Biodegradable Polymers Developed for Safer Gene Therapeutic Applications

In a project that could lead to safer and more effective techniques for gene therapy, investigators have found a way to modify the ability of biodegradable polymers to deliver genes.

Gene therapy, which involves inserting new genes into patients' cells to combat diseases including cancer, has a lot of possibilities but has yet to realize its full potential, partly because of safety concerns over the traditional technique of using viruses to carry the genes.

The new study, performed by scientists from the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA), and published in the September 2007 issue of the journal Advanced Materials, focuses on creating gene carriers from synthetic, non-viral materials. The team was led by Dr. Daniel Anderson, research associate in MIT's Center for Cancer Research.

"What we wanted to do is start with something that's very safe--a biocompatible, degradable polymer--and try to make it more effective, instead of starting with a virus and trying to make it safer,” said Jordan Green, an MIT graduate student in biological engineering and co-first author of the article.

Gene therapy has been a field of intense research for nearly 20 years. More than 1,000 gene-therapy clinical trials have been conducted, but to date there are no U.S. Food and Drug Administration- (FDA)-approved gene therapies. Most studies utilize viruses as carriers, or vectors, to deliver genes.

However, there are risks associated with using viruses. As a result, many researchers have been working on developing non-viral techniques to deliver therapeutic genes. The MIT scientists focused on three poly(beta-amino esters), or chains of alternating amine and diacrylate groups, which had shown potential as gene carriers. They hoped to make the polymers even more effective by modifying the very ends of the chains.

When combined these polymers can spontaneously assemble with DNA to form nanoparticles. The polymer-DNA nanoparticle can act in some ways similar to an artificial virus and deliver functional DNA when injected into or near the targeted tissue. The researchers developed methods to rapidly optimize and evaluate new polymers for their ability to form DNA nanoparticles and deliver DNA. They then chemically modified the very ends of the degradable polymer chains, using a library of different small molecules.

"Just by changing a couple of atoms at the end of a long polymer, one can dramatically change its performance,” said Dr. Anderson. "These minor alterations in polymer composition significantly increase the polymers' ability to deliver DNA, and these new materials are now the best non-viral DNA delivery systems we've tested.”

The polymers have already been shown to be safe in mice, and the researchers hope to eventually run clinical trials with their engineered polymers, according to Dr. Anderson. Non-viral vectors could prove not only safer than viruses but also more effective in some cases. The polymers can carry a larger DNA load than viruses, and they may avoid the immune system, which could allow multiple therapeutic applications if needed, according to the researchers.

One promising line of study involves ovarian cancer, where the MIT researchers, working with Drs. Janet Sawicki at the Lankenau Institute for Medical Research (Wynnewood, PA, USA), have demonstrated that these polymer-DNA nanoparticles can deliver DNA at high levels to ovarian tumors without harming healthy tissue.


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Massachusetts Institute of Technology