi1 (and also the Herpes Simplex Thymidine Kinase, HSTK). Immortal clones, selected for proper expression of h-Tert and Bmi1 and maintenance of a mesoangioblast phenotype, will be transfected with a human artificial chromosome expressing human dystrophin. Expressing clones will be selected and characterized. Before transplantation, selected clones will be infected with an adenoviral vector expressing the Cre recombinase and then treated with Gancyclovir. Transduced and selected cells will be transplanted into mdx/SCID (dystrophic and immune deficient) mice and the extent of dystrophin reconstitution and consequent functional benefit will be evaluated. In addition, the possible immune reaction to the transgenes or novel antigens generated by the experimental strategy will be monitored by an in vitro assay utilizing donor s dendritic cells and T lymphocytes. Finally this strategy will be repeated in Golden Retriever dystrophic dogs, the closest animal model to DMD. Dog mesoangioblasts will be reversibly immortalized, transduced with the dystrophin HAC and, after viral excision and GC selection, transplanted in the same dogs from which they had been directly isolated. Dystrophin expression, functional amelioration and possible toxic and immune reactions will be monitored. This project will therefore cover all pre-clinical experimentation and would set the stage for immediate clinical translation.

Field of science

  • /medical and health sciences/basic medicine/neurology/muscular dystrophy
  • /natural sciences/biological sciences/genetics and heredity/chromosome
  • /medical and health sciences/clinical medicine/transplantation
  • /agricultural sciences/animal and dairy science/pets
  • /medical and health sciences/basic medicine/neurology/muscular dystrophy/duchenne muscular dystrophy

Call for proposal

ERC-2008-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

THE UNIVERSITY OF MANCHESTER
Address
Oxford Road
M13 9PL Manchester
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 326 182,01
Principal investigator
Giulio Cossu (Prof.)
Administrative Contact
Claire Faichnie (Ms.)

Beneficiaries (3)

THE UNIVERSITY OF MANCHESTER
United Kingdom
EU contribution
€ 326 182,01
Address
Oxford Road
M13 9PL Manchester
Activity type
Higher or Secondary Education Establishments
Principal investigator
Giulio Cossu (Prof.)
Administrative Contact
Claire Faichnie (Ms.)
FONDAZIONE CENTRO SAN RAFFAELE DEL MONTE TABOR

Participation ended

Italy
EU contribution
€ 982 240,18
Address
Via Olgettina 60
20132 Milano
Activity type
Research Organisations
Administrative Contact
Massimiliano Meoni (Dr.)
UCL Elizabeth Garrett Anderson Institute for Women’s Health
United Kingdom
EU contribution
€ 591 577,81
Address
Gower Street
WC1E 6BT London
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Greta Borg-Carbott (Ms.)