Before gene therapy
becomes practical for treating human diseases, researchers must master the
details of safe and effective delivery. Cardiology researchers at The
Children's Hospital of Philadelphia have advanced delivery techniques by
creating a versatile synthetic material that can bind to a variety of gene
therapy vectors and can be custom-designed for controlled local release of
therapeutic genes at a disease site.
In an animal study, the research team used their new synthetic
formulation to bind adenoviruses to bare metal stents, tiny metal scaffolds
inside the carotid arteries of rats. Adenovirus served as a gene therapy
vector to carry genes for an enzyme that significantly reduced restenosis,
the hazardous narrowing of a blood vessel that often occurs despite the
presence of a stent designed to hold it open.
Although the materials are in an early stage, the hope is that this
method may help to treat artery disease in people. "We developed a
synthetic gene delivery system that can be used for any gene therapy
vector, not just adenoviruses," said study leader Robert J. Levy, M.D., the
William J. Rashkind Chair of Pediatric Cardiology at The Children's
Hospital of Philadelphia. "Furthermore, this new formulation allows us to
increase the dosage of gene therapy vectors delivered, and we can tune the
materials for sustained release over a longer time period."
Levy's group reported its study this week in the online version of the
journal Circulation, published by the American Heart Association.
Over the past decade, stents have become increasingly useful in
treating constricted blood vessels in heart disease and in peripheral
artery disease. Stents, which expand partially blocked blood vessels to
improve circulation, may be made of bare metal or may have a coating of
polymers that release drugs.
Neither type is ideal. Polymer coatings cause inflammation in vessels,
which may lead to new bottlenecks at the same time the coating releases
drugs meant to reduce vessel injury. Bare metal stents produce less
inflammation, but without the benefit of drug delivery. Previously, in a
proof-of-principle study in animals, Levy's group attached to stents an
extremely thin layer of protein, one molecule thick, containing adenovirus
vectors that delivered genes that successfully inhibited restenosis.
However, that method had serious limitations; it operated only within a
narrow range of temperatures and acidity levels, and was useable only with
adenovirus vectors.
The new formulation, said Levy, is more robust, more controllable and
adaptable to any virus used as a gene therapy vector, not just
adenoviruses. His team synthesized three components into a complex that
tethers viral vectors to stent surfaces. One of the three components is an
amplifier that increases the dose of gene vector more than fourfold over
the previous formulation.
In addition, by varying another component, the stent can be tuned to
release vector at a controlled rate that can theoretically be tailored to a
schedule appropriate for the particular treatment. "Prior studies have
shown that 90 percent of the gene vector is released within 12 to 24 hours,
after which vessel blockages regrow," said Levy. "In this study, the stents
had significant coverage of the vector seven days later--and less
restenosis. Our goal is to customize the materials to allow peak release of
the vector when it can have the maximum benefit."
The adenovirus vector carries genes that code for inducible nitric
oxide synthase (iNOS), a protein that controls cell damage in blood
vessels. In the current study, the iNOS reduced restenosis by 56 percent in
the carotid arteries of treated rats, as compared with control animals.
Although this particular study used adenovirus vectors, said Levy, the
synthetic formulation could tether any other type of viral gene therapy
vector to the metal stents. It might also carry other therapeutic agents in
addition to gene vectors. Further studies, he added, will refine these
methods and investigate them in larger animal models that more closely
simulate human vessel disease.
The National Institutes of Health and the American Heart Association
provided grant support for the research. Levy's co-authors from The
Children's Hospital of Philadelphia are Ilia Fishbein, M.D., Ph.D.; Ivan
Alferiev, Ph.D.; Marina Bakay, Ph.D.; Stanley J. Stachelek, Ph.D.; Peter
Sobelewski, Ph.D.; Meizan Lai, M.D.; and from the University of
Pennsylvania School of Engineering and Applied Sciences, Hoon Choi, Ph.D.;
and I-W Chen, Ph.D.
About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking third in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit chop.
The Children's Hospital of Philadelphia
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