Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers report major advance in gene therapy technique

04.06.2004


Despite a roller-coaster ride of ups and downs during the past 15 years, gene therapy has continued to attract many of the world’s brightest scientists. They are tantalized by the enormous potential that replacing missing genes or disabling defective ones offers for curing diseases of many kinds.



One group, consisting of researchers from the University of Wisconsin Medical School, the Waisman Center at UW-Madison and Mirus Bio Corporation of Madison, Wis., now reports a critical advance relating to one of the most fundamental and challenging problems of gene therapy: how to safely and effectively get therapeutic DNA inside cells.

The Wisconsin scientists have discovered a remarkably simple solution. They used a system that is virtually the same as administering an IV (intravenous injection) to inject genes and proteins into the limb veins of laboratory animals of varying sizes. The genetic material easily found its way to muscle cells, where it functioned as it should for an extended period of time.


"I think this is going to change everything relating to gene therapy for muscle problems and other disorders," says Jon Wolff, a gene therapy expert who is a UW Medical School pediatrics and medical genetics professor based at the Waisman Center. "Our non-viral, vein method is a clinically viable procedure that lets us safely, effectively and repeatedly deliver DNA to muscle cells. We hope that the next step will be a clinical trial in humans."

Wolff conducted the research with colleagues at Mirus, a biotechnology company he created to investigate the gene delivery problem. He will be describing the work on June 3 at the annual meeting of the American Society for Gene Therapy in Minneapolis, and a report will appear in a coming issue of Molecular Therapy. The research has exciting near-term implications for muscle and blood vessel disorders in particular.

Duchenne’s muscular dystrophy, for example, is a genetic disease characterized by a lack of muscle-maintaining protein called dystrophin. Inserting genes that produce dystrophin into muscle cells could override the defect, scientists theorize, ensuring that the muscles with the normal gene would not succumb to wasting. Similarly, the vein technique can be useful in treating peripheral arterial occlusive disease, often a complication of diabetes. The disorder results in damaged arteries and, frequently, the subsequent amputation of toes.

What’s more, Wolff says, with refinements the technique has the potential to be used for liver diseases such as hepatitis, cirrhosis and PKU (phenylketonuria).

In the experiments, the scientists did not use viruses to carry genes inside cells, a path many other groups have taken. Instead, they used "naked" DNA, an approach Wolff has pioneered. Naked DNA poses fewer immune issues because, unlike viruses, it does not contain a protein coat (hence the term "naked"), which means it cannot move freely from cell to cell and integrate into the chromosome. As a result, naked DNA does not cause antibody responses or genetic reactions that can render the procedure harmful.

Researchers rapidly injected "reporter genes" into a vein in laboratory animals. Under a microscope, these genes brightly indicate gene expression. A tourniquet high on the leg helped keep the injected solution from leaving the limb.

"Delivering genes through the vascular system lets us take advantage of the access blood vessels have - through the capillaries that sprout from them - to tissue cells," Wolff says, adding that muscle tissue is rich with capillaries. Rapid injection forced the solution out of the veins into capillaries and then muscle tissue.

The injections yielded substantial, stable levels of gene activity throughout the leg muscles in healthy animals, with minimal side effects. "We detected gene expression in all leg muscle groups, and the DNA stayed in muscle cells indefinitely," notes Wolff.

In addition, the scientists were able to perform multiple injections without damaging the veins. "The ability to do repeated injections has important implications for muscle diseases since to cure them, a high percentage of therapeutic cells must be introduced," he says.

The researchers also found that they could use the technique to successfully administer therapeutically important genes and proteins. When they injected dystrophin into mice that lacked it, the protein remained in muscle cells for at least six months. Similar lasting power occurred with the injection of erythropoietin, which stimulates red blood cell production.

Furthermore, in an ancillary study, the researchers learned that the technique could be used effectively to introduce molecules that inhibit - rather than promote - gene expression, a powerful new procedure called RNA interference.

"This could be very useful if you want to down-regulate a protein that’s causing a muscle disorder, such as with myotonic dystrophy," says Wolff.

In the late 1980s, Wolff and his UW-Madison colleagues surprised the scientific world with their discovery that they could get genes to express in muscle cells simply by injecting naked DNA into rodent muscle. The Wisconsin Alumni Research Foundation (WARF) licensed the technology to Vical, a California biotechnology company.

Once Wolff created Mirus, a local company, he and his colleagues turned their attention to the vascular system, a conduit to multiple leg and arm muscles they felt would work more efficiently than direct injection into muscle. WARF licensed the vascular technique to Mirus, which now holds the patent and continues to commercialize the technique.

In their first studies, the researchers focused on arteries, but then began to concentrate on veins. "Injecting any substance into arteries carries a degree of risk since, unlike veins, only one artery feeds a whole limb," notes Wolff.

In a related procedure, they experienced excellent results with high-pressure injection of genes into the tail veins of rodents, a technique that yielded extensive gene expression in the animals’ livers.

"We think the genes traveled from the capillaries through the relatively large holes that exist in liver cells," Wolff says, adding that the technique has become a successful research tool for many laboratories around the world.

"For delivering genes to limb muscles, the vein approach is so simple," he says. "We never expected it to work so well."


Collaborating on the study were James Hagstrom, Julia Hegge, Mark Nobel, David Lewis and Hans Herweijer, from Mirus Bio; and Guofeng Zhang and Vladimir Budker, from the Waisman Center.

Dian Land | EurekAlert!
Further information:
http://www.wisc.edu/

More articles from Health and Medicine:

nachricht Collagen nanofibrils in mammalian tissues get stronger with exercise
14.12.2018 | University of Illinois College of Engineering

nachricht New discoveries predict ability to forecast dementia from single molecule
12.12.2018 | UT Southwestern Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Data use draining your battery? Tiny device to speed up memory while also saving power

The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.

Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...

Im Focus: An energy-efficient way to stay warm: Sew high-tech heating patches to your clothes

Personal patches could reduce energy waste in buildings, Rutgers-led study says

What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...

Im Focus: Lethal combination: Drug cocktail turns off the juice to cancer cells

A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.

The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...

Im Focus: New Foldable Drone Flies through Narrow Holes in Rescue Missions

A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.

Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...

Im Focus: Topological material switched off and on for the first time

Key advance for future topological transistors

Over the last decade, there has been much excitement about the discovery, recognised by the Nobel Prize in Physics only two years ago, that there are two types...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

New Plastics Economy Investor Forum - Meeting Point for Innovations

10.12.2018 | Event News

EGU 2019 meeting: Media registration now open

06.12.2018 | Event News

 
Latest News

Data use draining your battery? Tiny device to speed up memory while also saving power

14.12.2018 | Power and Electrical Engineering

Tangled magnetic fields power cosmic particle accelerators

14.12.2018 | Physics and Astronomy

In search of missing worlds, Hubble finds a fast evaporating exoplanet

14.12.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>