Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Muscle-Targeted Gene Therapy Reverses Rare Muscular Dystrophy in Mice

30.03.2005


Gene therapy methods that specifically target muscle may reverse the symptoms of a rare form of muscular dystrophy, according to new research in mice conducted by medical geneticists at Duke University Medical Center. Infants born with the inherited muscular disorder called Pompe disease usually die before they reach the age of two. The researchers also said their approach of targeting corrective genes to muscles may have application in treating other muscular dystrophies.



Patients with Pompe disease have a defect in a key enzyme that converts glycogen, a stored form of sugar, into glucose, the body’s primary energy source. As a result, glycogen builds up in muscles throughout the body, including the heart, causing muscles to degenerate.

Using genetically altered mice in which the gene for the enzyme had been rendered nonfunctional, the researchers demonstrated they could introduce the functioning gene and correct glycogen buildup in heart and skeletal muscle. The findings suggest that such an approach should be considered as a potential gene therapy strategy for Pompe disease patients, the researchers report in a forthcoming issue of Molecular Therapy (now available online).


"Gene therapy in muscular dystrophies presents a unique challenge, because replacement of deficient, therapeutic proteins invokes an immune response that limits the efficacy of the treatment," said Duke medical geneticist Dwight Koeberl, M.D., senior author of the study. "By restricting the expression of introduced genes to muscle, the immune response can be prevented or attenuated."

The muscle-targeted gene therapy might therefore apply to other forms of muscular dystrophy, they added. Muscular dystrophies include many genetic diseases, all of which are characterized by progressive weakness and degeneration of the skeletal muscles which control movement.

The Muscular Dystrophy Association and Genzyme Corporation supported the research.

Several forms of Pompe disease affect more than 5,000 people in the U.S. If symptoms appear during infancy, the disease is usually fatal. Those for whom symptoms first appear late in childhood live longer, but life expectancy remains greatly decreased. Although Pompe disease is a relatively rare disease, it is but one of a group of related "lysosomal storage diseases," which in total occur in about one in 5,000 births.

The current study is part of a large, collaborative effort at Duke University Medical Center to find an effective treatment for Pompe disease. The Duke team earlier developed enzyme replacement therapy, in which a normal version of the faulty enzyme in those with the disease is infused weekly. In clinical trials of the replacement therapy, the infusions have already prolonged the lives of many babies with Pompe disease, Koeberl said.

"A number of babies have been receiving enzyme replacement therapy for several years," said Koeberl. "They are walking, living longer, and meeting developmental milestones."

Despite the early success of enzyme replacement therapy for some children with Pompe disease, a need for gene therapy remains, he added. In gene therapy, a therapeutic gene is delivered to patient cells, often using a modified virus.

Gene therapy might offer an alternative treatment for those children who fail to respond to enzyme replacement therapy, he said. Even for those that respond well to enzyme infusions, treatment requires weekly injection of a large amount of the enzyme.

"Gene therapy has the potential to reverse the course of the disease with a single treatment," Koeberl said.

The researchers delivered the glycogen-degrading enzyme with an adeno-associated virus (AAV) vector. AAV is not associated with any known human disease. The DNA coding for the enzyme was linked to a specialized DNA "promoter" region that restricted its activity to muscle. The investigators either injected the viral particles into the muscle or injected it intravenously in Pompe disease mice.

Six weeks after muscular injection with the virus containing the muscle-restricted gene, mice exhibited high levels of the enzyme and reduced glycogen content in the injected muscle. The mice also had a reduced immune response to the new enzyme, compared to those in which gene expression was not limited to muscle, they found.

Moreover, intravenous administration of the muscle-targeted gene reduced the glycogen content of heart and skeletal muscle and corrected individual muscle fibers. The effect persisted for 24 weeks post-injection, the team reported.

A second gene therapy strategy, in which the enzyme involved in Pompe disease is inserted into the liver, is also under investigation at Duke, said Koeberl. In the January 2005 issue of Molecular Therapy, the researchers reported that the liver-targeted method also corrected symptoms of Pompe disease in mice.

"The muscle-targeted gene therapy method could circumvent the complications of neutralizing antibodies against introduced enzyme, which currently present obstacles to enzyme replacement therapy and liver-targeted gene therapy in Pompe disease," Koeberl said.

Clinical trials of either the muscle- or liver-targeted gene therapies will likely take several years to launch, Koeberl said.

Collaborators on the gene therapy studies include Baodong Sun, Haoyue Zhang, Luis Franco, Andrew Bird, Ayn Schneider, Sarah Young, Y.T. Chen, and Andy Amalfitano, all of Duke Medical Center, and Talmage Brown, of North Carolina State University College of Veterinary Medicine.

Kendall Morgan | EurekAlert!
Further information:
http://www.duke.edu

More articles from Life Sciences:

nachricht Unique genome architectures after fertilisation in single-cell embryos
30.03.2017 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

'On-off switch' brings researchers a step closer to potential HIV vaccine

30.03.2017 | Health and Medicine

Penn studies find promise for innovations in liquid biopsies

30.03.2017 | Health and Medicine

An LED-based device for imaging radiation induced skin damage

30.03.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>