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 Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

Im Focus: Computer-Designed Customized Regenerative Heart Valves

Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.

Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...

Im Focus: Light-induced superconductivity under high pressure

A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.

Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Supersonic waves may help electronics beat the heat

18.05.2018 | Power and Electrical Engineering

Keeping a Close Eye on Ice Loss

18.05.2018 | Information Technology

CrowdWater: An App for Flood Research

18.05.2018 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>