First Successful Gene Therapy Against Human Aging? It May Be So


IN BRIEF

Should these results prove to be accurate, it means that scientists have actually managed to create a way to reverse aging.

MEET ELIZABETH PARRISH

The CEO of Bioviva USA Inc, Elizabeth Parrish, claims to be the first human in world history to have successfully reversed the effects of natural aging—thanks to experimental gene therapy provided by her company.

Parrish first underwent gene therapy in 2015—one designed to protect against muscle mass depletion that is inherent to aging and another to fight stem cell depletion due to age-related diseases.

Originally meant to prove that her company’s gene therapy was safe, the results—should they prove to be effective in the long-term and withstand due scientific scrutiny—would be the very first successful demonstration of telomere lengthening in any human.

“Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we’ve made history,” Parrish notes.

To that end, even Parrish is clear that more investigation is necessary in order to verify the methods; however, if verified, this work will be revolutionary.

BioViva aims to provide regenerative medicine to the masses through gene and cell therapies.
BioViva aims to provide regenerative medicine to the masses through gene and cell therapies.

TELOMERES: HOW THEY WORK

Telomeres are short segments of DNA that are found on the ends of each chromosome. These act as “buffers” for the wear and tear of natural aging. But with sustained cell division, telomeres eventually get too short to protect the chromosome. When this happens, it causes the call to malfunction and leads to aging.

The basis for the success of Parrish’s gene therapy is related to the telomere scores—which are calculated based on the telomere length in white blood cells (T-lymphocytes). Higher telomere scores indicate “younger cells.” Compared to average T-lymphocytes of the American population within the same age range, 44 year old Parrish claims that the gene therapies she underwent worked and showed that it reversed 20 years of telomere shortening.

As stated, it’s important to note that the results have yet to be verified by an independent source (which is really what science is all about). And Bioviva is still carefully monitoring Parrish’s blood and will continue to do so in the coming months, and even years, to ensure that the success it has seen in leukocytes can translate to the body’s other tissues and organs; or simply if the effects can be safely replicated in other human patients.

Genetically Engineered T-cells Show Promise in Treating Multiple Myeloma


Genetically-engineered t-cells can cure multiple meyloma

If genetic engineering sounds a little creepy to you, akin to lab-produced glow-in-the-dark worms and mutant humans with superpowers, I know some really cool researchers who might change your mind.

These researchers, led by Dr. Aaron P. Rapoport , the Gary Jobson Professor in Medical Oncology and Director of Gene Medicine/Lymphoma at the University of Maryland in Baltimore, are using genetic engineering to get some pretty impressive results for people suffering with difficult-to-treat multiple myeloma (MM), a type of cancer that starts in bone marrow.

Although about 35 percent of patients benefit from standard treatment, i.e. longer life, less pain and fewer complications, there is virtually no cure for multiple myeoma. Rapoport says standard treatment is effective — at least for a while, but in many MM patients it eventually stops working and there is a recurrence of disease.

Unfortunately, standard treatment is less effective for people with aggressive MM, who realize limited benefits for short intervals. The disease is marked by a high prevalence of infections such as pneumonia, bone pain, hypercalcemia (elevated calcium in the blood), renal failure and spinal cord compression.

That’s where genetic engineering comes in.

Genetic engineering, technically known as recombinant DNA technology, is a fairly new concept that’s increasingly becoming an important tool in treating HIV-AIDS and cancer. Perhaps, in the future, conditions such as hemophilia, Parkinson’s disease, diabetes and a form of inherited high cholesterol (hypercholesterolemia).

Researchers are investigating right now to determine whether or not recombinant DNA technology will slow or cure these diseases.

There are two main ways in which genetic engineering is being used.

In the first, researchers pluck genes from one type of organism, say algae or sheep for example, and combine them with genes from a second organism — like you and me.

We’re not talking science fiction animal-human hybrids here.

These engineered genes can be coaxed to make human hormones such as insulin, or human proteins capable of fighting hard-to-treat hepatitis and the AIDS virus.

The second option is gene therapy. Doctors replace defective or missing genes with normalized genes capable of slowing or stopping the disease progression—and in a best-case scenario, curing them.

In the phase-II clinical trial , Rapoport’s team has engineered T-cells in 13 patients with difficult-to-treat multiple myeloma, or in people with recurrent or high-risk disease.

“Gene therapy is taking the bull by the horns and retraining the cells rather than relying on standard vaccine treatments alone with less response rate,” Rapoport said.

“Four of the patients in the study had previous stem cell transplants without getting results. So while this treatment is still in the early stages, we are feeling encouraged by the outcome.”

Cancers can develop when T-cells — specialized “killer cells” produced by the human immune system — lose their ability to target harmful “invader” cells (in this case, cancer cells) they are designed to seek out and destroy, in keeping the body disease-free.

Rapoport and his team add a new gene to each patient’s T-cells and infuse the immune system with vaccines. The new gene effectively retrains the existing T-cells to recognize a new target present on the myeloma cells and do their job, that is, attacking cancer cells. It also builds an army of new potent T-cells equipped to destroy or neutralize the cancer cells.

Days later, the supercharged genes are injected back into patients. At day 100 after treatment, 10 of the 13 patients in the trial are in remission or very close to it — a 77 per cent response rate — and the others showed drastic reduction in their cancer, Rapoport said. By contrast, standard MM treatment alone gives a response rate of between 33 and 69 percent.

Rapoport said that the clinical trial is still recruiting patients.

Cystic Fibrosis: New Hope for Gene Therapy?


Gene therapy to treat cystic fibrosis patients was associated with stabilization — but not improvement — in lung function, according to the results of a randomized, double-blinded phase IIb trial of the therapy in the U.K.

In a per protocol analysis, Professor Eric W.F.W. Alton, of Imperial College in London, and colleagues found a significant, but modest, treatment effect in cystic fibrosis patients treated with the nonviral, chemically designed gene-liposome pGM169/GL67A compared with those treated with a placebo of 0.9% saline (3.7%, 95% CI 0.1-7.3, P=0.046).

While a significant ANCOVA-adjusted effect was observed after 12 months’ follow-up, relative differences in FEV1 after 12 months of treatment were -0.4% (95% CI -2.8 to 2.1) for the treatment group compared to -4.0% (CI -6.6 to -1.4) for the placebo, they reported in The Lancet Respiratory Medicine.

The primary endpoint of the study was defined as relative percent change in forced expiratory volume (FEV1) after 12 months. The authors achieved that because while treatment with pGM169/GL67A did not improve lung function, it did not worsen it either.

Modest Benefit

“This study proves for the first time that copies of the normal CF gene delivered by aerosol inhalation can have a measurable beneficial effect on lung function, compared with placebo, in patients with cystic fibrosis,” senior co-author Dr. Alastair Innes, of Western General Hospital in Edinburgh, Scotland, told MedPage Today. He added that while the effect was statistically significant, he also described it as “modest.”

A small number of patients in both groups did experience improvements in lung function. The authors note that a post-hoc analysis showed 18% of patients (15 in the treatment group and six in the control group) showed an improvement in percent predicted FEV1 of 5% or more of their initial baseline values. By contrast, overall treatment effect in the 65 patients in the treatment group and 56 in the control group was 3.6% (95% CI 0.2-7.0,P=0.039). Of the 20 patients who did not complete the full treatment of one dose per 28 days for 12 months, they received a mean 3.7 doses (SD 1-9).

Patients were randomized into a number of stratified subgroups, but the authors attributed any treatment effect to a greater decline in FEV1 from the placebo group as opposed to greater improvement from pGM169/GL67A. Stratifying by baseline predicted FEV1 (<70% versus ≥70%) found that patients with a more severe disease (FEV1 49.6%-69.2% predicted) had a treatment effect of 6.4% (95% CI 0.8-12.1). By contrast, those with less severe disease (FEV1 69.6%-89.9% predicted) had a 0.2% treatment effect (CI -4.6 to 4.9, P interaction=0.065).

The authors also cited the post-trial and pre-trial changes in the placebo group (-4.9%) compared with the treatment group (1.5%) as contributing to the treatment effect. There were no differences observed by age, sex, or CTFR mutation.

The study also had a number of secondary outcomes, which achieved mixed results. Patients in the treatment group experienced greater improvements in forced vital capacity (FVC) and CT gas trapping, or the inability to exhale completely (P=0.031 andP=0.048, respectively) than the control group. But authors observed no treatment effect for other measures of lung function, imaging, and quality of life. Similar to the primary analysis, they did note that secondary outcomes tended to be more favorable for those with more severe disease.

The authors commented that patients with more severe disease seemed to experience an enhanced treatment effect, and saw this as an opportunity for further research.

“A larger trial with a stratified trial entry design, powered to assess subgroups, and that addresses the mechanisms of response heterogeneity will be important to verify or refute these data,” they wrote.

A total of six serious adverse events were recorded from the pGM169/GL67A group. The committee judged that they were unrelated to the treatment, though one may have been related to a trial procedure (bronchoscopy), the authors said. Two patients total discontinued treatment; one in the placebo group due to fatigue and one in the treatment group due to flu-like symptoms. There were no deaths during the study, and the authors saw no clinically relevant changes in patients throughout the study.

This randomized, double-blinded, placebo-controlled trial consisted of two cystic fibrosis centers in London and Edinburgh at 18 sites in the U.K. from June 12, 2012, to June 24, 2013. Participants were eligible if they were ages ≥12 years, had a FEV1 of 50%-90% predicted and had any combination of CFTR gene mutations. Of the 140 patients, 78 received pGM169/GL67A and 62 received a placebo. There were 116 patients (83%) completing the treatment and included in the per protocol analysis.

Limitations

The most important limitation the authors cite is that the mean difference is at the lower end of clinical trials for gene therapy in patients with cystic fibrosis, mainly due to the reduction in FEV1 volume in the placebo group. They suggest several reasons for this, such as optimal respiratory health for patients at time of trial entry, enthusiasm for the trial leading to improvements in lung function during the recruitment period, and that the trial included all available data, even if the patients were unstable, while registry data only contains measurements from an annual review. They also note the trial’s heterogeneous response and that the fact that changes may be the result of a “non-specific response” to the pGM169/GL67A treatment.

The authors describe their conclusions as a “proof of concept” for nonviral CFTR gene therapy, calling it “another step along the path of translational cystic fibrosis gene therapy.”

Innes said that the efficiency of the gene uptake needs to be improved before the therapy is applicable to clinical practice, adding that the UK Gene Therapy Consortium is engaged in pursuing several lines of research.

“We are exploring whether increased or more frequent dosing would increase benefit, the possible additional benefit of combining gene therapy with other basic treatments which help the CF ion channel to remain open, and novel viral gene therapy vectors which may increase the efficiency of gene transfer,” he said.

Yale scientists use gene editing to correct mutation in cystic fibrosis


Left to right, cystic fibrosis cells treated with gene-correcting PNA/DNA show increasing levels of uptake, or use to correct the mutation. (Images by Rachel Fields)

Yale researchers successfully corrected the most common mutation in the gene that causes cystic fibrosis, a lethal genetic disorder.

The study was published April 27 in Nature Communications.

Cystic fibrosis is an inherited, life-threatening disorder that damages the lungs and digestive system. It is most commonly caused by a mutation in the cystic fibrosis gene known as F508del. The disorder has no cure, and treatment typically consists of symptom management. Previous attempts to treat the disease through gene therapy have been unsuccessful.

To correct the mutation, a multidisciplinary team of Yale researchers developed a novel approach. Led byDr. Peter Glazer, chair of therapeutic radiology, Mark Saltzman, chair of biomedical engineering, and Dr. Marie Egan, professor of pediatrics and of cellular and molecular physiology, the collaborative team used synthetic molecules similar to DNA — called peptide nucleic acids, or PNAs — as well as donor DNA, to edit the genetic defect.

“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” Egan explained.

The researchers also developed a method of delivering the PNA/DNA via microscopic nanoparticles. These tiny particles, which are billionths of a meter in diameter, are specifically designed to penetrate targeted cells.

In both human airway cells and mouse nasal cells, the researchers observed corrections in the targeted genes. “The percentage of cells in humans and in mice that we were able to edit was higher than has been previously reported in gene editing technology,” said Egan. They also observed that the therapy had minimal off target, or unintended, effects on treated cells.

While the study findings are significant, much more research is needed to refine the genetic engineering strategy, said Egan. “This is step one in a long process. The technology could be used as a way to fix the basic genetic defect in cystic fibrosis.”

Gene therapy using HIV-derived vector has cured rare condition.


A small study using an experimental gene therapy to correct defects in DNA has transformed the lives of six boys with a deadly immune disorder, researchers report.

Wiskott-Aldrich syndrome is a rare genetic disorder that affects up to 10 children in every million born, and occurs almost exclusively in males.

The syndrome is characterised by eczema, low platelet counts in the blood, which results in bruising, and a compromised immune system that leaves people vulnerable to a suite of recurring and potentially deadly infections such as pneumonia. People with the condition can also suffer severe nose bleeds and bloody diarrhea.

In the two years since the treatment was administered, there has been a significant decrease in the number of infectious complications that often arise with the illness, and the average number of days spent in hospital for the study participants has dropped from 25 per year in the two years before the treatment to zero days in the two years following.

“This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome,” the researchers noted.

The findings, which were published in the Journal of the American Medical Association, could revitalise interest in gene therapy, which involves functional genes being inserted into cells to correct defects and help reverse genetic diseases.

But the researchers also caution that, “controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.”

As James Gallagher from the BBC explains, the syndrome “stems from an error in the genetic code that contains the building instructions for a key element in the immune system – a protein called WAS.”

Current treatment options involve bone marrow transplants, whereby hematopoietic stem cells from a donor can help restore some level of immune function.

But these transplants are only viable when there’s a prospective donor with a close tissue match, and even then, researchers say there’s usually a high rate of complications involved.

So researchers in the UK and France have begun investigating a gene therapy option, which they say could be more effective and safer.

With this technique, researchers use stem cells from the sick individual rather than from a donor. These cells are extracted and modified – or infected, rather – with an advanced lentiviral vector, which is derived from HIV.

These vectors have become an important tool for gene delivery to cells, and arepromising for gene therapy because they can infect both dividing and non-dividing cells, and can change the expression of their target cell’s gene for long periods of time.

In a trial that took place at the Great Ormond Street Hospital in the UK and Necker Children’s Hospital in France, researchers administered this gene therapy to seven male patients with severe Wiskott-Aldrich syndrome between 2010 and 2014. These patients ranged in age from about eight months to 16-years-old.

While one of the seven patients passed away from a pre-existing infection, the results for the surviving patients seem encouraging.

In the 24 months following treatment, researchers reported that infectious complications related to the illness were resolved in all six patients, with three of them able to stop taking preventative antibiotics.

Furthermore, severe eczema was cured in all affected patients, as were signs and symptoms of autoimmunity.

Patients have also recorded no severe bleeding episodes after treatment, and have seen a remarkable decline in hospital visits.

“I think it is very significant, it is another clear and powerful demonstration that a gene therapy approach is an effective one.” study co-author and immunologist, Adrian Thrasher, from Great Ormond Street Hospital, told the BBC.

“What we hope, and the evidence is certainly suggestive of this, is that the therapeutic effect will last for a very substantial amount of time, such that the patients should not need another treatment and so therefore we hope that it will be lifelong.”

Gene therapy slows vision loss in mouse models of retinal degeneration


Researchers have developed an antioxidant gene therapy that slows cone-cell death and prolongs vision in mouse models of retinal degeneration.

Led by Harvard Medical School geneticist Connie Cepko and postdoctoral researcher Wenjun Xiong, the research team hopes the work will one day lead to new treatment options for people with inherited progressive blindness, such as , as well as other diseases involving oxidative damage.

“People who have inherited disease genes that lead to blindness know it’s inevitable: They will lose vision. We don’t have good therapies in almost any case for them,” said Cepko, the Bullard Professor of Genetics and Neuroscience at HMS. “We’re studying how these diseases cause to die and whether there’s a way to save them.”

Photoreceptor cells include the rods and cones that allow us and many other animals, including mice, to sense light and translate it into signals for the brain to interpret. In diseases like retinitis pigmentosa (RP), excess oxygen damages these cells. Cepko and her team investigated whether they could at least slow down, if not prevent, vision loss in laboratory mice by boosting the cells’ own antioxidant powers.

“We asked, ‘Do the photoreceptors live longer and can the mice see better?'” Cepko said. “We were happy to find that yes, they could. We’re excited to explore whether this might work across species and ultimately in humans.”

The therapy also slowed the death of in a mouse model of nerve crush injuries, which mimic human conditions such as glaucoma and spinal cord injury. This suggests may be useful for combating oxidative damage in different kinds of cells in the eye and beyond, the authors said.

The findings were published March 23 in the Journal of Clinical Investigation.

Booster shot

Scientists have seen that oxidative damage occurs in , but they haven’t been able to combat it.

“People have tested small-molecule antioxidant treatments—taking high doses of antioxidants every day—in clinical trials. But the results haven’t been really promising,” said Xiong, who is first author of the paper.

Such treatments could be failing because the blood-retinal barrier prevents antioxidants from reaching the eye, or for other reasons, said Cepko. Delivering high doses of antioxidants to the whole body also risks side effects, because oxidation plays a role in many normal biological processes.

Cepko’s team wanted to develop a therapy that would circumvent those problems. First, they aimed to boost antioxidant activity not by feeding mice antioxidants but by providing extra copies of genes that fight oxidative damage. To achieve this, they delivered those genes (packaged in a viral shell) directly into the mice’s eyes.

“This gives us a more directed and potent way to regulate the oxidation,” said Cepko.

Three (kinds of) blind mice

The researchers chose three types of , each of which had one of the hundreds of different gene mutations that cause RP in humans. The mice represented fast, moderate and slow rates of retinal degeneration.

The team tested several kinds of antioxidant genes separately and together in each mouse model “to try to save as many cones as possible,” said Xiong.

One pair of genes makes enzymes called SOD2 and catalase that sweep out particular reactive oxygen species from cells. Another two genes, Nrf2 and PGC1a, are transcription factors that turn on hundreds of other genes, including many .

“There are advantages and disadvantages in using the enzymes or the master transcription switches,” said Xiong. “As far as we know, there hasn’t been a study before to compare their effectiveness in animal models of human diseases.”

Nrf2 worked best. Cone cells lived longer and retained their normal shapes longer in eyes treated with Nrf2 than in untreated eyes. To test whether that meant better vision, the team put the mice in chambers with visual stimuli and tested their reactions.

“Mice that are blind won’t respond. Mice with some vision will,” said Cepko.

Nrf2 indeed slowed down vision deterioration. At the therapy’s peak effectiveness, vision in the mice’s treated eyes was twice as good as in the untreated eyes.

SOD2 and catalase combined were also effective. But to the researchers’ surprise, PGC1a didn’t prolong cone cells’ survival. In fact, it accelerated their death.

There is already a large amount of PGC1a in photoreceptor cells. The researchers wonder whether adding more through their gene therapy may have overwhelmed the cells.

None of the treatments was able to cure the mice of their blindness.

Overall, however, “This makes us hope that developing antioxidant gene therapies may be a way to treat human patients,” said Xiong.

Nrf2 alone, and SOD2 and catalase together, similarly improved retinal ganglion cell survival in the of nerve crush.

Of human blindness

The study showed that one gene therapy can work for three different RP mutations in mice. The researchers hope this means it will also work for some or all of the other mutations that cause RP and other retinal degeneration diseases in people—and beyond. That could include neurodegenerative diseases, macular degeneration, spinal cord injury and amyotrophic lateral sclerosis (ALS).

“We think the vectors will probably work to reduce oxidation in any kind of cell,” said Cepko.

The therapy has a lot going for it. The viral shell used to deliver the genes, adeno-associated virus or AAV, has been shown to be safe for use in human eyes.

Still, it takes many steps to translate findings from to people.

“Mice have a short lifespan and rapid onset of blindness; they’re protected for a couple of months. Humans need protection over decades,” said Cepko. “I don’t know how to extrapolate from the time span we saw in the mouse to what we’d like to see in humans.”

Human eyes are also 10 times bigger than mouse eyes. And timing of delivery will have to be tested. Most people don’t know they have retinal degeneration until their rods are already dead and their cones are dying.

Cepko and team are looking at other strategies they can combine with antioxidant gene therapy, such as optogenetic therapy or stem cell therapy.

“My gut feeling is we will need a combination therapeutic to give long-lasting photoreceptor survival,” she said. “It will be a long road, and it will take more basic science to figure out which genes and which animal models to use.”

Germany poised to say yes to €1.1m a patient gene therapy drug


A laboratory technician examines blood samples
The western world’s first gene therapy drug is expected to go on sale in Germany next year.

The western world’s first gene therapy drug is set to go on sale in Germany, with a price tag that could amount to an £870,000 cost to treat a single patient.

Glybera, a treatment for the rare genetic condition lipoprotein lipase deficiency (LPLD), which clogs the blood with fat, has been developed by Dutch biotech firm UniQure and Italian MARKETING marketing partner Chiesi. It is undergoing an assessment of benefits by Germany’s federal joint committee, which will report by April 2015.

But the company is seeking a retail price of €53,000 (£42,000) per phial, which equates to €1.1m (£870,000) for a course of treatment for a typical LPLD patient. This price will be subject to a discount under Germany’s drug pricing system.

A Chiesi spokeswoman confirmed the launch price and added that a final figure would be set after the German authorities gave their verdict and negotiations are held with health insurance FUNDS. “First commercial treatments are expected in the first half of 2015,” she said.

UniQure, which will get a net royalty of between 23% and 30% on sales, said EU pricing was a matter for its Italian partner, although the Dutch firm does plan to discuss Glybera pricing during an investor meeting in New York next month.

With only 150 to 200 patients likely to be eligible for Glybera across Europe, the impact on healthcare budgets will be small, even at a very high price – but this case will be watched closely as a benchmark for future gene therapies.

UniQure also has plans to seek approval for Glybera in the United States, which it hopes to get in 2018.

Although there is already a gene therapy for cancer on the MARKETin China, that has not been rolled out to other countries, making Glybera a first for the west.

Proponents of the gene-fixing technology insist it stacks up as a cost-effective treatment, despite the high cost, as it could permanently cure many patients.

In the case of Glybera, Chiesi said the annualised cost was no morethan that charged for some expensive enzyme replacement therapies.

UniQure is also working on gene treatments for haemophilia and has an early-stage project in heart failure.

Assuming trials are successful, analysts expect gene medicines treating more common conditions to cost less, as manufacturers should be able to recoup their research and development INVESTMENT from a larger patient group.

Rivals in the gene therapy MARKET include privately-owned Spark Therapeutics, which has an eye drug in late-stage clinical tests, and Bluebird Bio, which is working on drugs for neurological and blood disorders.

Bluebird Bio and UniQure both staged successful floats on the Nasdaq MARKET in the past 18 months, reflecting growing investor interest in the field. Among major pharmaceutical companies, Bayer struck a gene therapy deal with Dimension Therapeutics in June, while Novartis recently established a new cell and gene therapies unit, and Sanofi has a long-standing tie-up with Oxford BioMedic.

New Gene Therapy Rapidly Helps Patients With Rare Blood Disorder.


Two patients who were given Bluebird Bio’s experimental gene therapy for the rare blood disorder beta-thalassemia were able to stop receiving blood transfusions within 12 days of receiving the treatment.

An earlier version of the treatment, which has allowed one beta-thalassemia patient to remain free of blood transfusions for six years, was published in the journal Nature in 2010. But that patient was not able to stop transfusions until 12 months after receiving the therapy. The new data offer hope that the new version of Bluebird’s therapy is more effective than the prototype.

“Thalessemia major patients are very sick,” says Marina Cavazzana, M.D., Ph.D., of Paris Descartes University, France. “They have to receive transfusions regularly for all of their life. Because of this huge number of transfusions they suffer from a huge iron overload. To set up a treatment that can make them free of any transfusion treatment should be a great step toward curative treatment.”

Cavazzana is presenting data on the two patients at the annual meeting of the European Hematological Society in Milan, Italy. Bluebird allowed me to review its data early under the condition that I not post my story until now.

It is estimated that about 288,000 patients with beta-thalassemia are alive, Bluebird says. About 15,000 live in the United States and Europe. The disease is caused by genetic defects in the beta chain of the protein hemoglobin, which carries oxygen throughout the body.

Bluebird’s treatment uses a modified HIV virus, known as a lentivirus, to replace the defective gene for beta globin in the blood-producing stem cells found in these bones. Since the 2010 Nature publication, Bluebird has improved both the ability of this virus to insert the corrected gene and the process by which it extracts the blood-forming stem cells. Both improvements are thought to account for the seemingly better track record so far.

Cavazzana says the treatment caused relatively few side effects, with depleted levels of white blood cells and platelets lasting for several weeks and an inflammation of the mucus membranes in the mouth and elsewhere caused by a chemotherapy drug that was part of the treatment and was easily treatable.

Nick Leschly, Bluebird’s chief executive, said in an interview that the new results are “hard to fathom.” He says: “When you look at the first few patients becoming transfusion independent right out of the gate, that’s really interesting.” Bluebird is planning to enroll another five patients in this trial, and to conduct another study of 15 patients in the U.S. and around the globe. Then, it had been assuming, it would do larger studies to get the treatment approved. But Leschly says that discussions with the U.S. Food and Drug Administration could begin sooner if these results continue to hold up.

“If we continue to see patients who look like this, then you’re going to have a conversation with the agency,” he says. The results also give him more confidence in Bluebird’s related efforts to create a treatment for sickle cell anemia. He cautions, however, that more patients need to be studied and that it’s likely that not all of them will respond as well as these first two.

Gene Therapy Shows Promise for Treating Heart Attack Victims


Injections of a normally silent gene sparked recovery in pigs induced to have heart attacks.
When a heart attack brings blood flow to a screeching halt, that’s only the first assault on our fist-size organ. Among survivors, the recovery itself fuels more permanent damage to the heart. Scar tissue can harden once-flexible heart muscle, making it less elastic. And as tentacles of this tissue creep over the aorta the heart muscle can no longer fully contract. This long-term damage can minimize the amount of oxygen-rich blood sent throughout the body, which can send patients spiraling into heart failure.

Heart transplants are one way to circumvent these scar tissue issues, but donor hearts are always in short supply. Devising other truly effective solutions has long eluded researchers. A form of gene therapy, however, is now showing promise in pigs.

It turns out that a normally silent gene called Cyclin A2, or CCNA2, can be coaxed into action to combat the formation of scar tissue in pigs that suffer a heart attack. This treatment sparked regeneration of heart muscle cells in pigs as well as improvements in the volume of blood pushed out with every beat. The finding is published in the February 19 issue of Science Translational Medicine.

Gene therapy, the authors hope, may one day join stem cell treatments as a contender for transforming the way doctors treat heart failure. Stem cell–based therapies have already resulted in more healthy tissue and decreased scar mass in human clinical trials as well as small improvements in how much blood the heart can pump from one chamber to another. But as Scientific American reported in April 2013, many questions remain about which stem cells to use and how to prepare them.

For this study, researchers randomly assigned 18 pigs recovering from heart attacks to either receive injections of the gene expressed under a promoter (which would force it to be expressed) or the same solution without the gene. Pigs treated with the gene had greater success pushing out blood with each heartbeat, but also produced a greater number of heart muscle cells. These findings echo the team’s earlier heart regeneration successes in mice and rats.

The researchers replicated their findings in a petri dish and watched adult porcine heart muscle cells treated with the same regimen of gene therapy undergo complete cell division in the dish—demonstrating under a microscope how the heart cells were dividing and thriving with the gene therapy. This new approach “mimics the kind of regeneration we see in the newt and zebra fish,” says lead author Hina Chaudhry, the director of cardiovascular regenerative medicine at The Mount Sinai Hospital in New York City.

If the technique proves successful in humans, it could boost patient recovery rates by helping strengthen heart muscles and improving blood flow, all while giving a needed lift to gene therapy research, which has been slow to gain momentum in the U.S. In 1999 Jesse Gelsinger, 18, died after a gene therapy experiment cost him his life. The virus used to deliver a gene that would potentially control his rare digestive disorder fueled a massive and fatal immune reaction. That highly publicized case, along with other gene therapy missteps, put a pall on the field.

Chaudhry says that her team is proceeding with caution and plans to be careful when administering this treatment to patient populations. “For patients who have a large heart attack who are at risk of heart failure, I think the therapy is going to be very beneficial,” she says. “If you have a small heart attack, it probably won’t make as much of a difference in overall survival because of advances with today’s medicines.” As more researchers look to gene therapy for previously intractable human conditions, a success with heart attack treatments could send ripples throughout the field.