Exon skipping as a therapeutic strategy for dysferlinopathy

Objective: 
The present project is aiming toward the clear objective of obtaining important preclinical information towards developing exon skipping as a therapeutic strategy in targeted cases of dysferlinopathies by:

(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.

Past

Preventing Dysferlinopathy Through Anti-Cholesterol Approaches

Objective: 
To evaluate how lipids associated with 'Western' diets can participate in pathogenesis of dysferlinopathy.

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.

Past

Creating Libraries of Nanobodies That Recognize Selected Regions of Dysferlin

Objective: 
To generate libraries of nanobodies that recognize selected regions of dysferlin

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.

Research

Bone marrow transplantation as a therapeutic approach for dysferlinopathies

Objective: 
To assess bone marrow transplantation as a therapeutic approach for dysferlinopathies

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.

Past

Proliferating Inflammatory Macrophages Mediate Dysferlinopathy

Objective: 
To test the hypothesis that dysferlinopathy is mediated by a defect in Mø that precludes a sufficient transition from M1 inflammatory to M2 reparative/regulatory phenotypes.

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.

Research

Monocytes and Dysferlinopathy: Role of Thrombospondin-1

Objective: 
To determine whether targeting monocytes/macrophages can ameliorate disease progression in dysferlinopathy.

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.

Research

Investigation of Pre-Pathological Aetiology of Dysferlinopathy in the mouse

Objective: 
Tracing the changes that accompany onset of disease in dysferlin-deficient muscle

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.

Past

AAV.Dysferlin Dual Vector Gene Therapy as a Treatment for Dysferlinopathies

Objective: 
Our AAV.Dysferlin Dual Vector gene transfer project is a stepwise, milestone driven approach to bring an efficacious product with a proven safety profile to clinical trial for LGMD2B/MM.

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

Past

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