Sep. 20, 2000 GAINESVILLE, Fla.--When doctors prescribe a drug, they indicate what strength should be taken and how often. But when it comes to using DNA to try to treat diseases, scientists have yet to standardize the way they measure a dose of gene therapy medicine.
Experts say that's an enormous barrier to evaluating the safety and effectiveness of new treatments -- and may even have played a role in last year's widely publicized death of a patient in Pennsylvania.
As a step toward overcoming the problem, University of Florida Genetics Institute researchers are creating the nation's first benchmark supply of a gene therapy drug, which scientists from across the country will be able to use to compare and report the strength of their own investigational medicines.
Supported by a $75,000 grant from the National Institutes of Health, scientists here are culturing a batch of adeno-associated virus, which can be engineered to direct a payload of corrective genes into selected tissues. A common virus that has not been linked to any illness, the AAV "vector" can be modified to carry a wide variety of genes in an effort to treat numerous diseases, such as cystic fibrosis and hemophilia. UF is home to one of the few facilities in the world where the virus can be produced at very high concentrations with a high degree of purity.
The UF batch will be stored at a national repository after extensive scrutiny by experts at several universities and biotechnology companies. Scientists will be able to request a vial they can use to compare with their own AAV stock.
"From what we know, the potential safety concerns of gene therapy come not from the insertion of the genes themselves, but from the vector used to carry them into the body's cells," said Dr. Terence R. Flotte, interim director of UF's Genetics Institute and co-director of the Powell Gene Therapy Center.
"But a major problem in gene therapy is that it has been almost impossible to combine data from different research groups because laboratories use a variety of techniques for measuring the concentration and the effective quantity of the vector," he said. "These tests can result in different answers about how strong the vector is. If there are side effects that develop at a particular concentration, you may not begin to get a handle on that until you can figure out how to pool information from different studies."
Flotte suspects that if there had been such a reference stock for adenovirus, the vector involved in the Pennsylvania death, its potential for adverse effects may have been recognized sooner.
Dr. Richard Knazek, a medical officer for the National Center for Research Resources, a component of the NIH, said UF's effort to develop a national reference standard for AAV grew out of a workshop sponsored last year by the NIH and the U.S. Food and Drug Administration. The consensus among the experts in attendance was that a reference standard was necessary.
"There has to be a way for these trials to be comparable to each other, which has not been done before in gene therapy," Knazek said. "It's become apparent that this would require a lot of cooperation among investigators, so that there can be synergy on this important issue rather than competition."
A reference standard will help researchers better understand the strength of the gene therapy medicine they are inserting both in animal experiments and in human trials. For example, scientists elsewhere could use their own techniques for measuring infectious particles in both a sample of the UF standard and their own batch, then compare the two when they report experimental results. The standard also can help scientists gain a clearer understanding of safety study results published by other laboratories.
"This addresses safety and efficacy issues too, as scientists will be able to document with greater assurance how much vector is being injected into a patient," Knazek said.
In its natural state, AAV dwells problem-free in most adults. Recognizing the potential of AAV's apparent harmlessness, UF's Dr. Kenneth I. Berns and Nicholas Muzyczka, pioneered its use as a vector that could be modified to carry corrective genes into the body. Berns is UF's vice president for health affairs and dean of the College of Medicine. Muzyczka directs UF's Powell Gene Therapy Center. In addition to Muzyczka and Dr. Berns, Barry Byrne, a UF pediatric cardiologist, also will be involved in the reference standard effort.
The AAV vector is being used in a growing number of animal experiments as well as in clinical trials involving patients, such as the UF study testing gene therapy in cystic fibrosis patients at Shands at UF medical center. To date, no adverse effects have been reported in any of the AAV studies.
When UF has completed testing its national reference standard stock, it will forward samples to scientists at Harvard University, Ohio State University, the University of North Carolina and the University of Pennsylvania, and to three companies, Targeted Genetics Corp., Avigen Inc. and Genovo Inc. They will evaluate the samples to confirm their strength and purity. The reference stock then will be available through a national repository, likely within the next six months.
"Our original idea was to develop a reference standard so that small groups of scientists investigating rare diseases would not have to strain their resources by independently determining the safety of AAV," said Flotte, an associate professor of pediatrics at UF's College of Medicine. "The thought was that scientists would pool their safety data and be able to move quickly into clinical trials in patients. This idea is still valid, but the very heightened concern about the safety of gene therapy adds another dimension to the reference standard effort."
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