Using customized nanoparticles that they developed, UB scientists have for
the first time delivered genes into the brains of living mice with an
efficiency that is similar to, or better than, viral vectors and with no
observable toxic effect, according to a paper published this week in
Proceedings of the National Academy of Sciences.
The paper describes how the 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 delivering therapeutic genes to repair malfunctioning brain
cells, the nanoparticles also provide promising models for studying the
genetic mechanisms of brain disease.
"Until now, no nonviral technique has proven to be as effective as the
viral vectors in vivo," said co-author Paras N. Prasad, executive director
of the Institute for Lasers, Photonics and Biophotonics, SUNY Distinguished
Professor in the Department of Chemistry and principal investigator of the
institute's nanomedicine program. "This transition, from in vitro to in
vivo, represents a dramatic leap forward in developing experimental,
nonviral techniques to study brain biology and new therapies to address
some of the most debilitating human diseases."
Viral vectors for gene therapy always carry with them the potential to
revert to wild-type, and some human trials have even resulted in fatalities.
As a result, new research focuses increasingly on nonviral vectors, which
don't carry this risk.
Viral vectors can be produced only by specialists under rigidly controlled
laboratory conditions. By contrast, the nanoparticles developed by the UB
team can be synthesized easily in a matter of days by an experienced chemist.
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.
A key advantage of the UB team's nanoparticle is its surface functionality,
which allows it to be targeted to specific cells, explained Dhruba J.
Bharali, a co-author on the paper and postdoctoral associate in the
Department of Chemistry and Institute for Lasers, Photonics and Biophotonics.
While they are easier and faster to produce, nonviral vectors typically
suffer from very low expression and efficacy rates, especially in vivo.
"This is the first time that a nonviral vector has demonstrated efficacy in
vivo at levels comparable to a viral vector," Bharali said.
In the experiments, targeted dopamine neurons?which degenerate in
Parkinson's disease, for example?took up and expressed a fluorescent marker
gene, demonstrating the ability of nanoparticle technology to deliver
effectively genes to specific types of cells in the brain.
Using a new, optical-fiber in vivo imaging technique (CellviZio developed
by Mauna Kea Technologies of Paris), the UB researchers were able to
observe the brain cells expressing genes without having to sacrifice the
animal.
The researchers then decided to go one step further: to see if they could
not only observe, but also manipulate the behavior of brain cells.
Their finding that the nanoparticles successfully altered the development
path of neural stem cells is especially intriguing because of scientific
concerns that embryonic stem cells may not be able to function correctly
since they have bypassed some of the developmental stages 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, co-author
on the paper and associate professor of pathology and anatomical sciences
in the School of Medicine and Biomedical Sciences. Stachowiak is in charge
of in vivo studies at the Institute for Lasers, Photonics and Biophotonics.
"It's likely that these stem/progenitor cells will grow into healthy
neurons," he said.
"In the future, this technology may make it possible to repair neurological
damage caused by disease, trauma or stroke," said Earl J. Bergey, co-author
and deputy director of biophotonics at the institute.
The group's next step is to conduct similar studies in larger animals.
The research was supported by the John R. Oishei Foundation, the National
Science Foundation, the American Parkinson Disease Association and UB's New
York State Center of Excellence in Bioinformatics and Life Sciences.
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