>>TARRYTOWN, N.Y., Nov 2, 2001 (BW HealthWire) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN chart, msgs) announced today important new discoveries in its muscle biology program, achieved using its Functionomics(TM) technology platforms.
In back-to-back papers to be published in the November 2001 issue of Nature Cell Biology, Regeneron scientists define the key molecular mediators that cause muscle growth, and then genetically over stimulate these so as to induce muscle growth in animal models. In a paper currently available online as a ScienceExpress report and to be published in a future issue of Science, Regeneron scientists define two key genes responsible for muscle shrinkage and atrophy, and then genetically delete these and thus block muscle atrophy in animal models.
Understanding the Critical Processes that Cause Muscle Growth and Atrophy
It is widely appreciated that exercise can promote muscle growth in humans. Reciprocally, many different medical conditions cause muscle shrinkage, such as when a limb is casted following injury, when a patient undergoes prolonged bed rest or suffers from cachectic conditions such as cancer or AIDS, or when a patient is treated with drugs such as steroids. In such settings, the patient has few therapeutic choices to prevent muscle loss. Muscle size is maintained by a balance between processes that promote muscle growth via increasing muscle protein synthesis, and antagonistic processes that cause muscle atrophy by causing muscle protein degradation. Regeneron scientists now report that they have identified the molecular mediators of both the muscle growth process, as well as of the muscle atrophy process. Furthermore, Regeneron scientists report that they can manipulate these mediators, primarily by using genetic approaches such as transgenics and knockouts, to cause either muscle growth or to block muscle atrophy in animal models. These findings provide new validated targets that may lead to novel therapeutics for healthy muscle maintenance and growth.
"Regeneron has been very successful in identifying potential medicines based on understanding of basic cellular mechanisms," noted George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron, President of Regeneron Laboratories, and a senior author on the papers. "We hope that our new insights into the molecular mediators of muscle growth and atrophy will lead to therapeutic drug discoveries that can prevent or reverse the negative effects of muscle deterioration."
David J. Glass, M.D., Vice President of the Muscle Program and New Technology at Regeneron, and a senior author on the manuscripts, noted, "Defining the gene products which cause the muscle growth which follows exercise or the muscle atrophy following various disease processes, and then showing that genetic manipulation of these can overcome the muscle loss seen in disease models, nicely demonstrates the power of our Functionomics(TM) capabilities. The next step is to target these molecules so as to discover highly specific therapeutic drug candidates that promote muscle growth and maintenance."
Sue Bodine, Ph.D., Director of the Muscle Program and a primary author of the papers, added, "Since muscle loss is such an important medical problem, not only in disease settings but even during normal aging, we're excited that we have the opportunity to explore the therapeutic implications of our findings."
The work described above was performed as part of a research and development collaboration with The Procter & Gamble Company (NYSE: PG chart, msgs). Regeneron and P&G jointly will commercialize any products derived from the work and share profits equally.
Nature Cell Biology study: The Akt pathway and skeletal muscle hypertrophy
- The studies described in the two Nature Cell Biology papers define the molecular mechanisms which normally lead to increases in muscle size in response to increased load on the muscle (akin to weight training), or in response to stimulation by a growth factor (Insulin-like Growth factor 1 or IGF-1). In both cases, increase in muscle size is due to an increase in the synthesis of muscle proteins. Regeneron scientists found that this increase in muscle protein synthesis, which involves molecules called "PI3 kinase" and "Akt", is activated and sets off a cascade of cellular responses that result in an increase in the rate of protein production.
- Regeneron scientists used a "mutant" form of the Akt protein, which was changed so as to always be in the "on" state. They showed that transgenic introduction of this mutant Akt in to muscle caused a rapid increase in the size of the treated muscle fibers and an increase in the activity of known protein synthesis pathways. They then showed that these increases could overcome the muscle loss that is seen in animal disease models of muscle atrophy.
- Regeneron scientists also demonstrated the mechanism by which Akt causes the increase in protein synthesis, by showing the exact molecules that are activated in response to Akt.
- Regeneron has filed for U.S. patents covering the use of these signaling molecules in the prevention of muscle disease and in muscle hypertrophy under a variety of settings.
Science study: Ubiquitin protein degradation pathway and skeletal muscle atrophy
- Skeletal muscle regulates its size through a balance between protein synthesis, which increases muscle size, and protein degradation, which decreases muscle size. The Science article demonstrates the mechanism by which protein degradation in muscle is increased in disease settings that normally cause muscle atrophy. During atrophy, a protein degradation pathway is critical in which a small peptide called "ubiquitin" is attached to target proteins, marking them for rapid breakdown. This increase in protein degradation causes a decrease in the size of muscle fibers.
- Regeneron scientists discovered two genes, which are specifically used in muscle, that encode the proteins that affix ubiquitin to the target proteins, thereby causing the loss of muscle mass.
- Regeneron scientists developed two sets of mice, each of which lacked one of the genes. In both cases, the animals preserved muscle mass even when subjected to atrophy conditions. This demonstrated that blocking the signals of either gene may help prevent muscle atrophy.
- Regeneron has filed for U.S. patents covering the inhibition of these ubiquitin-pathway genes for the prevention of muscle disease and muscle atrophy under a variety of settings.<<
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Cheers, Tuck |
