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
Dysferlin is a large protein with several tandem protein domains of unknown structure and function. However, mutations in these domains have been linked to LGMD. The identifiable domains include seven C2 domains, a FerA domain, and DysF. This project examined the structure and function of the C2 domains as well as the internal domains of dysferlin, FerA and DysF.
We have been studying dysferlin-null and control myofibers in culture, with and without drug treatments and with and without transfection with variants of dysferlin, to learn how dysferlin promotes protection of muscle from damage and repair after damage, and how drugs targeting the calcium channel proteins of the triad junction can help prevent damage to dysferlin-null muscle.
Dr. Michael Sinnreich recently conducted a clinical study of a drug called bortezomib in individuals who have a particular type of mutation (called ‘missense mutations’) in the dysferlin gene. Read the full summary of the article here.
The effects of exercise on LGMD2B/Miyoshi myopathy have not yet been studied in detail, so there is no consensus on whether exercise will help or hurt patients with the disease.
Dysferlin deficiency syndromes (dysferlinopathies) are late-onset muscular dystrophies characterized by muscle fiber regeneration, infiltration of inflammatory cells and muscle replacement by fatty tissue. Despite intense study, the molecular basis of dysferlin-deficiency disease remains uncertain. We think that dysferlinopathies may be developmental disorders, due the lack of dysferlin protein in development. The dysferlin protein (230 kDa) interacts (directly or indirectly) with many skeletal muscle proteins and may help to organize or stabilize fiber structural organization.
June 26-30, 2016 - PPMD Annual Connect Conference in Washington, DC, USA
The Connect Conference is the largest, most comprehensive annual, international conference focused entirely on Duchenne. It presents an opportunity for families, physicians, researchers, and experts of all kind, to speak face-to-face about Duchenne. These meetings open communication channels, lay the groundwork for future collaborations, and shape our understanding of the Duchenne landscape.