Beggs Laboratory | Research Approaches

After learning about the cell biology and biochemistry of normal genes and proteins, we are then in a position to look for abnormalities of these genes in patients with muscle weakness. Thus, the second approach is to ascertain and enroll patients and families with various congenital myopathies and then study their DNA and muscle to find and understand the causes of their disorders. In the past few years, we have made much progress in understanding the basis of nemaline myopathy, including the identification of three thin filament proteins involved in this disorder. Current studies are also focusing on myotubular/centronucluclear myopathy, multi/minicore myopathies, SELENON related myopathies, and other forms of congenital myopathy, including undefined cases without firm diagnoses. Knowing the genetic basis for each disorder will be critical to designing specific and effective treatments for some of these diseases.

The third approach is to learn as much as possible about the physiologic state of diseased muscle from patients with congenital myopathy. One frustrating aspect of medical genetics today is that knowing the exact genetic defect has often not allowed us to fully understand how the disease is caused and, more importantly, how we can treat it. Utilizing microarray technology, we are studying global gene expression patterns to determine the "downstream" or secondary consequences of particular genetic mutations and to identify novel muscle genes for further study. These genomic and proteomic approaches are yielding important new insights into basic muscle biology as well as the pathophysiology of inherited muscle diseases.

The fourth approach is to employ cellular and animal models of the congenital myopathies in order to better understand the disease process. In order to find a cure for a genetic disease, it is crucial to study the function of the normal gene to understand how its deficiency can cause the disease. Cellular and animal models have been proven to be indispensable tools for this purpose. In the case of muscular disease, C2C12 cells which are derived from a muscle cell line are an excellent choice since they can form myotubes (muscle cells) in vitro. These myotubes can twitch (contract) and to some extent mimic the muscle function. Furthermore, we now have the technology to easily inactivate ("turn off") a specific gene of interest in these cells in order to study the consequences of its deficiency. Using a mouse model of x-linked myotubular myopathy, we are learning more about various treatment options.

Our ultimate goal in the Beggs Laboratory is to discover and develop therapies to treat the various muscle and other diseases we are studying.  Our development of faithful animal models and new knowledge of the genetic basis for these diseases has allowed us to understand the mechanisms leading to weakness (i.e., the “pathophysiology”), and this is now leading to development and testing of novel treatments for some of these conditions.   Some recent exciting advances include the development of gene replacement therapy for XLMTM (now in clinical trials), and the recent approval and use of a novel oligonucleotide therapy personalized for a mutation in a single girl with Batten’s disease. Other areas of investigation have included tests of protein replacement therapy in XLMTM, myostatin inhibition therapy in XLMTM and Nemaline Myopathy, troponin activators in Nemaline Myopathy, and use of zebrafish and cellular models to screen for therapeutic drugs in SELENON - Related Myopathies, RYR1 Myopathy, and Diamond Blackfan anemia.