Tiny, magnetic spheres may help overcome gene therapy hurdle

The average person’s heart pumps about a gallon of blood per minute, a rate that can easily triple or quadruple during exercise.

The rapid flow of blood through the body is a major roadblock to the use of gene therapy to cure diseases. When injected into the blood, vector viruses – which carry corrective genes – tend to shoot past the target organ or tissue rather than sticking to it, like grains of sand moving past stones in a fast-flowing river.

Now, University of Florida gene therapy and biomedical engineering researchers have demonstrated a novel approach to the problem. In a July article in Molecular Therapy, they report attaching the adeno-associated virus, a widely used gene carrier, to the surface of tiny manufactured balls known as microspheres, each containing a miniscule particle of iron oxide. Using a magnet placed under culture dishes, the researchers were able to coax large amounts of the microspheres to target areas of the cultures. In related experiments in mice, the researchers showed the microspheres clung to cells or organs longer than the virus alone did.

The procedure, reminiscent of the toy that moves magnetized objects beneath transparent plastic, could someday evolve into a treatment that would enable doctors to guide corrective gene-containing microspheres injected into a patient with magnets placed outside the skin. Such procedures, could, for example, replace invasive catheterizations used to treat lung and heart diseases, the researchers said.

“By packaging the virus with the microsphere, we both guided it to the targeted area and got it to stick there,” said Barry Byrne, the lead researcher and a pediatric cardiologist with the UF College of Medicine who is affiliated with the UF Genetics Institute.

Byrne and Cathryn Mah, an assistant research professor in the department of pediatrics, collaborated on the project with UF colleagues in pharmaceutics, genetics, and materials science and engineering. The effort, partially funded by the Whitaker Foundation, is part of UF’s growing biomedical engineering initiative involving a wide range of medical and engineering researchers.

Byrne said the adeno-associated virus, a virus that is an ideal gene carrier because it is not associated with any disease, is expensive and time consuming to manufacture in quantity. As a result, if it is ever to be widely used in treating disease, clinicians must have the ability to bind it specifically to the organ, tissue or cells they hope to treat, instead of having it dispersed through the body thus diminishing its effect.

“There is no way you could provide a systemic therapy spread throughout the body if you were only after the kidney, for example,” said Byrne, of UF’s Powell Gene Therapy Center. “That even applies to dosing a mouse. Gene therapies are actually unachievable without some type of targeting.”

It also is important to avoid unintentional release of therapeutic genes into reproductive cells in part so that engineered genes are not passed on to children, effectively altering the human genome, Byrne said. Proof that therapeutic genes do not spread beyond their targets – such dispersion could cause tumors in non-targeted cells – is one of the Food and Drug Administration’s main criteria for approving gene therapies, he said.

Mah said the UF team’s experiments were conducted over a period of about two years, much of that time devoted to the experiments in mice. In one experiment, the team injected the virus-coated microspheres into the tail veins of three mice and the free virus into the tail veins of three others. They monitored what happened by tracking “marker” proteins produced by the virus. The procedure was similar with cell cultures containing either the free virus or the virus-coated microspheres, with the researchers tracking the marker proteins through a technique called fluorescence microscopy, in which the proteins appear fluorescent green.

The results were impressive. The mice tail vein experiments revealed 10 times the expression of the marker protein in the target organ – the lung – than in other organs, indicating the microspheres both could be targeted and made to reside longer in their target than the free virus. In the cell cultures, meanwhile, the researchers achieved more than 100 times the expression of the marker protein in the magnetized areas of the culture versus the others.

“If you think about it in terms of making doses, it might take about six months to make a single-patient dose of this vector currently,” Byrne said. “If this works, I’d say we could do it in four to six weeks or even less.”

The microspheres used in the experiment were polystyrene, a type of plastic. In order for the spheres to be used in actual treatment, they would have to be made of biodegradable materials, said Chris Batich, a UF professor of materials science and engineering and biomedical engineering and member of the team. Although he said he has created such biodegradable microspheres since the project was first launched, they have yet to be tested. Among other challenges, researchers will have to prove the microspheres are harmless, efficient and predictable before they can be considered for use in clinical treatment, he said.

“You have to make sure they have the right properties,” he said. “They have to have enough iron oxide to be pulled by the magnetic field, and you have to make sure they have the right rate of degradation, whether its two hours or two weeks.”

Writer: Aaron Hoover, ahoover@ufl.edu
Sources: Barry Byrne, (352) 846-1531, bbyrne@ufl.edu
Chris Batich, (352) 392-6630,cbati@ufl.edu

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