Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UNC studies target molecular defects implicated in cancer, genetic diseases

09.01.2003


In three separate studies, scientists at the University of North Carolina at Chapel Hill School of Medicine have shown that it is possible to correct defective molecular splicing pathways that would otherwise contribute to cancer, genetic diseases and possibly other disorders.



These corrections were accomplished by the insertion into the cell of antisense oligonucleotides, short strands of genetic material that target portions of RNA. RNA carries the DNA blueprint for cellular protein production in gene expression. The technique for correcting these defective molecular splicing pathways was pioneered by Dr. Ryszard Kole, professor of pharmacology and a member of the UNC Lineberger Comprehensive Cancer Center.

In a new study published Dec. 20 in the Journal of Biological Chemistry, Kole and colleagues used these techniques to eradicate certain cancer cells or to increase their sensitivity to treatment.


While tumors initially respond to radiation or chemotherapy, they frequently become resistant to subsequent treatments. One form of resistance develops when cancer cells no longer respond to signaling molecules that tell the cells to die, a process known as apoptosis. In the new report, RNA splicing of the gene that controls apoptosis was targeted with antisense oligonucleotides.

"RNA splicing is the essential process of cutting and pasting the genetic code into a continuous reading frame to produce protein," said Kole. "The cell can splice each RNA into multiple, alternative forms, which result in related but different proteins. In cancer cells, this process may be modified and contribute to resistance to apoptosis."

For example, RNA coded by a gene, bcl-x, is alternately spliced into two different forms, both of which play an important role in apoptosis. The short form, bcl-xS, promotes apoptosis and cell death, while the long form, bcl-xL, prevents apoptosis and promotes cell growth.

Accordingly, higher levels of bcl-xL have been found in malignant cancers of the prostate and have been correlated with increased resistance of these cancers to chemotherapeutic agents. In the new study, antisense molecules were used to shift the alternative splicing of bcl-x from the anti-apoptotic form to the pro-apoptotic form in cancer cell lines, including cancers of the prostate and breast. In doing so, the UNC researchers were able to sensitize these cell lines to various chemotherapeutic agents and radiation.

"Our gene-based therapy would presumably be specific for cancer cells, which overexpress the anti-apoptotic form of RNA," said Dr. Danielle Mercatante, first author of the study and a postdoctoral fellow at the Lineberger center. "This approach could offer a significant advantage over conventional therapies, which are non-specific and kill both cancerous and non-cancerous cells."

This study used cells in culture. But in a December report in Nature Biotechnology, Kole and colleagues demonstrated they could alter splicing defects in a mouse. In this report, they inserted a gene with a splicing defect into the mouse genome. The gene fluoresces bright green when the splicing defect has been successfully blocked with antisense oligonucleotides. Injection of antisense oligonucleotides into the transgenic mouse model blocked defective splicing, leading to green fluorescence activity in several tissues.

"To my knowledge, our study was the first demonstration that a systemically injected oligonucleotide could shift splicing in vivo," said Peter Sazani, first author of the study and postdoctoral researcher at the Lineberger center.

"The transgenic mouse provides a platform to compare the various oligonucleotide modifications that could lead to improvements in the stability, uptake and binding of the oligonucleotides to the target," said Kole. "These improvements will allow the oligonucleotides to modify splicing in patients in the not-too-distant future."

Besides these two reports, the Kole laboratory last year demonstrated the therapeutic potential of this method in blood from patients with a form of beta-thalassemia, a genetic disease that affects as many as one in 10 of the Mediterranean population. The study showed that antisense molecules could be used to increase the production of hemoglobin, the protein necessary to reduce the patient’s anemia. In September, the findings were published in the online edition of the journal Blood, a publication of the American Society of Hematology. They also appear in the Jan.1 issue of the journal.

"Taken together the three reports show the possibility of wide application of targeting splicing with antisense molecules," said Kole. "In fact, recent findings that a large fraction, if not a majority, of genes are alternatively spliced indicate that this approach may be applicable to hundreds of disorders."

The National Heart, Lung and Blood Institute, a component of the National Institutes of Health, provided funding for the research.

By MARLA M. VACEK UNC School of Medicine



Note: Contact Kole at 919-966-1143 or kole@med.unc.edu. Contact Mercatante at danielle@med.unc.edu. Contact Sazani at sazani@email.unc.edu. School of Medicine contact: Leslie H. Lang, 919-843-9687 or llang@med.unc.edu.




Leslie Lang | EurekAlert!
Further information:
http://www.med.unc.edu/

More articles from Life Sciences:

nachricht New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences

nachricht The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Previous evidence of water on mars now identified as grainflows

21.11.2017 | Physics and Astronomy

NASA's James Webb Space Telescope completes final cryogenic testing

21.11.2017 | Physics and Astronomy

New catalyst controls activation of a carbon-hydrogen bond

21.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>