Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Sleeping Beauty Hooks Up with Herpes to Fight Brain Disease

08.01.2010
Tag-team Approach Breaks the Size Barrier for Gene Therapy

Neuroscientists have forged an unlikely molecular union as part of their fight against diseases of the brain and nervous system.

The team has brought together the herpes virus and a molecule known as Sleeping Beauty to improve a technology known as gene therapy, which aims to manipulate genes to correct for molecular flaws that cause disease.

The work, detailed in a paper published online in Gene Therapy, has allowed scientists at the University of Rochester Medical Center to reach a long-sought goal: Shuttling into brain cells a relatively large gene that can remain on for an extended period of time.

Suresh de Silva“We’ve broken what is in effect a size barrier – a limit to how much genetic material we can put into the nucleus of a cell and keep functioning for a long period of time,” said neuroscientist William Bowers, Ph.D., a scientist in the Center for Neural Development and Disease and the leader of the team. “That opens up more diseases to possible treatment with gene therapy.”

The first author of the paper is Biochemistry graduate student Suresh de Silva, who defends his doctoral thesis later this month.

Rendezvous between Sleeping Beauty and herpes aids brain healthThe molecular rendezvous of Sleeping Beauty and herpes in human brain cells could spell good news in the search for treatments for horrific brain diseases known as pediatric leukodystrophies, or a group of diseases known as lysosomal storage disorders. In many of these diseases, even though just a single gene or protein is defective, the effects are devastating – the diseases slowly rob children of their brain cells and are often fatal after years of severe symptoms.

The findings bolster the tools that researchers have when approaching certain diseases, said Bowers, including Usher syndrome, which results in deafness and vision loss; Niemann-Pick disease Type C, a fatal childhood lysosomal storage disorder; and von Willebrand disease, an inherited disease that causes extensive, chronic bleeding.

“The field of gene therapy is just beginning to yield some successes for patients. Improvements like this are crucial for increasing the number of patients who might benefit from such an approach,” said Bowers, who is an associate professor of Neurology, Microbiology and Immunology, and of Pharmacology and Physiology.

The research is part of a decades-long endeavor by scientists trying to get the right genes into the right cells at the right time to improve human health.

In the new work, scientists dramatically increased the size of the “genetic payload” they can deliver to brain cells compared to some conventional techniques, nearly tripling the amount of genetic material by some measures. They hope to deliver even bigger genes in the future.

The team did this by bringing together in a new way two molecular players, herpes and Sleeping Beauty, which are commonly used in molecular technology.

For years Bowers’ team has been using the herpes virus – HSV-1, the type that causes cold sores – to shuttle genes into cells. Viruses like herpes are adept at infecting human cells, and scientists like Bowers use such viruses to carry into cells genes that would help people who are sick. Bowers and colleagues modify the viruses extensively, removing the portions that could make a person sick and using the portions that the virus uses to gain access to human cells.

Many scientists use other viruses, such as lentiviruses or a cold-related virus known as adeno-associated virus (AAV), to do a similar job. Each virus has its strengths and weaknesses when it comes to gene therapy. Herpes, for instance, readily infects cells, and it can carry a huge amount of genetic material, typically 15 to 30 times the amount of DNA that other viruses can carry into a cell.

But herpes as a genetic tool has a couple of big weaknesses. While the virus can deliver DNA into the nucleus of a cell, the genetic payload it carries does not become part of the package of genes that cells pass from one to another. Simply put, herpes cannot integrate the new DNA into the host genome. Instead, the DNA is adrift in the nucleus, where it’s silenced within a few weeks. The short time span spells trouble when scientists are trying to treat a disease that requires the genes to be active for months or years.

That’s where Sleeping Beauty comes in.

In molecular biology, Sleeping Beauty is a mobile genetic element that jumps into and out of longer segments of DNA. It’s normally silent, but years ago a team of scientists was able to activate or “awaken” the snippet – hence, Sleeping Beauty. Since Sleeping Beauty actually integrates segments of DNA into mammalian genomes, it sidesteps the main difficulties that herpes encounters inside a cell: Genes integrated within the cell’s chromosomes by Sleeping Beauty operate for much longer periods of time. The drawback: The molecule can insert only small snippets of DNA.

So the Rochester team brought herpes and Sleeping Beauty together in an attempt to get the best of both worlds: Delivery of the bigger genetic package made possible by herpes, and the integration of the DNA into the host genome made possible by Sleeping Beauty.

And that’s exactly what happened. In the tag-team approach funded by the National Institute of Neurological Disorders and Stroke, herpes gets the genetic package into the right neighborhood, the cell’s nucleus, and then Sleeping Beauty delivers the package precisely where it needs to go to be most effective – into the cellular genome.

In the current experiments, the herpes virus carried into cell nuclei the gene for green fluorescent protein, which allows scientists to track where the gene is active. The team also outfitted the herpes package with special molecular signals that Sleeping Beauty would recognize. Separately, the team introduced Sleeping Beauty into the cells. When the two met, Sleeping Beauty transferred the gene for GFP from the herpes package to the genome of the human cells, where the gene was stably expressed.

The team has previously shown that the Sleeping Beauty/herpes combination works efficiently in brain cells known as neural progenitor cells, which go on to form brain cells known as neurons. Modifying these cells – perhaps by adding a gene that creates a protein crucial for health – is one technique scientists are experimenting with to try to treat several brain diseases that are currently untreatable.

The gene segment used in the experiment described in Gene Therapy was about 12 kilobases long, which is larger than the limit of either AAV (4.5 kb) or lentiviruses (9 kb). Those few kilobases matter, a lot. The ability to transfer bigger genes gives scientists room to try to address more diseases with a gene therapy approach. The added space also makes it possible to include more regulatory elements – instructions that help determine how and when genes are turned on or off. This allows scientists to package additional safety directives, in the form of more DNA, along with the gene designed to treat the disease.

In addition to de Silva and Bowers, authors include technical associates Michael Mastrangelo, Louis T. Lotta Jr., and Clark Burris, as well as Howard J. Federoff, M.D., Ph.D., a former Rochester faculty member who is now executive vice president for health sciences at Georgetown University.

For Media Inquiries:
Tom Rickey
(585) 275-7954
Email Tom Rickey

Tom Rickey | EurekAlert!
Further information:
http://www.rochester.edu

More articles from Life Sciences:

nachricht Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>