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​University of Pittsburgh Researchers Receive $5.3 Million for Gene Studies to Improve Muscle Function

PITTSBURGH, July 23, 1999 — Gene therapy offers the promise to one day repair diseased, injured or old muscles. One problem in achieving this goal, however, has been developing vehicles that can deliver therapeutic genes to muscles effectively. The University of Pittsburgh School of Medicine has received a five-year, $5.3 million grant from the National Institutes of Health to help overcome this hurdle by exploring different gene delivery methods and experimental models.

"These funds should help lead to novel treatment methods for inherited muscle-wasting diseases, such as Duchenne Muscular Dystrophy, or DMD," remarked Leaf Huang, Ph.D., professor of pharmaceutical sciences at the University of Pittsburgh and director of this multi-project grant. "We also believe that our research will aid the development of therapies for more common-place problems, such as muscle injuries or tears."

Making up 30 percent of the body’s mass, skeletal muscle is the largest organ. Very adaptable, it responds quickly to use and disuse, and muscle is capable of regeneration, enlargement and metabolic changes over short periods of time. Unfortunately, inherited disorders of muscles, primarily muscular dystrophies, are some of the most prevalent and devastating diseases. Muscle weakness due to aging is also a major contributor to loss of muscle function.

Each gene delivery system has unique advantages and disadvantages, according to Dr. Huang. Scientists need to understand better how each of these systems, or vectors, transfers genes to muscle cells, in addition to gathering more information about the molecular biology of muscle cells to facilitate the most effective delivery of genes to muscles that are widely dispersed throughout the body.

The University grant involves four separate projects:

  • One study, led by Xiao Xiao, Ph.D., assistant professor of molecular genetics and biochemistry, focuses on gene vectors derived from adeno-associated virus (AAV), which is especially effective in delivering genes to both immature and mature muscle cells. AAV vectors are useful in gene transfer because they are harmless to the cells they enter; they permanently integrate with a cell’s own genetic material, or DNA; and they do not provoke the body’s immune system to react against them, as other viral vectors often do. A major shortcoming of AAV, however, is that it cannot hold large genes such as the dystrophin gene, which makes the normal dystrophin protein that is missing in boys with DMD. Dr. Xiao’s team will attempt to circumvent this engineering problem by using an AAV to deliver a dystrophin "mini-gene," a shortened version of the gene that produces an abbreviated protein in a mouse model of DMD. This altered protein may be enough to replace the role of normal dystrophin and thus improve or completely restore muscle function in the animals.

  • Another project, led by Paula Clemens, M.D., assistant professor of neurology, and Marcia Ontell, Ph.D., associate professor of cell biology and physiology, focuses on using a large virus, adenovirus (Ad), to deliver the full dystrophin gene to muscle cells. In previous work, Dr. Clemens and her colleagues gutted Ad of genes that trigger a vigorous immune response which would render this gene-delivery vehicle unusable. A remaining major limitation of Ad has been its poor ability to enter mature muscle cells. Drs. Clemens and Ontell will work on ways to improve Ad’s ability to enter mature muscle cell. In addition, they will determine whether using Ad to deliver the dystrophin gene to fetal muscles in developing DMD mice enhances the uptake of the gene and improves muscle function in these mice after birth compared with untreated fetal DMD mice.

  • A third project under the direction of Johnny Huard, Ph.D., assistant professor of orthopaedic surgery, will explore using Ad to deliver the dystrophin gene to precursors of mature muscle cells called myoblasts. These cells, according to Dr. Huard, appear to pick up Ad more readily. With the aim to improve the dystrophin gene transfer, Dr. Huard also will explore various muscle structures that affect the ability of Ad to enter muscle cells. For instance, parts of muscle cell bundles, or myofibers, appear to inhibit the entry of Ad vectors, whereas the junction between muscles and tendons may provide an easy way for Ad to reach and enter muscle cells, according to Dr. Huard.

  • A fourth project, led by Dr. Huang and Eric Hoffman, Ph.D., professor of genetics at Children’s National Medical Center in Washington, D.C., involves developing ways to deliver genes throughout the body to improve upon current limited methods that rely upon injecting vectors/genes directly into muscles. They have established experimental systems to identify, compare and test molecules specifically targeted against myofibers. Already, some of these molecules have been combined with viral vectors and non-viral vectors (these vectors encase genes in a bubble of fatty lipids). Attached to a vector, such molecules act like entrance tickets, allowing the vector to enter mature muscle cells through special gates. Once inside, the vector can deliver its therapeutic gene.


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