Les leçons à tirer des essais thérapeutiques négatifs

Wednesday, March 27, 2019
27-AM-Plenary 9:00 AM > 10:30 AM Les leçons à tirer des essais thérapeutiques négatifs Amphi A

9:00 AM S09-01 GNE Myopathy Therapy Trial With Sialic Acid Supplementation: Why did phase 3 'fail'? > Z. Zohar ARGOV 9:30 AM S09-02 Lessons Learned From Myostatin Trials > K. Kathryn WAGNER 10:00 AM S09-03 Stem cell therapies for muscular dystrophies – lessons from failed trials > J. Jennifer MORGAN
Objectives : Stem cells have been suggested as a possible treatment for muscular dystrophies, such as Duchenne muscular dystrophy (DMD). This was based on work using pre-clinical animal models of DMD, showing that different muscle stem cells contributed to regenerated muscle fibres following either their local or systemic delivery. The muscle fibres of donor origin expressed dystrophin, which should protect them from undergoing further rounds of necrosis and regeneration. As well as contributing to regenerated muscle fibres, some types of donor stem cell also functionally reconstituted the skeletal muscle stem cell pool, thus providing long-term benefit.

The first clinical trials of stem cells in DMD, performed in the 1990s, involved the intra-muscular transplantation of myoblasts derived from normal donors. The outcomes of these and subsequent trials have been disappointing, with little evidence of donor cell engraftment and no significant functional benefit. But findings from these trials and from stem cell transplantation experiments in mouse models, highlight several major hurdles that need to be overcome.

The majority of cells die very rapidly following their intra-muscular transplantation and the minority that survive may not proliferate extensively. Also, the transplanted cells do not migrate far from the site of injection. Systemic transplantation of stem cells would be required to treat patient muscles body-wide, but ensuring that they reach, enter and contribute to muscle fibres within downstream muscles are major obstacles.

Immune rejection of either the transplanted cells, or the donor-derived muscle fibres that express de novo dystrophin, is another potential problem. This might be circumvented by cell-mediated gene therapy of autologous stem cells, or by genetically-correcting autologous stem cells.

Generating sufficient cells for either local or systemic delivery is a further issue. Expansion of skeletal muscle stem cel

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