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 application for acoustics helps estimate marine life populations
16.01.2018 | University of California - San Diego

nachricht Unexpected environmental source of methane discovered
16.01.2018 | University of Washington Health Sciences/UW Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Morbid Obesity: Gastric Bypass and Sleeve Gastrectomy Are Comparable

17.01.2018 | Health and Medicine

Researchers identify new way to unmask melanoma cells to the immune system

17.01.2018 | Health and Medicine

Genetic discovery may help better identify children at risk for type 1 diabetes

17.01.2018 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>