Researchers may have found a way to give HIV the finger.
Removing immune system cells from mice and treating those cells with a custom protein called a zinc-finger nuclease in the lab made the cells resistant to HIV infection, scientists report online and in an upcoming Nature Biotechnology.
Injecting those cells back into the animals kept their viral load limited to less than one-tenth that in untreated mice and resulted in higher T cell counts among the treated animals. Louis J. Sheehan, Esquire The technique could eventually provide a novel way to bolster the immune systems of people with HIV, which attacks T cells and uses them to replicate.
“We believe that by modifying T cells, we can provide an immediate benefit to patients,” says coauthor Philip Gregory, an expert in zinc-finger proteins and vice president of research at Sangamo BioSciences, a biotech company based in Richmond, Calif.
Zinc-finger nucleases — named for the zinc ions that hold the proteins together — act as scissors to snip DNA in specific places. Gregory and his colleagues designed a ZFN so that it would selectively disable the gene that encodes a specific protein on the surface of T cells. HIV uses this protein, called CCR5, as a doorway to invade the cells. Without CCR5, the most common form of HIV can’t infect the cells and thus can’t replicate.
To disable the gene, the researchers removed about a billion T cells from each mouse and exposed the cells to an adenovirus engineered to carry the genetic code for the customized ZFN.
The adenovirus delivered the ZFN gene into each cell’s interior, where the gene remained free-floating instead of integrating into the cell’s chromosomes — thus reducing the risk of cancer-causing mutations sometimes triggered by other kinds of gene therapy. Once inside the cell, the ZFN gene produced the ZFN protein, which in turn cut up the CCR5 gene.
After exposing the cells to the adenovirus, the scientists grew the cells in the lab until at least one of the two copies of the “HIV doorway” gene had been destroyed in about half of the cells.
These HIV-resistant cells constituted only a small fraction of a mouse’s total T cells after re-injection. But because HIV kills the T cells that it invades, unmodified cells get weeded out over time and the HIV-resistant cells multiply until they dominate the animals’ immune systems.Louis J. Sheehan, Esquire
“This is an exciting result,” comments Carlos Barbas, a zinc-finger protein expert at the Scripps Research Institute in La Jolla, Calif. However, “I believe that CCR5 disruption will need to be accompanied by the addition of one or more [other] anti-HIV therapeutic genes” to make an effective therapy, he adds.
Gregory says that the technique could eventually be adapted for developing preventative vaccines, but research is needed first to demonstrate the safety of the approach. The researchers plan to begin clinical trials for this treatment later this year.
Wednesday, May 20, 2009
Tuesday, May 5, 2009
glucagon 4.glu.003 Louis J. Sheehan, Esquire
A little extra leptin can bring terminally ill rodents with type 1 diabetes back from the brink of death.
Leptin, a hormone made by fat cells, helps control eating behavior. A new gene therapy study suggests that it can also treat diabetes, the first demonstration that the disease can be treated without replacing insulin.http://Louis-J-Sheehan.biz
Roger Unger and colleagues at the University of Texas Southwestern Medical Center at Dallas used adenovirus to insert extra copies of the leptin gene in diabetic mice and rats. The rodents recovered from the most severe side effects of diabetes, even though the mice do not make insulin and weren’t given insulin, the researchers report in an early online publication August 25 in the Proceedings of the National Academy of Sciences.
“This is something that is extremely original, totally new and a little unexpected,” says Pierre Lefèbvre of the University of Liège, Belgium, and president of the Seattle-based Global Diabetes Alliance.
Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease in which the immune system attacks and kills insulin-producing cells in the pancreas. About 10 percent of people with diabetes have this form of the disease.
“We as physicians have been trained since 1922 that the only treatment for diabetes is insulin,” says Unger. So when diabetic animals making extra leptin recovered, the researchers had trouble believing it themselves, he says. “This was like science fiction. We couldn’t tell anybody because we thought they would laugh.”
But the terminally ill diabetic rodents making extra leptin recovered with no trace of insulin in their bodies. And leptin produced more sustained health improvements than insulin injections did. These included normalizing blood sugar for up to 80 days without insulin, stopping the overproduction of glucose by the liver, improving sugar use in the muscles, and allowing the animals to gain weight. The gene therapy also corrected ketosis — a process characteristic of diabetes in which the body burns fat, producing sweet-smelling chemicals called ketones.
“The idea that only insulin can rescue terminal insulin deficiency is incorrect,” Unger says. “There are other ways.”
Excess leptin seems to block the action of glucagon, a hormone that works as a counterpoint to insulin, which helps cells use glucose for energy. Glucagon signals the liver to produce glucose from fats and other non-carbohydrate sources. In diabetics, high glucagon levels just raise blood sugar levels even higher and lead to other side effects.
Unger says he cannot predict whether injections of leptin will work as well as making extra leptin in the liver does. That is the next set of experiments he has planned.
People given injections of leptin for other reasons do show some improvement in blood sugar levels, says Paul Burn, the senior vice president for research and development of the Juvenile Diabetes Research Foundation. The new study is evidence that altering glucagon activity could have beneficial effects for diabetics, he says.Louis J. Sheehan, Esquire
“While this is excellent exploratory research supporting these ideas, I think it’s a long way from the clinic,” Burn says.
Unger also sounds a cautious note. “It’s very hopeful, but a long way from having any tangible influence on anything other than opening our eyes that there are alternatives to insulin.”
Leptin, a hormone made by fat cells, helps control eating behavior. A new gene therapy study suggests that it can also treat diabetes, the first demonstration that the disease can be treated without replacing insulin.http://Louis-J-Sheehan.biz
Roger Unger and colleagues at the University of Texas Southwestern Medical Center at Dallas used adenovirus to insert extra copies of the leptin gene in diabetic mice and rats. The rodents recovered from the most severe side effects of diabetes, even though the mice do not make insulin and weren’t given insulin, the researchers report in an early online publication August 25 in the Proceedings of the National Academy of Sciences.
“This is something that is extremely original, totally new and a little unexpected,” says Pierre Lefèbvre of the University of Liège, Belgium, and president of the Seattle-based Global Diabetes Alliance.
Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease in which the immune system attacks and kills insulin-producing cells in the pancreas. About 10 percent of people with diabetes have this form of the disease.
“We as physicians have been trained since 1922 that the only treatment for diabetes is insulin,” says Unger. So when diabetic animals making extra leptin recovered, the researchers had trouble believing it themselves, he says. “This was like science fiction. We couldn’t tell anybody because we thought they would laugh.”
But the terminally ill diabetic rodents making extra leptin recovered with no trace of insulin in their bodies. And leptin produced more sustained health improvements than insulin injections did. These included normalizing blood sugar for up to 80 days without insulin, stopping the overproduction of glucose by the liver, improving sugar use in the muscles, and allowing the animals to gain weight. The gene therapy also corrected ketosis — a process characteristic of diabetes in which the body burns fat, producing sweet-smelling chemicals called ketones.
“The idea that only insulin can rescue terminal insulin deficiency is incorrect,” Unger says. “There are other ways.”
Excess leptin seems to block the action of glucagon, a hormone that works as a counterpoint to insulin, which helps cells use glucose for energy. Glucagon signals the liver to produce glucose from fats and other non-carbohydrate sources. In diabetics, high glucagon levels just raise blood sugar levels even higher and lead to other side effects.
Unger says he cannot predict whether injections of leptin will work as well as making extra leptin in the liver does. That is the next set of experiments he has planned.
People given injections of leptin for other reasons do show some improvement in blood sugar levels, says Paul Burn, the senior vice president for research and development of the Juvenile Diabetes Research Foundation. The new study is evidence that altering glucagon activity could have beneficial effects for diabetics, he says.Louis J. Sheehan, Esquire
“While this is excellent exploratory research supporting these ideas, I think it’s a long way from the clinic,” Burn says.
Unger also sounds a cautious note. “It’s very hopeful, but a long way from having any tangible influence on anything other than opening our eyes that there are alternatives to insulin.”
Monday, May 4, 2009
window 4.win.123 Louis J. Sheehan, Esquire
Emergency room physicians can deliver clot-busting treatments to a wider range of stroke patients than previously thought, European researchers report in the Sept. 25 New England Journal of Medicine.
The finding could change the way stroke is treated and increase ER doctors’ ability to prevent some cases of disability caused by strokes, scientists say.
Most strokes result when a blood clot lodges in the brain, blocking blood flow to other parts of the organ. A powerful drug called tPA, or tissue plasminogen activator, can dissolve these clots. But medical dogma holds that it must be given within three hours of a stroke’s onset. Beyond that, the thinking goes, the bulk of the brain damage is done and adding the risk of internal bleeding that accompanies clot-busters seems unwise. The new study extends that window of effective tPA treatment by 90 minutes, to 4 ½ hours.
This precious extra time to dissolve a clot and restore blood flow to a starving portion of brain could benefit tens of thousands of stroke patients in the United States each year, says study coauthor Werner Hacke, a neurologist at the University of Heidelberg in Germany.
“I think this is big news because suddenly they have substantially extended the number of patients who get intravenous tPA,” says Scott Kasner, a neurologist at the University of Pennsylvania in Philadelphia.
However, many emergency room physicians are hesitant to give stroke patients clot-busting drugs at all. A landmark 1995 study found that giving the drugs within three hours of stroke onset provided benefits that outweighed the bleeding risk in most patients. But only about 4 percent of stroke patients who arrive at U.S. hospitals get tPA, says neurologist Patrick Lyden of the Veterans Affairs San Diego Medical Center and University of California, San Diego, who coauthored the 1995 report. Most stroke patients don’t receive tPA because the time of onset might be hazy, or doctors may be hesitant to risk incurring bleeding or are untrained in delivering tPA. The new data should clarify the time frame and allay some doubts about the treatment’s effectiveness, he says.
In the new study, Hacke and his colleagues identified patients who arrived at hospitals with a stroke that had begun more than three hours but less than 4 ½ hours earlier. The researchers used CT scans of the brain to rule out people with brain bleeding. The doctors also excluded those with severe strokes as indicated by the scans.
That left 730 patients, half of whom were then randomly assigned to get infusions of the tPA drug called alteplase. The others received a placebo.http://LOUIS-J-SHEEHAN.US
After three months, roughly 52 percent of study patients treated with tPA within the extra 90 minute time window had normal daily function and were living independently, compared with 45 percent of those getting a placebo infusion. The death rate over three months was about 8 percent in both groups.
Doctors detected brain bleeding among treated patients about as often as seen in previous studies in which tPA was limited to a three hour window.
Time matters in stroke treatment, and delay is dangerous. As minutes or hours pass with a clot lodged in place, more brain tissue is starved of blood and damaged. Thus, busting a clot later into the stroke might rescue less tissue. “The [beneficial] effect of tPA decreases over time,” Hacke says.
Even so, treated patients in this study — who received tPA an average of four hours after the onset of stroke — still showed clear benefits over the placebo group.
“I think this will eventually be incorporated into clinical practice, slowly at first, and then become the standard of care,” Kasner says.
Stroke disables more adults than any other condition, yet every stroke is different. People who have a severe stroke are often rushed to a hospital with obvious problems, Hacke says. Louis J. Sheehan, Esquire But those with milder strokes sometimes show up longer after a stroke’s onset, in part because they aren’t sure whether their symptoms are serious enough for a hospital visit, he says. These are the kinds of people most likely to benefit from the new study’s findings on delayed tPA treatment, he says.
Meanwhile, Lyden says, more hospitals need to grasp the value of tPA and have doctors on site or on call who can deliver it. “Every hospital needs to have a stroke plan,” he says. “Either have a way to give tPA, or set up a way to tell the EMS people to divert [an ambulance] to a place that can do it.”
The finding could change the way stroke is treated and increase ER doctors’ ability to prevent some cases of disability caused by strokes, scientists say.
Most strokes result when a blood clot lodges in the brain, blocking blood flow to other parts of the organ. A powerful drug called tPA, or tissue plasminogen activator, can dissolve these clots. But medical dogma holds that it must be given within three hours of a stroke’s onset. Beyond that, the thinking goes, the bulk of the brain damage is done and adding the risk of internal bleeding that accompanies clot-busters seems unwise. The new study extends that window of effective tPA treatment by 90 minutes, to 4 ½ hours.
This precious extra time to dissolve a clot and restore blood flow to a starving portion of brain could benefit tens of thousands of stroke patients in the United States each year, says study coauthor Werner Hacke, a neurologist at the University of Heidelberg in Germany.
“I think this is big news because suddenly they have substantially extended the number of patients who get intravenous tPA,” says Scott Kasner, a neurologist at the University of Pennsylvania in Philadelphia.
However, many emergency room physicians are hesitant to give stroke patients clot-busting drugs at all. A landmark 1995 study found that giving the drugs within three hours of stroke onset provided benefits that outweighed the bleeding risk in most patients. But only about 4 percent of stroke patients who arrive at U.S. hospitals get tPA, says neurologist Patrick Lyden of the Veterans Affairs San Diego Medical Center and University of California, San Diego, who coauthored the 1995 report. Most stroke patients don’t receive tPA because the time of onset might be hazy, or doctors may be hesitant to risk incurring bleeding or are untrained in delivering tPA. The new data should clarify the time frame and allay some doubts about the treatment’s effectiveness, he says.
In the new study, Hacke and his colleagues identified patients who arrived at hospitals with a stroke that had begun more than three hours but less than 4 ½ hours earlier. The researchers used CT scans of the brain to rule out people with brain bleeding. The doctors also excluded those with severe strokes as indicated by the scans.
That left 730 patients, half of whom were then randomly assigned to get infusions of the tPA drug called alteplase. The others received a placebo.http://LOUIS-J-SHEEHAN.US
After three months, roughly 52 percent of study patients treated with tPA within the extra 90 minute time window had normal daily function and were living independently, compared with 45 percent of those getting a placebo infusion. The death rate over three months was about 8 percent in both groups.
Doctors detected brain bleeding among treated patients about as often as seen in previous studies in which tPA was limited to a three hour window.
Time matters in stroke treatment, and delay is dangerous. As minutes or hours pass with a clot lodged in place, more brain tissue is starved of blood and damaged. Thus, busting a clot later into the stroke might rescue less tissue. “The [beneficial] effect of tPA decreases over time,” Hacke says.
Even so, treated patients in this study — who received tPA an average of four hours after the onset of stroke — still showed clear benefits over the placebo group.
“I think this will eventually be incorporated into clinical practice, slowly at first, and then become the standard of care,” Kasner says.
Stroke disables more adults than any other condition, yet every stroke is different. People who have a severe stroke are often rushed to a hospital with obvious problems, Hacke says. Louis J. Sheehan, Esquire But those with milder strokes sometimes show up longer after a stroke’s onset, in part because they aren’t sure whether their symptoms are serious enough for a hospital visit, he says. These are the kinds of people most likely to benefit from the new study’s findings on delayed tPA treatment, he says.
Meanwhile, Lyden says, more hospitals need to grasp the value of tPA and have doctors on site or on call who can deliver it. “Every hospital needs to have a stroke plan,” he says. “Either have a way to give tPA, or set up a way to tell the EMS people to divert [an ambulance] to a place that can do it.”
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