Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene therapy a step closer to mass production

25.06.2010
Researchers in Latvia and Finland have synthesised and studied a range of organic compounds able to carry genetic material into individual cells where it can remedy the diseases caused by defective genes. Still under development, these compounds are much more readily produced than the viral carriers now in use and avoid their side-effects. Most importantly, they are much more effective than other organic carrier substances developed so far.

EUREKA project E! 3371 Gene Transfer Agents has made great advances in the development of novel non-viral carriers able to introduce genetic material into the target cells. These new agents, derivatives of cationic amphiphilic 1,4-dihydropyridine (1,4-DHP), avoid the problems of the recipient’s immune system reacting against a viral carrier.

The project partners have developed methods to produce them in large amounts, which solves another of the problems with viral delivery. But the greatest advantage is that the new compounds are significantly more effective at delivering DNA into cell nuclei than other standard synthetic carriers; increasing the chance of the DNA successfully controlling the defective genes, and the disease.

Gene therapy involves the insertion of DNA into human cells within the body to treat disease. The technique is still in its early days, and has been demonstrated successfully only in the last decade. Most investigation has been into the possibilities for treating hereditary diseases related to a genetic defect, and the technique also has potential uses in treating the early stages of cancer, and in cardiovascular and neurodegenerative diseases.

Gene therapy faces many difficulties as a practical method; not the least of which is that DNA is a large and complicated structure which needs to be delivered and attached to the correct section of the recipient’s set of DNA. A number of methods are in use or under investigation for introducing DNA into cells (a process known as transfection) – using viruses, chemical agents or physical injection.

"The big, open molecules of DNA collapse and combine with the organic carrier molecules to make very tiny particles. When you give these particles to the cells, they bind to the cells in such a way that the cell is almost eating them – it folds in around the particles in a vesicle."
Professor Arto Urtti, University of Helsinki Centre for Drug Research ,FinlandViruses or chemical carriers

With viral carriers, the DNA to be introduced is injected into the virus, which carries it into the cell by way of a vesicle formed around the virus particle by the cell wall. Once inside the cell, the vesicle breaks down and the virus injects the DNA into the cell’s nucleus. The viral route does, however, have major disadvantages. The immune system of the person receiving treatment often interferes with viral activity; and viruses can have unpredictable mutagenic side-effects. Also large-scale production of viral vectors is problematic.

A wide range of chemical agents are already known to be able to form a complex of 1,4-DHP with DNA and deliver it into the recipient’s cells. These agents are much easier to produce on a large scale than viruses and do not usually cause an immune response. However they are not so effective at introducing the DNA as the viral carriers.

Seeking the best of both worlds

The challenge facing the partners in the EUREKA project was to combine the effectiveness of the viral vectors with the production advantages and lack of immune response shown by chemical agents. Scientists at the Latvian Institute of Organic Synthesis and the University of Kuopio in Finland had discovered new groups of possible DNA transfer agents: 1,4-DHP derivatives. These compounds were found to be more effective in gene transfer than two widely-used standard gene delivery agents (known as DOTAP and PEI 25) and the discovery was covered by a patent. This finding offered the exciting prospect of better efficiency from a non-viral carrier.

“We have significantly widened the potential uses of self-assembling 1,4-dihydropyridine derivatives into nanomedicine, gene delivery and even into drug delivery systems.”

Dr Arkadijs Sobolevs,Latvian Institute of Organic Synthesis,LatviaProfessor Arto Urtti of Helsinki University (formerly from Kuopio) explains: “When these compounds are in solution and DNA is added, they bind together. The large, loose DNA molecule collapses and tiny particles of about 10-50nm in diameter are formed, composed of both DNA and carrier. When you present this to the cells, the nanoparticles bind to the cell surface, which folds inwards to form a vesicle within the cell. The particles then escape from the vesicle, releasing the DNA.”

Researchers at Helsinki University found that out of all the compounds tested, the most effective were those which succeeded in transferring DNA into the nucleus. The mechanism by which the DNA enters the nucleus is not yet clearly understood, but it is known that gene transfer is more effective in cells which are actively dividing, e.g. cancer cells.

Dr Aiva Plotniece, Dr Arkadijs Sobolevs and their colleagues at the Latvian Institute then set out to synthesise dozens of different DHP derivative compounds. Dr Plotniece comments: “The great advantage of these compounds is the biologically active 1,4-DHP fragment, which with proper substitution, can show certain biological and physico-chemical properties. During the project we have designed different 1,4-DHPs, which allowed us to establish structure-activity relationships.”

“This project was very helpful for us in building a new research group and in developing fruitful international collaboration.”

Dr Aiva Plotniece,Latvian Institute of Organic Synthesis,LatviaThe third project partner, the independent Latvian chemical producer Bapeks, contributed its experience of larger-scale synthesis and advised the Latvian Institute researchers on how best to scale up the synthesis methodology. The compounds were then distributed to a number of other research colleagues in Latvia, Finland and Lithuania for further study. At present, project partners feel that the main uses will be in laboratory experiments, and much further research is needed before they can be used for gene transfer in the human body.

Partners in the EUREKA project believe that although more research is needed, the project has been very successful. “It was the first big, important project for us” says Dr Sobolevs. “We have significantly widened the potential uses of self-assembling 1,4-dihydropyridine derivatives into nanomedicine, gene delivery and even into drug delivery systems.” The project team found that EUREKA support helped greatly in preparing, managing and reporting the project. It was also through EUREKA that the other partners were introduced to Bapeks.

Piotr Pogorzelski | EurekAlert!
Further information:
http://www.eurekanetwork.org

More articles from Life Sciences:

nachricht A novel synthetic antibody enables conditional “protein knockdown” in vertebrates
20.08.2018 | Technische Universität Dresden

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

There are currently great hopes for solid-state batteries. They contain no liquid parts that could leak or catch fire. For this reason, they do not require cooling and are considered to be much safer, more reliable, and longer lasting than traditional lithium-ion batteries. Jülich scientists have now introduced a new concept that allows currents up to ten times greater during charging and discharging than previously described in the literature. The improvement was achieved by a “clever” choice of materials with a focus on consistently good compatibility. All components were made from phosphate compounds, which are well matched both chemically and mechanically.

The low current is considered one of the biggest hurdles in the development of solid-state batteries. It is the reason why the batteries take a relatively long...

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

A novel synthetic antibody enables conditional “protein knockdown” in vertebrates

20.08.2018 | Life Sciences

Metamolds: Molding a mold

20.08.2018 | Information Technology

It’s All in the Mix: Jülich Researchers are Developing Fast-Charging Solid-State Batteries

20.08.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>