Take a patient who has a virus whose very initials stand for Human Immunodeficiency Virus. Disable that virus with an infusion of the patient’s own immune cells, which have been genetically modified for HIV-resistance. Deliver it to the patient.
A team of Penn researchers recently conducted such a study of five HIV-positive patients, with encouraging results. One patient showed a “sustained decrease in viral load,” while the viral loads of two others showed a “significant decrease” and those of the other two remained stable. In addition, the number of T-cells, which help regulate the immune system, remained steady or increased in four of the patients.
“The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced,” explains Dr. Bruce Levine C’84, associate professor of pathology and laboratory medicine. “Essentially, the vector puts a wrench in the HIV-replication process.”
Furthermore, the study was the first demonstration of safety in humans for a lentiviral vector (a group that includes HIV) for any disease. The anti-HIV vector, known as VRX496, was produced by VIRxSYS, a private biotech company that “came to us knowing that we were one of the best labs in the world, if not the best, at growing T-lymphocytes,” says Levine. “They had the gene vector, or Trojan horse, but needed the expertise in T-lymphocyte ‘engineering,’ access to patients, and clinical and scientific expertise that we could provide at Penn.”
Each patient received one infusion of his or her owngene-modified T-cellsabout 10 billion of them, which is 2 to 10 percent of the number of T-cells in an average person.
“We were able to detect the gene-modified cells for monthsand, in one or two patients, a year or more later,” says Levine. “That’s significantshowing that these cells just don’t die inside the patient.”
“The goal of this Phase 1 trial was safety and feasibility, and the results established that,” says Dr. Carl June, professor of pathology and laboratory medicine. “But the results also hint at something much more.” Noting that another trial has already started that will “determine if multiple doses are safe,” June adds: “We need more results from our current trial to determine if the vector is working in two distinct mechanisms, which is our suspicion.”
The results of the study were published in the November 7, 2006 online edition of the Proceedings of the National Academy of Sciences. S.H.
Found in Translation: Cholesterol-Cutting Drug
About one person in a million suffers from homozygous familial hypercholesterolemia (FH), a genetic disorder that leads to abnormally high cholesterol levels. Left untreated, those who have the disorder often develop cardiovascular disease before they are 20 and seldom live past age 30. Existing cholesterol-lowering drugs are, for these patients, relatively ineffective.
Recently a team of Penn researchers showed that a new drug that inhibits the production of microsomal triglyceride transfer protein (MTP) is “highly effective in reducing cholesterol levels in these very high-risk patients,” in the words of Dr. Daniel Rader, the Cooper-McClure Professor of Medicine and director of preventive cardiovascular medicine who served as the study’s principal investigator.
The study, which appeared in the January 11 issue of The New England Journal of Medicine, is a “great example of ‘translational research,’” says Rader, referring to discoveries in basic science that are translated into new therapies. (Rader is also director of Penn’s Clinical and Translational Research Center.) In this case, scientists at the pharmaceutical firm Bristol-Myers Squibb, knowing that genetic defects in MTP lead to very low levels of the “bad cholesterol” known as low-density lipoprotein (LDL), were searching for compounds that could inhibit MTP. They discovered a drug (originally known as BMS-201038) and donated it to Penn for use in clinical trials made up of patients with severe cholesterol problems.
“Bristol-Myers Squibb concluded that it was unlikely to be a ‘blockbuster’ drug based on some mechanism-based increases in liver fat when given at relatively high doses,” explains Rader. “Once they decided to no longer develop it, I persuaded them to allow us to continue to study the compound in homozygous FH patients due to their very high risk and lack of other options. To BMS’ credit, they agreed to this, paving the way for our study.”
Rader and his Penn team designed and carried out the study in homozygous FH patients (with support from the Doris Duke Charitable Foundation). They found that the drug reduced LDL cholesterol by 51 percent, total cholesterol by 58 percent, triglyceride levels by 65 percent, and apolipoprotein B levels by 56 percent. Unlike statin drugs, the MTP inhibitor reduced the liver’s ability to produce LDL.
Penn has since licensed the drug to Aegerion Pharmaceuticals (on whose scientific advisory board Rader sits, and in which he holds an equity interest). Rader notes that Aegerion was formed “in light of the results of this study, in part with the idea that this compound might potentially be useful for two other types of patients: those unable to get their LDL cholesterol to goal despite being on maximal therapy, and those intolerant of statins.”
Another member of the Penn team, Dr. Marina Cuchel, will lead a follow-up study funded by the Food and Drug Administration’s “orphan drug” program.S.H.
Bending DNA No Problem at Nano-Scale
The image of the double-helix-shaped DNA molecule is one of elegantly twined curves. Yet its very structure has posed a conundrum to scientists.
“Common sense and physics seemed to tell us that DNA just shouldn’t spontaneously bend into such tight structures, yet it does,” says Dr. Philip Nelson, professor of physics, who recently led a team of scientists from the United States and the Netherlands to examine DNA in nano-scale detail. Even though DNA “constantly needs to bend, forming loops and kinks, as other molecules interact with it,” he says, “when people look at long chunks of DNA, it always seemed to behave like a stiff plastic rod.”
One example of its need to bend comes when DNA wraps itself around proteins, forming nucleosomes, which help regulate how genes are read, Nelson notes. “In the conventional view of a DNA molecule, wrapping DNA into a nucleosome would be like bending a yardstick around
Using high-resolution atomic-force microscopy, which enabled them to obtain a direct measurement of the energy it would take to bind lengths of DNA just a few nanometers long, Nelson and his colleagues found that DNA is a lot more flexible than scientists had previously believed. By dragging an extremely sharp tip across the contours of the molecule in order to create a picture of its structure, they were able to measure the energies needed to make bends in DNA at lengths of five to 50 nanometersabout a thousand times smaller than the diameter of a typical human cell. And those bends turned out to have 30 times as many curvatures as would have been expected using an earlier formula.
DNA has “different apparent properties when probed at short lengths than the entire molecule does when taken as a whole,” says Nelson. “Its resistance to large-angle bends at this scale is much smaller than previously suspected.”
Nelson, a member of Penn’s Nano/Bio Interface Center (which explores how the fields of nanotechnology, biology, and medicine intersect), notes that the nanoscale “just happens to also be the scale at which cell biology operates,” adding: “We’re entering an era when we are able to use the tools of nanotechnology to answer fundamental puzzles of biology.” S.H.
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