Hemophilia, a disease whose victims can suffer serious internal bleeding and may bleed to death from injuries, has a long and eventful history. Caused by defective blood clotting factors, the disease has been with us since at least the second century, when a rabbi gave mothers whose first two sons had bled to death from circumcision wounds permission to leave the third sons uncircumcised. It also famously afflicted several members of European royal families. But a study published in the New England Journal of Medicine brings us a bit closer to a new kind of historic event: a cure.

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Vaccines usually work by getting the body to make antibodies against a virus, so when the virus appears on the scene, the immune system is prepared to tag it for destruction. But getting the body excited about making such antibodies isn’t always easy. It’s this stumbling block that has made HIV vaccines so disappointing so far, and in response, some scientists have reached for the big guns of biology. In a paper published today in Nature, one team reports that they’ve been able to make mice immune to HIV using, of all things, gene therapy.

Best known as a process for replacing faulty genes with fresh ones to treat chronic diseases, gene therapy seems, at first glance, like overkill. It involves engineering a lab-grown virus to permanently insert a gene into a patient’s genome, and it can be dicey, to say the least. Despite two decades of research, no gene therapy treatments have made it out of clinical trials. But given the difficulty of getting the immune system to buckle down and make antibodies against HIV on its own, using gene therapy starts to make a kind of sense. (more…)

What’s the News: After a bone marrow transplant cured a Berlin man of HIV in 2008, scientists have been working to see whether similar, though less drastic, measures could be a treatment for the disease. And judging from the results of a recent clinical trial that used gene therapy to accomplish the goal, there’s potential.

What’s the Context:

• In the original case, an HIV-positive patient was diagnosed with leukemia, and after having chemotherapy to knock down his cancer, he received multiple transplants of blood stem cells from a donor, which took up permanent residency in his body.
• Those stem cells had a rare mutation that deactivated the CCR5 receptor, which the HIV virus uses to enter the blood cells it destroys. The end result was that the patient became the first person in the world to be cured of HIV—with that receptor out of commission, the virus couldn’t grow, and he longer has any detectible levels of HIV.

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Biologist George Church, examining a molecular model.

George Church, the geneticist behind the Personal Genome Project, is envisioning a package deal: get your genome sequenced, and he and his collaborators will develop a line of induced pluripotent stem cells (IPS) from your tissue, so in the future, you’ll be able upgrade your system with organs and tissues bearing both your genes and special extras like genes from centenarians. It’s combining stem cells with gene therapy. In an interview with Church, David Ewing Duncan over at Technology Review asks him to elaborate. Why does he think this science fiction scenario is in our near future?

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What’s the News: Medicine in the age of genes overflows with daring new techniques and treatments, from personalized chemotherapy to prenatal genetic testing, each heralded as a game-changer. But rarely do we get an assessment of a treatment’s long-term good, which is why recent papers following up on one of the most controversial genetic treatments, gene therapy, are making waves: though one patient developed leukemia from the treatment, 13 of 16 kids treated with gene therapy for a severe immune disorder at least 9 years ago have been cured, adding to the sense that the field is on its way to recovery from early setbacks.

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Modified immune cells decimated chronic lymphocytic leukemia, scientists found.

What’s the News: Striking results in a very small study have got the web a-buzz about a new cancer treatment: With three leukemia patients at the ends of their ropes, scientists modified some of their immune cells with a gene that enabled them to hunt down cancer cells. Remarkably, the treatment wiped out more than two pounds of tumor tissue in each patient, and the three have now been in remission for a year.

But what weight does such a small study carry, what about the side effects, and what do these results mean for people with other cancers?

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What’s the News: Hemophilia is perhaps best known as a disease of nineteenth-century royalty (specifically, of the oft-intermarried Hapsburgs), but it has evaded our efforts at a cure for thousands of years. And its effects are gruesome: mutations in the gene for a crucial clotting factor mean that victims can rapidly bleed to death from even small cuts.

Now, researchers working with hemophiliac mice have demonstrated a simple and apparently safe technique to swap in a functioning gene, giving hope for a future respite for sufferers of the disease.

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Back in the 1980s, gene therapy was one of science’s greatest hopes and hypes, and researchers predicted the technique would be used to cure a huge range of illnesses. During the 90s, many early gene therapy trials were effective or downright dangerous, some causing cancer or even death. But more recently, scientists who stuck with gene therapy have started to see positive results, with promising treatments for malformed hemoglobin, color blindness, and depression. (See the DISCOVER magazine feature “The Second Coming of Gene Therapy” for more.) Now, researchers have announced that they’ve successfully treated the symptoms of Parkinson’s disease in a small group of people—a far cry from a cure, but still a step in the right direction.

I Once Was Blind but Now I See

The theory behind gene therapy is simple: A healthy gene hitches a ride into the patient’s genome on a virus, replacing the genes responsible for some genetic disease or disorder. Actually doing this is more difficult, because humans have a little thing called an immune system that’s remarkably efficient at finding and destroying foreign bodies. After the first U.S. death from gene therapy in 1999, and leukemia cases in France the same year, many started to think that gene therapy was more of a problem than an answer.

The early and awful failures forced all of the researchers in the field to retreat and reconsider the staggering complexity that challenged them. They could not just replace a bad gene with a good gene, as some early pundits had hoped—they also had to orchestrate the nuanced and elaborate dance between the gene products (proteins) and the patient’s immune system, which could recognize a foreign body and viciously attack it. After that was settled, gene therapists still had to find a suitable virus, or vector, to carry replacement genes into human cells without inciting a damaging or deadly immune response…. It was this new perspective more than anything else that turned gene therapy from a simple but failed and frustrated hope into, once again, medicine’s next big thing—a stunning spectacle of hubris, ignominy, and redemption on the scientific stage. [DISCOVER]

New: Gene Therapy and Parkinson’s Disease

While there’s no cure for Parkinson’s as of yet, doctors have an arsenal of methods, ranging from drugs, brain stimulation, and (now) gene therapy that help reduce the disease’s symptoms. Hopes for using gene therapy to alleviate Parkinson’s effects aren’t new. What is new is that scientists have successfully completed the first randomized, controlled, double-blind trial of treating Parkison’s patients with gene therapy—and they found that it significantly improved debilitating symptoms such as tremors, motor skill problems, and rigidity. (more…)

Earlier this week at a scientific conference in Boston, HIV researchers announced a remarkable success in countering the virus’ drain on the immune system. But this early step is far from a cure.

Why it’s exciting:

Carl June and colleagues tested six male patients who already had HIV and were taking a standard antiviral regimen. Like many HIV patients, the drugs helped them, but their counts of immune cells stayed low. June’s team tested a therapy created by Sangamo BioSciences in Richmond, California, that alters a patient’s actual white blood cells to make them more HIV-resistant.

Researchers removed a sample of CD4⁺ T cells, the type of immune cells affected by HIV, from each man and used Sangamo’s enzyme to disrupt the CCR5 gene, which encodes a protein that HIV uses to enter CD4⁺ cells. The engineered cells were then infused back into the patients. Immune-cell counts subsequently rose for five of the six patients who received the therapy. “It’s very exciting,” says John Rossi, a molecular biologist at the City of Hope’s Beckman Research Institute in Duarte, California. “If they did this several times in a given patient, you could establish a high percentage of resistant cells.” [Nature]

The idea came from the “Berlin Patient,” who we’ve written about before at 80beats. He became famous after receiving a donation of bone marrow from someone who carried a mutation in CCR5 that made them resistant to HIV.

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According to a new study out in Science Translational Medicine, treating depressed mice with gene therapy in the brain to bolster a protein connected to the neurotransmitter serotonin can make those depressive symptoms dissipate.

Here’s the gist: The gene in question creates a protein called p11 that help carry serotonin receptors up to the surface of a brain cell where they can receive signals from other brain cells. Poor serotonin signaling may be one of the major drivers behind depression, and a dearth of p11 could worsen the problem, according to study author Michael Kaplitt.

“In the absence of p11, a neuron can produce all the serotonin receptors it needs, but they will not be transported to the cell surface,” said Kaplitt. [AFP]

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When it comes to research on HIV and AIDS treatments, it can be hard to know when to celebrate a small advance–everyone wants to see progress, but so many experimental avenues that seemed promising have turned out to be dead ends. Still, a new study that tried a sophisticated form of gene therapy as an HIV treatment seems cause for cautious optimism. If it bears out under further testing, the technique could lead to a one-shot, long-lasting treatment that could replace the punishing regimen of daily medications.

Treating HIV currently comes down to managing the viral load with a mixture antiretroviral drugs. Researcher John Rossi and his colleagues tried to craft a more direct treatment by genetically modifying the HIV-infected patients’ own blood stem cells and increasing the cells’ ability to fight off the virus. The researchers weren’t able to truly combat the virus in this experiment–the patients’ viral loads remained the same–but their work moved beyond previous attempts in two ways: They successfully modified blood stem cells by giving them anti-HIV genes, and those cells survived for two years in patients.

Earlier clinical studies the group conducted with the same strategy made little headway, but now the researchers have overcome two key obstacles, says Rossi, a molecular geneticist. One is that they managed to stitch the anti-HIV genes into a high percentage of the appropriate stem cells. The other is that the cells lived for a long time. “If we could increase the number of modified cells by 10- or 100-fold, we might be able to stop the virus itself,” says Rossi. [ScienceNow]

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We’re only a week away from the 2010 Winter Olympics opening in Vancouver, and the return of the games brings with it the return of crazy stories about how far world-class athletes will go to get even the tiniest edge, legal or illegal. In the journal Science this week, researchers led by geneticist Theodore Friedmann take the opportunity to warn about gene doping, the next looming crisis in cheating at high-stakes athletics.

Genetic doping isn’t new to the headlines—the International Olympic Committee banned it in 2003. But its prevalence is growing, especially since improving testing is starting to weed out more standard forms of cheating like steroids and EPO, a hormone that boosts red blood cell production. Three years ago, German track coach Thomas Springstein was busted after unsuccessfully trying to score Repoxygen, an experimental gene therapy drug that boosts red blood cell production, for his runners. At the Olympics in Beijing, an unidentified Chinese doctor offered stem cell injections to a German journalist posing as a swim coach [Wired.com].

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The genomes of lung and skin cancer have been decoded by scientists at the UK-based Wellcome Trust Sanger Institute near Cambridge, which is the first time an entire cancer gene map has been created.

The scientists say they have pinpointed specific DNA errors that may cause tumors in these two cancers, both of which have direct known causes—smoking for lung cancer and sun exposure for skin cancer. Researchers predict these maps will offer patients a personalized treatment option that ranges from earlier detection to the types of medication used to treat cancer. The genetic maps will also allow cancer researchers to study cells with defective DNA and produce more powerful drugs to fight the errors, according to the the study’s scientists [CNN]. News reports are heralding the new research as revolutionary, however it will be years, perhaps decades, before the full implications of the work are understood.

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A gene therapy treatment intended to reverse muscle weakness appears to restore muscle mass in monkeys, raising hopes that doctors may soon be able to treat this condition in humans with degenerative diseases like multiple sclerosis and muscular dystrophy. Scientists injected a gene into the monkeys’ thighs that causes cells to produce human follistatin, which interferes with another compound called myostatin. Myostatin breaks down muscle, so in theory adding follistatin should encourage muscles to grow [Reuters].

And grow they did. Within three months the monkeys’ thigh muscle mass increased, and the effect lasted for 15 months, according to the research published in the journal Science Translational Medicine. (Not quite the same effect as the whippet turned hugely muscular by a natural genetic defect.) The relatively long-lasting effect is promising for researchers looking to treat lifelong conditions such as multiple sclerosis and muscular dystrophy. The researchers say the treatment was safe and that no other organs were affected.

But there could be a downside to this promising work–some experts are asking whether this therapeutic technique could be used by unscrupulous athletes looking to tweak their genetics and to build stronger muscles. The drugs companies Amgen and Wyeth have already begun testing myostatin inhibitors in humans and such studies have already prompted fears about the potential for myostatin inhibitors to be abused by athletes hoping to gain the competitive edge. If gene therapy can achieve similar outcomes in humans, such modifications will be even harder to detect [New Scientist]. The World Anti-Doping Authority has banned gene doping in athletic competitions for obvious reasons, even though there’s no evidence that any athletes are tinkering with their genes.

Of course there wouldn’t be: If some jock were gene doping, there would be no way to detect it.

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Image: Wikimedia Commons / Muhammad Mahdi Karim

Researchers may have taken a step towards curing the rare, inherited brain disease made famous by the movie Lorenzo’s Oil–and also towards ushering a new era of gene therapy. To help two young boys suffering from the disease, researchers tried an experimental treatment using a deactivated version of the HIV virus. The virus delivered working copies of a gene to stem cells from the patients’ bone marrows. The HIV virus, stripped of genetic material that makes it toxic, integrates permanently into the DNA of cells it enters, scientists said. That means the modified gene remains in the blood-forming stem cells for the life of the patient [Bloomberg].

Adrenoleukodystrophy, or ALD, is a progressive disease characterized by the gradual destruction of the myelin sheaths that insulate neurons and nerves, allowing electrical signals to be transmitted through them. The disease is caused by a genetic defect, which prevents cells in the bone marrow from producing a crucial protein necessary for the formation of the myelin sheaths. Typically, children with ALD are given bone marrow transplants to provide them with healthy blood-forming stem cells, but in the two cases described in the study, no matching donors could be found.

In the experimental treatment, described in a paper published in Science, researchers took blood stem cells from the patients’ bone marrow and used the new vector system to genetically alter them by inserting a working copy of the … gene. The modified cells were then put back into the patients [Reuters].

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