Monthly Archives: March 2014

The approach involves using enzymes to destroy a gene in the immune cells of people with HIV, thereby increasing resistance to the virus

Scanning electron micrograph of a human T cell from the immune system of a healthy donor. Credit:NIAID/NIH - Wikimedia Commons

A clinical trial has shown that a gene-editing technique can be safe and effective in humans. For the first time, researchers used enzymes called zinc-finger nucleases (ZFNs) to target and destroy a gene in the immune cells of 12 people with HIV, increasing their resistance to the virus. The findings were published March 5 in The New England Journal of Medicine.

This is the first major advance in HIV gene therapy since it was demonstrated that the Berlin patient Timothy Brown was free of HIV, says John Rossi, a molecular biologist at the Beckman Research Institute of the City of Hope National Medical Center in Duarte, California. In 2008, researchers reported thatBrown gained the ability to control his HIV infectionafter they treated him with donor bone-marrow stem cells that carried a mutation in a gene calledCCR5. Most HIV strains use a protein encoded byCCR5as a gateway into the T cells of a hosts immune system. People who carry a mutated version of the gene, including Brown's donor, are resistant to HIV.

But similar treatment isnot feasible for most people with HIV: it is invasive, and the body is likely to attack the donor cells. So a team led by Carl June and Pablo Tebas, immunologists at the University of Pennsylvania in Philadelphia, sought to create the beneficialCCR5 mutation in a persons own cells, using targeted gene editing.

Personalized medicine The researchers drew blood from 12 people with HIV who had been taking antiretroviral drugs to keep the virus in check. After culturing blood cells from each participant, the team used a commercially available ZFN to target theCCR5gene in those cells. The treatment succeeded in disrupting the gene in about 25% of each participants cultured cells; the researchers then transfused all of the cultured cells into the participants. After treatment, all had elevated levels of T cells in their blood, suggesting that the virus was less capable of destroying them.

Six of the 12 participants then stopped their antiretroviral drug therapy, while the team monitored their levels of virus and T cells. Their HIV levels rebounded more slowly than normal, and their T-cell levels remained high for weeks. In short, the presence of HIV seemed to drive the modified immune cells, which lacked a functionalCCR5gene, to proliferate in the body. Researchers suspect that the virus was unable to infect and destroy the altered cells.

They used HIV to help in its own demise, says Paula Cannon, who studies gene therapy at the University of Southern California in Los Angeles. They throw the cells back at it and say, Ha, now what?

Long-term action In this first small trial, the gene-editing approach seemed to be safe: Tebas says that the worst side effect was that the chemical used in the process made the patients bodies smell bad for several days.

The trial isnt the end game, but its an important advance in the direction of this kind of research, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. Its more practical and applicable than doing a stem-cell transplant, he says, although it remains to be seen whether it is as effective.

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Gene-Editing Technique Shown to Work as HIV Treatment

China was the first country to approve a gene therapy product for commercial use, in 2004. The U.S. has yet to endorse any such treatments and the field has been plagued by carcinogenicity

Flickr/hermida

From Nature magazine

Europes drugs regulator has for the first time recommended a gene therapy medicine for approval.

Glybera, a treatment for patients who cannot produce enough of an enzyme crucial for breaking down fat, was backed by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP). This recommendation has to be endorsed by the European Commission before it becomes available, but it would be unusual for the Commission to reject the recommendation.

Gene therapy involves transferring genes into patients to treat their diseases. In this case Glybera uses a virus injected into a patient to deliver a working copy of a gene for producing lipoprotein lipase (LPL). LPL deficiency affect no more than one or two people in a million.

Back in 2004 China became the first country to approve a gene therapy product for commercial use, with a treatment for cancer. But Europe and the United States have yet to endorse any gene therapy treatments and the field has been plagued by issues such as carcinogenicity.

Jrn Aldag, chief executive of uniQure, the Amsterdam-based company that owns Glybera, says todays announcement from the EMA is an overdue signal to the gene therapy community that things are changing. It unlocks the potential, he told Nature. You will see more investment coming.

Fantastic news Tim Cot, former head of the US Food and Drug Administrations Office of Orphan Products Development and now an independent consultant, says the approval is "astounding, fantastic news. It puts Europe at the forefront.

Glybera had previously received negative opinions from both the CHMP and the EMA Committee for Advanced Therapies (CAT), which advises on cutting edge treatments. However, after re-evaluating the treatment in just those patients who experience severe or multiple attacks of pancreatitis as a result of LPL deficiency, the CAT gave a positive opinion in June, and this has now been endorsed by the CHMP.

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Europe Nears First Approval for Gene Therapy Treatment

By Amy Norton HealthDay Reporter

WEDNESDAY, March 5, 2014 (HealthDay News) -- In an early step toward drug-free HIV therapy, researchers are reporting the first success in genetically "editing" T-cells in patients' immune systems to become resistant to the virus.

The findings, published in the March 6 issue of the New England Journal of Medicine, are based on only 12 patients. But experts were cautiously optimistic about what the study accomplished.

Specifically, researchers were able to take T-cells from the HIV patients' blood, then "knock out" a gene known as CCR5, which controls a protein that allows HIV to enter a cell.

The scientists then infused the genetically altered T-cells back into patients' blood, where they expanded in number. What's more, a few patients were taken off their HIV drugs temporarily and saw their virus levels decrease.

"This is impressive," said Rowena Johnston, director of research for amfAR, the Foundation for AIDS Research.

The altered T-cells "actually seem to be doing exactly what [the researchers] wanted them to," said Johnston, who was not involved in the study.

Still, she said, there are plenty of questions left and much research ahead. The investigators on the study agreed.

"This was a first-in-human study," said researcher Bruce Levine, an associate professor of cancer gene therapy at the University of Pennsylvania School of Medicine, in Philadelphia.

That means the trial was designed to see whether it's even safe to use this approach in people with HIV -- and not whether it's an effective therapy.

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Gene Therapy for Controlling HIV Shows Early Promise

Two doses of gene therapy restore vision to three women who were born nearly blind

Garretttaggs55, Wikimedia Commons

Gene therapy has markedly improved vision in both eyes in three women who were born virtually blind. The patients can now avoid obstacles even in dim light, read large print and recognize people's faces. The operation, researchers predict, should work even better in children and adolescents blinded by the same condition.

The advance, reported in the February 8 issue of Science Translational Medicine, extends earlier work by the same group. Between 2008 and 2011, Jean Bennett of the University of Pennsylvania's Mahoney Institute of Neurological Sciences and her colleagues used gene therapy to treat blindness in 12 adults and children with Leber's congenital amaurosis (LCA), a rare inherited eye disease that destroys vision by killing photoreceptorslight-sensitive cells in the retina at the back of the eye. Typically, afflicted children start life with poor vision, which worsens as more and more photoreceptors die.

The treatment grew out of the understanding that people with the disorder become blind because of genetic mutations in retinal cells. One mutated gene that causes the disorder is named RPE65. An enzyme encoded by RPE65 helps break down a derivative of vitamin A called retinol into a substance that photoreceptors need to detect light and send signals to the brain. Mutant forms of RPE65 prevent the production of this enzyme in a "nursery" layer of cells called the retinal pigment epithelium, which is attached to the retina and nourishes photoreceptors by breaking down retinol, among other cellular services.

In the initial study, retina specialist and Bennett's co-author Albert Maguire of Penn Medicine injected a harmless virus carrying normal copies of RPE65 into an area of the retinal pigment epithelium, which subsequently began producing the enzyme. In each of the 12 patients, Maguire treated one eyethe one with worse vision. Six patients improved so much they no longer met the criteria for legal blindness.

In the new study, Maguire injected the functional genes into the previously untreated eye in three of the women from the first group. Bennett followed the patients for six months after their surgeries. The women's vision in their previously untreated eye improved as soon as two weeks after the operation: They could navigate an obstacle course, even in dim light, avoiding objects that had tripped them up before, as well as recognize people's faces and read large signs. Bennett showed that not only were the women's eyes much more sensitive to light, their brains were much more responsive to optical input as well. Functional magnetic imaging showed regions of their visual cortices that had remained offline before gene therapy began to light up.

Surprisingly, Bennett reports, the second round of gene therapy further strengthened the brain's response to the initially treated eye as well as the newly treated one. "That wasn't something we had been expecting, but it makes sense because the two eyes act in concert, and some aspects of vision rely on binocularity." In the new paper, the authors suggest that neuroplasticity plays a role: It is possible that regions of the visual cortex responding to the newly flowing channel of information from the second eye bolster activity in areas of the visual cortex responding to the initially treated eye.

An institutional review board required that Bennett work with adults in the follow-up study, but she thinks the therapy will work even better in younger patients who have not lost as many photoreceptors. She says the results "really bode well" for restoring meaningful vision to people with LCA and other forms of inherited blindness.

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Sight Seen: Gene Therapy Restores Vision in Both Eyes

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In a small trial, researchers have successfully used gene therapy to boost the immune system of 12 patients with HIV to resist infection. They removed the patients' white blood cells to edit a gene in them, then infused them back into the patients. Some of the patients who showed reduced viral loads were off HIV drugs completely.

In fact, one of the patients showed no detectable trace of HIV at all after therapy. The researchers, who report their phase I study in the New England Journal of Medicine believe theirs is the first published account of using gene editing in humans.

The team included researchers from the University of Pennsylvania (Penn), PA, Albert Einstein College of Medicine, Bronx, NY, and Sangamo BioSciences, Richmond, CA, the company that developed the gene editing technology.

Carl H. June, senior author of the study and professor at Penn's Perelman School of Medicine, says:

"This study shows that we can safely and effectively engineer an HIV patient's own T cells to mimic a naturally occurring resistance to the virus, infuse those engineered cells, have them persist in the body, and potentially keep viral loads at bay without the use of drugs."

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Gene therapy used to block HIV without drugs