If you live within the US and have believe you have LGMD2B/Miyoshi Myopathy, please send a message to us and we will update you on programs in support of genetic diagnosis.
(1) Characterizing a KI mouse model carrying an exon 32 nonsense mutation.
(2) Evaluating the functionality of exon 32 skipping in a living animal.
(3) Extending the exon skipping strategy to the entire C2D domain (comprising exon 32, and in addition exons 31, 33 and 34) using a multiple exon skipping approach.
Our laboratory is interested in how lipids associated to ‘Western’ diets, such as triglycerides and cholesterol, can participate to the pathogenesis of dysferlinopathy. Using various genetic models of altered lipid metabolism in combination with dysferlinopathic mice, we are currently studying how muscle fibers respond to changes in circulating lipid and lipoproteins levels, and whether correcting certain plasma lipid parameters would attenuate the rate of decline in muscle function associated with dysferlinopathies.
Brian Chait, D.Phil., is the Camille and Henry Dreyfus Professor at the Rockefeller University in New York and head of the Laboratory for Mass Spectrometry and Gaseous Ion Chemistry. He specializes in the development and use of mass spectrometry as a tool for investigating a variety of biological and biochemical phenomena.
The aim of the study is to assess the therapeutic effect of bone marrow transplantation in A/J mice. So far, there is no effective treatment for dysferlinopathies. Preliminary studies from our group have shown some functional improvement in A/J mice treated with bone marrow transplantation. We have observed some functional improvements 22 weeks after bone marrow transplantation (BMT). We are interested in studying if this beneficial effect is maintained over time.
Dysferlinopathy is a chronic, progressive skeletal muscle wasting disease resulting from loss of function mutations in the gene dysferlin. Macrophages and adipocytes are prominent in the inflamed skeletal muscles of patients with dysferlinopathy. These myeloid cells increase and localize to fat depots within skeletal muscles of mice on a high fat diet. However, it is not clear whether macrophages and adipocytes directly and/or indirectly interact in inflamed muscles. Macrophages are integral to both tissue repair and destruction.
A common characteristic of dysferlinopathy is an exuberant inflammatory response with abundant macrophage infiltration that may contribute to the pathogenesis of the disease. Our specific hypothesis for this proposal is that thrombospondin-1 (TSP-1) promotes a destructive monocyte/macrophage response that exacerbates muscle damage. Our initial studies indicate that TSP-1 levels correlate with macrophage accumulation and phagocytosis leading to loss of muscle mass in dysferlin deficient mice.
We are interested in one of the main mysteries of dysferlin deficiency; how individuals who lack dysferlin appear to have perfectly normal muscle function for much of the early part of their lives but go on to have increasingly severe loss of muscle later in life. This change is seen in the mouse models of dysferlin deficiency, too. Young BlaJ mice show no sign of spontaneous muscle pathology, but after the end of growth at about 4 months there are signs of degeneration and regeneration.
This project is devoted to translating AAVrh.74.Dysferlin Dual Vector (DV) gene transfer to the clinic. In this approach, two viral vectors are co-administered to reconstitute the full-length dysferlin gene. This is mediated by a 1 kb region of homology between the two vectors. The first phase of the project focused on completing the pre-clinical data necessary to support IND application and includes: long term assessment of dysferlin expression following dual vector delivery; definition of the minimum effective dose to achieve functional restoration in dysferlin deficient mice; and demo