Can MSCs induce tolerance to ESCs?
Mesenchymal stem cells (MSCs) have been reported to be immune privileged. Puymirat et al. assessed whether the transplantation of human MSCs in an immunocompetent rat model of myocardial infarction could create a suppressive local microenvironment that would mitigate the expected rejection of co-injected embryonic stem cells (ESCs) and thus favorably affect cell engraftment and functional recovery. They found that simultaneous transplantation of ESCs and MSCs provided better functional preservation of the heart than transplantation of either cell type alone. However, there was only modest evidence for an immunosuppressive effect of co-injected MSCs, and their beneficial effects seemed instead to be mediated by trophic effects on the host tissue. See page 176.
Restoring the elasticity of dystrophic muscle
Dystrophin mediates a physical link between the cytoskeleton of muscle fibers and the extracellular matrix, and its absence leads to muscle degeneration. Puttini et al. show that the lack of dystrophin affects the elasticity of individual fibers within muscle tissue explants, as probed using atomic force microscopy. The rescue of dystrophin expression by exon skipping or by the ectopic expression of the utrophin analogue normalized the elasticity of dystrophic muscles, and these effects accompanied the functional recovery of whole-muscle strength. However, a more homogeneous and widespread restoration of normal elasticity was obtained by the exon-skipping approach when individual myofibers were compared. See page 19.
Examining AAV8 to treat a canine model of DMD
Recombinant adeno-associated virus (rAAV)-mediated gene transfer is an attractive approach for the treatment of Duchenne muscular dystrophy (DMD). Ohshima et al. examine muscle transduction profiles and immune responses following administration of rAAV2 and rAAV8 in normal dogs and dogs with muscular dystrophy. A greater number of transduced fibers were detected in rAAV8-transduced skeletal muscle. Although there was a lower T-cell response to rAAV8 than to rAAV2, transgene expression lasted less than 4 weeks in rAAV8-injected muscle. Intravenous administration of rAAV8 resulted in transgene expression in the skeletal muscles over a period of 8 weeks, but with a declining trend. The authors suggest that immune modulation may enhance rAAV8-mediated transduction and have therapeutic benefits in DMD gene therapy. See page 73.
Cell-penetrating peptide delivers siRNA
RNA interference is both a powerful biological tool and a developing therapeutic strategy. However, strategies based on small interfering RNAs (siRNAs) suffer from their poor delivery and biodistribution. Cell-penetrating peptides have been shown to improve the intracellular delivery of various biologically active molecules. Crombez et al. describe a secondary amphipathic peptide (CADY) comprising aromatic tryptophan and cationic arginine residues that forms stable complexes with siRNA, thereby increasing stability and improving delivery into cells. CADY-mediated delivery of subnanomolar concentrations of siRNA led to significant knockdown of the target gene at both the mRNA and protein levels without any detectible toxicity. See page 95.
Shielding Sleeping Beauty from silencing
The Sleeping Beauty (SB) transposon is an important alternative to viral integrating vectors, but it may also be subject to transcriptional silencing. Dalsgaard et al. investigate shielding of SB-delivered transgene cassettes against transcriptional repression. They found that one-third of clones carrying one or more SB transposon vectors were immediately silenced, and most of the remaining clones moved toward silencing during prolonged passage. However, stable transfection of SB vectors was significantly improved by flanking the transgene with heterologous 5'-HS4 chicken 
-globin (cHS4) insulators. In addition, clones containing cHS4-insulated vectors were better protected against transcriptional silencing. See page 121.
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NEWS AND VIEWS
Skipping to new gene therapies for muscular dystrophyNature Medicine News and Views (01 Aug 2003)
