Can we enlist substitute genes to fight muscular dystrophy

May 15, 2002

(Philadelphia, PA) - Substitutes. If your teacher is out sick or the secretary is on vacation, calling in a substitute is always an option. But what if one of your genes is not working? In recent years, researchers have eyed utrophin as a substitute for a similar gene, dystrophin, which is responsible for Duchenne's muscular dystrophy (DMD), a fatal neuromuscular disease. In the May 15th issue of the Journal of Neurological Sciences, researchers at the University of Pennsylvania School of Medicine detail the cellular mechanisms that promote and regulate the transcription of the utrophin gene into protein. Their findings may open the door to creating therapeutics that will produce excess utrophin in people suffering from DMD.

"Utrophin has been a major focus in muscular dystrophy. Dystrophin and utrophin perform similar tasks at the neuromuscular junction - where nerve cells meet muscle tissue - and studies have shown that utrophin over-production reverses the symptoms of muscular dystrophy in mice," said Tejvir S. Khurana, MD, PhD, assistant professor in the Department of Physiology and researcher at the Pennsylvania Muscle Institute at Penn. "It is not a perfect substitute in the way that a putter is not the same as a driver if you are playing golf, for example. But when you are on the fairway and your driver is broken, you can use your putter - you just have to hit the ball much, much harder." Duchenne's muscular dystrophy is one of the most frequent hereditary diseases of men, affecting one in 3,500 boys. DMD occurs when the dystrophin gene, located on the short arm of the X-chromosome, is broken. Since males only carry one copy of the X-chromosome, they only have one copy of the dystrophin gene. Without the dystrophin protein, muscle tissue cannot compensate sufficiently and will eventually break down. "Over-production of utrophin may be a viable alternative to adding a working copy of the dystrophin gene through gene therapy," said Khurana. "The available research supports the idea that if you can crank up the production of utrophin, you will compensate for the lack of dystrophin."

In the article, Khurana and his colleagues describe how specific intercellular signals, such as heregulin, set into motion a series of reactions within the cell that lead to the activation of the utrophin gene. In cultured muscle cells, the researchers demonstrated how heregulin ultimately switches on Sp1, a transcription factor, which then binds to a specific region of the DNA that drives the utrophin gene. Once attached to DNA, Sp1, along with another heregulin-stimulated transcription factor called GABP /, attracts the cellular machinery responsible for transcribing genes into proteins.

The utrophin protein bears many functional similarities to dystrophin, although it is expressed in more types of cell tissue. At the neuromuscular junction, the two proteins work as part of the complex network of molecules that sustain muscle tissue through wear and tear. In healthy muscle tissue, dystrophin works as a sort of shock absorber to keep the cell membrane from tearing apart during muscle contraction. Since it is so similar to dystrophin, utrophin can also function as this molecular shock absorber, although not as well.

The idea that utrophin has a protective effect against DMD has been gaining favor as researchers looked deeper into the causes of the disease. In fact, studies have shown that disease progresses slowly in the first two weeks after birth in dystrophin deficient mice, since the levels of utrophin are still quite high, but much more quickly in mice that lack both the utrophin and dystrophin genes.

"These findings will help define targets for stimulating the muscle cells' native mechanisms into producing more utrophin," said Khurana. "And while a substitute isn't always as good as the original, in this case good enough may well result in a substantial improvement." Contributors to this study include Mads Gyrd-Hansen and Thomas O.B. Krag of the University of Copenhagen, Denmark and Alan G. Rosmarin of Brown University.
This work was supported by grants from the Dutch Duchenne Parents Project (The Netherlands), the Muscular Dystrophy Association (USA), Association Francaise contre Les Myopathies (France), Statens Sundhedsvidenskabelige Forskingsråd, the Lundbeck, Novo Nordisk, AP Møller and Kong Christian den X Foundations (Denmark).

Editor's Note: You may also find this news release online at The University of Pennsylvania Health System (UPHS) is an international leader in biomedical research, medical education and quality care. UPHS is distinguished not only by its historical significance - first hospital (1751), first medical school (1765), first university teaching hospital (1874), and first fully integrated academic health system (1993) - but also by its position as a major player on the world stage of medicine in the 21st century.

University of Pennsylvania School of Medicine

Related Gene Therapy Articles from Brightsurf:

Risk of AAV mobilization in gene therapy
New data highlight safety concerns for the replication of recombinant adeno-associated viral (rAAV) vectors commonly used in gene therapy.

Discovery challenges the foundations of gene therapy
An article published today in Science Translational Medicine by scientists from Children's Medical Research Institute has challenged one of the foundations of the gene therapy field and will help to improve strategies for treating serious genetic disorders of the liver.

Gene therapy: Novel targets come into view
Retinitis pigmentosa is the most prevalent form of congenital blindness.

Gene therapy targets inner retina to combat blindness
Batten disease is a group of fatal, inherited lysosomal storage disorders that predominantly affect children.

New Human Gene Therapy editorial: Concern following gene therapy adverse events
Response to the recent report of the deaths of two children receiving high doses of a gene therapy vector (AAV8) in a Phase I trial for X-linked myotubular myopathy (MTM).

Restoring vision by gene therapy
Latest scientific findings give hope for people with incurable retinal degeneration.

Gene therapy/gene editing combo could offer hope for some genetic disorders
A hybrid approach that combines elements of gene therapy with gene editing converted an experimental model of a rare genetic disease into a milder form, significantly enhancing survival, shows a multi-institutional study led by the University of Pennsylvania and Children's National Hospital in Washington, D.C.

New technology allows control of gene therapy doses
Scientists at Scripps Research in Jupiter have developed a special molecular switch that could be embedded into gene therapies to allow doctors to control dosing.

Gene therapy: Development of new DNA transporters
Scientists at the Institute of Pharmacy at Martin Luther University Halle-Wittenberg (MLU) have developed new delivery vehicles for future gene therapies.

Gene therapy promotes nerve regeneration
Researchers from the Netherlands Institute for Neuroscience and the Leiden University Medical Center have shown that treatment using gene therapy leads to a faster recovery after nerve damage.

Read More: Gene Therapy News and Gene Therapy Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to