Results for “HOMOLOGOUS WASTING DISEASE” — Page 8

PubMed2006

Flies deficient in Muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts.

Myotonic dystrophy (DM) is a dominantly inherited neuromuscular disorder characterised by muscle weakness and wasting. There are two forms of DM; both of which are caused by the expansion of repeated DNA sequences. DM1 is associated with a CTG repeat located in the 3' untranslated region of a gene, DMPK and DM2 with a tetranucleotide repeat expansion, CCTG, located in the first intron of a different gene, ZNF9. Recent data suggest a dominant RNA gain-of-function mechanism underlying DM, as transcripts containing either CUG or CCUG repeat expansions accumulate as foci in the nuclei of DM1 and DM2 cells respectively, where they exert a toxic effect, sequestering specific RNA binding proteins such as Muscleblind, which leads to splicing defects and the disruption of normal cellular functions. Z-band disruption is a well-known histological feature of DM1 muscle, which has also been reported in Muscleblind deficient flies. In order to determine whether there is a common molecular basis for this abnormality we have examined the alternative splicing pattern of transcripts that encode proteins associated with the Z-band in both organisms. Our results demonstrate that the missplicing of ZASP/LDB3 leads to the expression of an isoform in DM1 patient muscle, which is not present in normal controls, nor in other myopathies. Furthermore the Drosophila homologue, CG30084, is also misspliced, in Muscleblind deficient flies. Another Z-band transcript, alpha actinin, is misspliced in mbl mutant flies, but not in DM1 patient samples. These results point to similarities but subtle differences in the molecular breakdown of Z-band structures in flies and DM patients and emphasise the relevance of Muscleblind proteins in DM pathophysiology.

Actinin↗

PubMed1997

Non-autologous transplantation with immuno-isolation in large animals--a review.

Transplantation has become a successful method for the management of functional failure of a variety of tissues or organs. However, the majority of clinical transplantations use non-autologous allogeneic donor tissue implanted from one human to another. In order to prevent rejection of the allogeneic tissue, methods to overcome the immune barrier are necessary. Although prevention of organ rejection is currently achieved with pharmacological immune suppression, the undesirable side effects of this method have incited interest in novel methods to overcome the immune barrier. One such novel method of preventing immune reaction is immuno-isolation, in which the non-autologous tissues are physically isolated from the host tissues by placement in devices with perm-selective membranes. The membranes of these devices allow release of the therapeutic product required from the transplanted tissues, as well as diffusion of nutrients and waste necessary for survival of the non-autologous tissues. The membranes also prevent host immune mediators from contacting the non-autologous cells, thus preventing immune rejection. This technology has been tested for efficacy in large animal models, and is currently in the process of clinical trials in humans. This review will discuss the progress made in using immuno-isolation of non-autologous tissues in large animals. Immuno-isolation can be subdivided into two major areas of interest based on whether the non-autologous tissue used in the immuno-isolation device is genetically altered (gene therapy) or not. Studies using non-genetically altered non-autologous cells for immune-isolation have been dominated by the use of pancreatic islet cells for the treatment of diabetes. This work has been tested in large animal models of diabetes, including canine and primate model animals, and human clinical trials are underway. As well, there has also been work on treatment of neurological disorders such as Parkinson's disease or chronic pain using non-autologous immuno-isolated adrenal chromaffin cells or dopaminergic PC12 cells in large animals such as sheep and primates. This work will be reviewed in detail as to the types of disorders, immuno-isolation devices used and the type of large animals involved. Immune-isolation for gene therapy is a more recently developed field of research. In this case, the non-autologous cells used are first genetically altered to secrete a recombinant therapeutic product before placement in the immune-isolation devices. Genetic engineering of the non-autologous cells is beneficial, as it allows the use of a cell type that tolerates well the environment of the immune-isolation device, while still delivering the therapeutic product of interest. This form of gene therapy has been tested in our laboratory for delivery of marker products such as human growth hormone to canines. As several large animal models of human genetic disorders are available, such as canines affected with hemophilia or the lysosomal storage disease mucopolysaccharidosis, testing the efficacy of immuno-isolation for gene therapy in large animal models is an important prelude to human clinical trials. This review will discuss the topics outlined above, as well as some further considerations of the usefulness of large animal models in studying immune-isolation for non-autologous transplantation. Large animals may be more appropriate model organisms than rodents in which to study immune-isolation, as issues such as biocompatibility and immune response in a larger animal can be addressed. As well, large animal studies of immune isolation may provide data that are more relevant than rodent studies to the eventual application to human clinical trials.

Animals↗