Category Archives: Gene Medicine

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.

Read more:
Sight Seen: Gene Therapy Restores Vision in Both Eyes

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.

Original post:
Gene Therapy for Controlling HIV Shows Early Promise

NIBSC/Science Photo Library

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.

Read the original here:
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.

Read the original post:
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

La Jolla researcher J. Craig Venter is opening the largest genetic sequencing center in the world, the latest chapter of his historic, lifelong quest to identify the genes that cause and contribute to everything from cancer to dementia.

Venter says he will exploit a major advance in technology to sequence up to 40,000 genomes a year -- a figure that will rise to 100,000 as he phases in more cutting-edge sequencing machines from San Diegos Illumina.

He raised $70 million to co-found Human Longevity, Inc. (HLI), a company that will sequence genes for a fraction of what it cost just over a decade ago.

The sequencing will initially be offered to patients at UC San Diegos Moores Cancer Center before being rolled out to hospitals around the nation. The company also will analyze a persons microbes and metabolic condition to get a fuller picture of a patients health and to improve treatment.

Knowledge about yourself, your genome, gives you power, said Venter, an alumnus of the University of California San Diego. If you have lung cancer the most important thing you can know is your genome. It is probably the most democratic way for people to have control over their own medical outcomes.

Venter, 67, co-founded HLI with two notable futurists and physicians, Robert Hariri and Peter Diamandis. His investors include Malaysian billionaire K.T. Lim, Steve Jurvetson and Illumina.

Diamandis said he believed the having your genome sequenced would become as common as a urinalysis and that, eventually, "100 will be the next 60."

Cancer is the company's first target. HLI also will tackle increasingly common afflictions such as Alzheimers and Parkinsons disease. The diseases are a large and growing focus of local scientists, including those at UC San Diego, which last year created an Institute for Genomic Medicine.

Venter is moving to capitalize on a major technological advance by San Diegos Illumina, widely considered to be the worlds leading sequencing company. As recently as 2007 it cost about $10 million to sequence one genome. Illumina found ways to process samples more quickly and cheaply. In January, the company announced a new sequencing system that lowered the cost of analyzing one genome to less than $1,000 a figure that seemed inconceivable when the Human Genome Project began in the 1990s.

The company is buying two of Illuminas new HiSeq X Ten Sequencing systems, which sell for $10 million each. These can sequence genomes in about three days, and do roughly 32 of them in one week. It took scientists 13 years, and cost about $3 billion, to sequence the first genome, a project that was completed in 2003.

More here:
Biggest gene sequence project to launch

Scientists have identified a rare gene mutation that prevents Type 2 diabetes, the New York Times reported.

In a study of 150,000 people, researchers identified a mutation that destroys a gene used by pancreas cells where insulin is made. People with the mutation were found to produce slightly higher levels of insulin and have slightly lower blood glucose levels for life. As a result, that the mutation reduces diabetes risk by two-thirds even among people who are overweight.

The results, published in Nature Genetics, are a first for diabetes research, as they show a benefit of a mutation that destroys a gene.

Researchers hope they may someday be able to develop a drug that mimics the mutation, offering protection against diabetes. However, Pfizer, which helped finance the study, cautions that bringing a new drug to market can take 10 to 20 years.

Scientists say these results are surprising and a powerful step for drug development.

The study is a tour de force, and the authors are the top people in the field, Dr. Samuel Klein, director of the center for human nutrition at Washington University School of Medicine, who was not involved in the study, told The New York Times.

Click for more from The New York Times.

Read more here:
Gene mutation may prevent Type 2 diabetes

Scientists have uncovered gene mutations that slash the risk of Type 2 diabetes regardless of age and weight, offering drugmakers a novel target to combat one of the major health threats confronting the modern world.

About 347 million people globally, including 25.8 million in the U.S., have diabetes, according to the World Health Organization. The Type 2 form, tied to excess weight and a sedentary lifestyle, is soaring as obesity rates rise. The ailment occurs when the body cant control blood-sugar levels with insulin made naturally by the pancreas.

The research, funded in part by Pfizer Inc., may give the New York-based drugmaker a wedge into a diabetes market that generated $42.4 billion in 2012. A drug mimicking the mutations would provide a unique way to hold the disease at bay, the researchers said in a report yesterday in the journal Nature Genetics. While current therapy slows the disease, patients eventually worsen and many need insulin shots.

The study provides important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine, said Tim Rolph, Pfizers chief scientific officer of cardiovascular, metabolic and endocrine research, in a statement.

The researchers studied the genomes of older people with excess weight, prime targets for Type 2 diabetes who nonetheless had normal blood-sugar levels. They homed in on the SLC30A8 gene, known to affect diabetes risk.

Finally, they used advanced genetic sequencing to search the genomes of 150,000 people in the U.S., Iceland, Sweden and Finland and were able to identify a dozen variations that blocked the genes function.

Those who inherited just one copy of the damaged gene had a 65 percent lower risk of diabetes, the study found.

The protein that typically comes from the gene is critical in the production of insulin by the beta cells found in the pancreas. The researchers still arent sure exactly why or how the mutations provide protection.

Human genetics is not just a tool for understanding biology, said David Altshuler, deputy director and chief academic officer at the Broad Institute and a professor at Harvard Medical School. It can also powerfully inform drug discovery by addressing one of the most challenging and important questions - knowing which targets to go after.

The research was a five-year collaboration between researchers at the Broad Institute, Massachusetts General Hospital, Pfizer and Lund University Diabetes Center in Sweden. The National Institutes of Health, the Doris Duke Charitable Foundation and other organizations also helped fund the research.

The rest is here:
Type 2 Diabetes Gene Mutations Seen as Drugmaker Target

By Mary Brophy Marcus HealthDay Reporter

THURSDAY, Feb. 27, 2014 (HealthDay News) -- A new DNA study begins to explain why girls are less likely than boys to have an autism spectrum disorder.

It turns out that girls tend not to develop autism when only mild genetic abnormalities exist, the researchers said. But when they are diagnosed with the disorder, they are more likely to have more extreme genetic mutations than boys who show the same symptoms.

"Girls tolerate neurodevelopmental mutations more than boys do. This is really what the study shows," said study author Sebastien Jacquemont, an assistant professor of genetic medicine at the University Hospital of Lausanne, in Switzerland.

"To push a girl over the threshold for autism or any of these neurodevelopmental disorders, it takes more of these mutations," Jacquemont added. "It's about resilience to genetic insult."

The dilemma is that the researchers don't really know why this is so. "It's more of an observation at a molecular level," Jacquemont noted.

In the study, the Swiss researchers collaborated with scientists from the University of Washington School of Medicine to analyze about 16,000 DNA samples and sequencing data sets from people with neurodevelopmental disorders, including autism spectrum disorders.

The investigators also analyzed genetic data from almost 800 families affected by autism for the study, which was released online Feb. 27 in the American Journal of Human Genetics.

The researchers analyzed copy-number variants (CNVs), which are individual variations in the number of copies of a particular gene. They also looked at single-nucleotide variants (SNVs), which are DNA sequence variations affecting a single nucleotide. Nucleotides are the basic building blocks of DNA.

The study found that females diagnosed with any neurodevelopmental disorder, including attention-deficit/hyperactivity disorder and intellectual disability, had more harmful CNVs than males who were diagnosed with the same disorder. Females with autism also had more harmful SNVs than males with the condition.

View post:
Gene Study Offers Clues to Why Autism Strikes More Males