Category Archives: Transhuman News

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HIV attacks a type of immune cell known as a T cell (shown here) using a protein encoded by the CCR5 gene.

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 to the virus. The findings are published today in The New England Journal of Medicine1.

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 that Brown gained the ability to control his HIV infection after they treated him with donor bone-marrow stem cells that carried a mutation in a gene called CCR5. Most HIV strains use a protein encoded by CCR5 as 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 is not 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 beneficial CCR5 mutation in a persons own cells, using targeted gene editing.

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 the CCR5 gene 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 functional CCR5 gene, 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?

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 US 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 method tackles HIV in first clinical test

Engineering a patients own immune cells to resist HIV could eliminate the need for lifelong antiretroviral therapies.

The immune cells of HIV patients can be genetically engineered to resist infection, say researchers. In a small study in humans, scientists report that by creating a beneficial mutation in T cells, they may be able to nearly cure patients of HIV.

In a study published in the New England Journal of Medicine on Wednesday, researchers report that they can use genome editing to re-create the rare mutations responsible for protecting about 1 percent of the population from the virus in infected patients. They report that some of the patients receiving the genome-modifying treatment showed decreased viral loads during a temporary halt of their antiretroviral drugs. In one patient, the virus could no longer be detected in his blood.

Zinc-finger nucleases are one of a few genome-editing tools that researchers use to create specific changes to the genomes of living organisms and cells (see Genome Surgery). Scientists have previously used genome-editing techniques to modify DNA in human cells and nonhuman animals, including monkeys (see Monkeys Modified with Genome Editing). Now, the NEJM study suggests the method can also be safely used in humans.

From each participating patient, the team harvested bone marrow stem cells, which give rise to T cells in the body. They then used a zinc finger nuclease to break copies of the CCR5 gene that encodes for proteins on the surface of immune cells that are a critical entry point of HIV. The stem cells were then infused back into each patients bloodstream. The modification process isnt perfect, so only some of the cells end up carrying the modification. About 25 percent of the cells have at least one of the CCR5 genes interrupted, says Edward Lanphier, CEO of Sangamo Biosciences, the Richmond, California, biotech company that manufactures zinc finger nucleases.

Because the cells are a patients own, there is no risk of tissue rejection. The modified stem cells then give rise to modified T cells that are more resistant to infection by HIV, say the researchers.

One week after the infusion, researchers were able to find modified T cells in the patients blood. Four weeks after the infusion, six of the 12 patients in the study temporarily stopped taking their antiretroviral drugs so the researchers could assess the effect of the genome-editing treatment on the amount of the virus in the patients bodies. In four of these patients, the amount of HIV in the blood dropped. In one patient, the virus could no longer be detected at all. The team later discovered that this best responder had naturally already had one mutated copy of the CCR5 gene.

Patients who carry one broken copy of the CCR5 progress to AIDS more slowly than those who dont, says Bruce Levine, a cell and gene therapy researcher at the University of Pennsylvania School of Medicine and coauthor on the study. Because all of the cells in that best-responder patient already carried one disrupted copy of CCR5, the modification by the zinc finger nuclease led to T cells with no functional copies of the gene. That means the cells are fully resistant to HIV infection. The team is now working to increase the number of immune cells that end up carrying two broken copies of CCR5.

Link:
Can Gene Therapy Cure HIV?

PUBLIC RELEASE DATE:

5-Mar-2014

Contact: Shawna Williams shawna@jhmi.edu 410-955-8632 Johns Hopkins Medicine

Johns Hopkins researchers say they have found one way that a recently discovered genetic mutation might cause two nasty nervous system diseases. While the affected gene may build up toxic RNA and not make enough protein, the researchers report, the root of the problem seems to be snarls of defective genetic material created at the mutation site.

The research team, led by Jiou Wang, Ph.D., an assistant professor of biochemistry and molecular biology and neuroscience at the Johns Hopkins University School of Medicine, reports its finding March 5 on the journal Nature's website.

Two years ago, researchers linked the gene C9orf72, named for its location on the ninth human chromosome, to amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, and to frontotemporal dementia (FTD).

In ALS, motor neurons nerve cells that carry messages from the brain to muscles degenerate and eventually die, which gradually paralyzes the patient. In FTD, neurons in the frontal and temporal lobes of the brain die. Some scientists think the same genetic and biological processes cause both disorders, but with very different symptoms, depending on where in the brain they occur.

The mutation in C9orf72 is called a hexanucleotide repeat expansion, a six-letter "word" of DNA repeated over and over, in a part of the gene that doesn't contain instructions for making any proteins. Although it's normal to have up to 20 such repeats, some people with ALS or FTD have dozens or even hundreds of them. Studies show the mutation is likely responsible for 4 to 8 percent of cases of sporadic ALS the kind that isn't necessarily hereditary and, in some groups, up to 40 percent of the kind that is.

To learn how the repeated sequence causes disease, the Johns Hopkins scientists looked at the structure of the DNA that makes up the gene and the RNA that carries its instructions. Although DNA and RNA are generally seen as long strands, they can bunch and curl to make 3-D structures.

Working with DNA and RNA they made that bore the six-letter "word" repeat, the researchers figured out that both were forming structures called G-quadruplexes. In these formations, guanines called "G" for short, one of the letters in the repeating DNA "word" link up, making stacks that stick together like tiny shelves. The RNA also forms other shapes in the repeating section hairpins and bulges. The researchers speculate that the G-quadruplexes and other structures might be getting in the way of the nucleic acids' normal functions.

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ALS-linked gene causes disease by changing genetic material's shape

A strategy to genetically modify cells from people infected with HIV could become a way to control the virus that causes AIDS without using antiviral drugs, according to results from an early-stage trial that were published on Wednesday.

Data from the small study of the Sangamo BioSciences therapy, known by the code name SB-728-T, were issued in the New England Journal of Medicine, the first publication of data from a human trial of a technology called "gene editing."

The technique is designed to disrupt a gene, CCR5, used by HIV to infect T-cells, the white blood cells that fight viral infections. A patient's cells are removed and processed to alter the DNA that codes for the CCR5 receptor. The altered cells are multiplied and tested, then infused back into the patient.

The Phase 1 trial, led by the University of Pennsylvania, enrolled 12 HIV patients. The study's main goal was safety, but it also showed that the modified T-cells persisted and the presence of HIV DNA decreased, the researchers said.

"It's very solid, elegant science," said Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "There is a strong suggestion that cells that are generated are less susceptible to dying."

Sangamo plans to release more trial results this week in Boston at the Conference on Retroviruses and Opportunistic Infections. It will also discuss strategies to improve patient outcomes.

The gene editing technique seeks to mimic the resistance to HIV observed in the small number of people who have inherited CCR5 mutations from both parents. A patient in the trial who carried a naturally occurring mutation in one copy of the CCR5 gene saw the presence of HIV drop to undetectable levels.

"The target we are going after, CCR5, is the most advanced and most promising approach for a functional cure for HIV," said Sangamo Chief Executive Officer Edward Lanphier.

The human immunodeficiency virus, or HIV, surfaced more than 30 years ago and now infects more than 34 million worldwide. Prevention measures have helped check its spread, while early detection and new antiretroviral drugs can control the disease for decades, meaning it is no longer a death sentence.

But the complexity of the virus has stymied scientists seeking a cure. Antiviral drugs are less than ideal due to factors including cost, side effects and drug resistance.

Excerpt from:
Gene therapy may control HIV without drugs