Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers engineer virus that blocks common genetic defect

19.09.2002


Scientists for the first time have engineered a harmless virus to correct, rather than replace, the genetic defect causing the most common single gene disorder.



The new research presents a novel approach to gene therapy in treating the most common inherited anemias: the thalassemias. Thalassemias are genetic blood diseases that result in failure to produce sufficient hemoglobin, the oxygen-carrying protein component of blood cells. This failure is caused by defects in the genetic code responsible for the production of this protein.

Scientists have explored gene therapy for these disorders for more than 20 years; only recently has this area seen a glimmer of hope. The report from the University of North Carolina at Chapel Hill is slated to appear in the Dec. 15 issue of Blood, the journal of the American Society of Hematology, and is currently online at www.bloodjournal.org.


"This research offers a new way to treat the thalassemias, by blocking a deleterious process that causes several forms of the disease," said senior study author Dr. Ryszard Kole, professor of pharmacology, and a member of UNC Lineberger Comprehensive Cancer Center and the curriculum in genetics and molecular biology at the UNC School of Medicine.

The thalassemias are caused by a variety of different mutations in the globin gene, many of which adversely affect a process known as RNA splicing.

Three billion bases - molecules that constitute DNA - form the human genome. Only a small percentage actually code for the gene products necessary for existence. These small coding regions are like words that make sense in a long continuous string of gibberish, which must be spliced out to create a meaningful message that can then be read to make the corresponding protein. Short sequences at the border between the sense and nonsense regions, called splice sites, tell the splicing machinery where to cut, where to paste and what information can be disregarded.

Some mutations can affect splicing by creating additional splice sites in places where they should not occur. Even though the correct splice sites are still intact, the splicing machinery preferentially recognizes the incorrect splice sites, resulting in the inclusion of extra, noncoding sequences, which interfere with subsequent production of hemoglobin. Kole and colleagues found that using molecules designed to bind specific regions of RNA to block aberrant splice sites could prevent splicing machinery from using those sites.

With the aberrant sites blocked, the splicing machinery goes back to the original, correct splice sites and uses these to cut and paste the correct globin message.

"In our approach the defect in the RNA is ’masked,’ thereby effectively ’repaired.’ This is different from replacing the gene with a good copy, which will then produce additional RNA and hemoglobin," Kole said. "Since we only repair the existing RNA, we do not need to worry that too much of the good thing will be made. This can sometimes be harmful."

In collaboration with Dr. Tal Kafri, co-senior author of the study, assistant professor of microbiology and immunology and a member of the Gene Therapy Center, the antisense sequences were incorporated into a lentiviral vector.

"Lentiviral vectors appear to be the most attractive vehicles to carry therapeutic genes into non-dividing target cells such as the hematopoietic stem cells," Kafri said. "Gene delivery into these cells allows us to reconstitute a patient’s bone marrow with vector-corrected stem cells that confer a lifelong remedy. The use of antisense technology coupled with these lentiviral vectors allows us to propel this field forward in the treatment of hematopoietic disorders."

In the UNC study, the genetically modified lentiviral vector was used to treat blood cells obtained from a thalassemic patient. The treatment partially restored correct splicing in the cells and resulted in a marked increase in correct hemoglobin protein. "The results are very encouraging because even hemoglobin levels that reach less than 50 percent of normal can have a therapeutically relevant effect," said Kole.

The antisense technology explored in this study is not limited to thalassemia. The finding that the human genome comprises far fewer genes than previously thought suggests that the complexity of human beings must arise from mechanisms of gene regulation, such as splicing. According to current estimates, at least 60 percent of the human genes may be alternatively spliced.

"We have been successful in the laboratory in shifting the aberrant splicing of a few other genes involved in genetic disorders and cancer," said Kole. "With the discovery that thousands of genes are spliced, as far as potential targets for this new form of gene therapy are concerned, the sky’s the limit."

Along with Kole and Kafri, UNC co-authors include Marla M. Vacek, first author of the study and a doctoral student in the curriculum in genetics and molecular biology, and Hong Ma, a researcher in the Gene Therapy Center.

Leslie Lang | EurekAlert!
Further information:
http://www.bloodjournal.org/papbyrecent.shtml.

More articles from Health and Medicine:

nachricht How cancer metastasis happens: Researchers reveal a key mechanism
19.01.2018 | Weill Cornell Medicine

nachricht Researchers identify new way to unmask melanoma cells to the immune system
17.01.2018 | Duke University 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: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

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...

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

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

Method uses DNA, nanoparticles and lithography to make optically active structures

19.01.2018 | Materials Sciences

More genes are active in high-performance maize

19.01.2018 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>