Nanoparticles Used To Deliver Gene Therapy

According to a paper published this week inProceedings of the National Academy of Sciences, scientists say they have superseded previous methods of gene delivery into living organisms, without the usual side-effects. Instead of using potentially toxic and unstable viral vectors, University of Buffalo (UB) scientists developed and customized nanoparticles that they successfully used to deliver genes into the brains of living mice. The new findings build onprevious research from the same institution.

The new paper describes how the UB scientists used gene-nanoparticle complexes to activate adult brain stem/progenitor cells in-vivo, demonstrating that it may be possible to “turn on” these otherwise idle cells as effective replacements for those destroyed by neurodegenerative diseases, such as Parkinson’s. In addition to repairing damaged brain cells, UB researchers say that the nano-particles provide promising models for studying the genetic mechanisms of brain disease.

“Until now, no non-viral technique has proven to be as effective as the viral vectors in-vivo,” said study co-author Paras N. Prasad, principal investigator with the University’s nanomedicine program. “This transition, from in-vitro to in-vivo, represents a dramatic leap forward in developing experimental, non-viral techniques to study brain biology and new therapies to address some of the most debilitating human diseases.” Viral vectors are benign lab modified viruses used to delivery therapeutic tumor antigens that cause the immune system to make a specific immune response.

Viral vector gene therapy always carries with it the risk that the virus will revert back to its previous deadly state, with some human trials even resulting in fatalities. As a result, new research focuses increasingly on non-viral vectors, which don’t carry this risk.

As a result, UB’s latest advance in gene therapy has made life a lot less difficult for scientists developing in-vivo delivery systems. Only specialists under rigidly controlled laboratory conditions can produce viral vectors. By contrast, the nanoparticles developed by the UB team can be synthesized easily in a matter of days by an experienced chemist.

While previous non-viral vectors were easier and faster to produce, they typically suffered from very low expression and efficacy rates, especially in-vivo. The UB researchers make their nanoparticles from hybrid, organically modified silica (ORMOSIL), the structure and composition of which allow for the development of an extensive library of tailored nanoparticles to target gene therapies for different tissues and cell types. This is a key advantage of the UB team’s nanoparticle, as its surface functionality allows it to be targeted to specific cells, explained Dhruba J. Bharali, a co-author on the paper. “This is the first time that a non-viral vector has demonstrated efficacy in-vivo at levels comparable to a viral vector.”

In the UB experiments, targeted dopamine neurons – which degenerate in Parkinson’s disease – took up and expressed a fluorescent marker gene, demonstrating the ability of nanoparticle technology to effectively deliver genes to specific types of cells in the brain. Then, the UB researchers decided to go one step further, to see if they could not only observe, but also manipulate the behavior of brain cells. Importantly, the nanoparticles successfully altered the development path of neural stem cells. Previously, scientists were uncertain whether embryonic stem cells would be able to function correctly, having bypassed some of the developmental stages that cells normally go through.

“What we did here instead was to reactivate adult stem cells located on the floor of brain ventricles, germinal cells that normally produce progeny that then die if they are not used,” said Michal K. Stachowiak, a co-author at the UB School of Medicine and Biomedical Sciences. “It’s likely that these stem/progenitor cells will grow into healthy neurons,” he said.

The researchers are upbeat about the future of this technology, with further studies on larger animals planned. “In the future, this technology may make it possible to repair neurological damage caused by disease, trauma or stroke,” they concluded.

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