Editing Out Blood Disease

Gene therapy successful in 22 patients with severe form of the blood disorder beta-thalassemia


In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in the clinic, an international team of investigators has announced that gene therapy can be safe and effective for patients with a severe form of the blood disorder beta-thalassemia.

Led by Philippe Leboulch, lecturer in medicine, part-time, at Harvard Medical School and a sponsored collaborator in the Brigham and Women’s Hospital Division of Genetics, an international research team reports that a one-time treatment with the gene therapy known as LentiGlobin BB305 vector reduced or eliminated the need for blood transfusions in 22 patients with severe beta-thalassemia.

The results have been published in The New England Journal of Medicine.

“It was always our hope to bring our research findings to patients,” said Leboulch, whose primary appointment has transitioned to the University of Paris as professor of medicine and institute director. “We have taken our work from the lab, through preclinical models and past the proof-of-principle stage and are now able to gauge its effectiveness in patients with this disease. It is immensely gratifying.”

Restoring hemoglobin production

Beta-thalassemia is a genetic disorder that impairs the body’s ability to produce a key component of hemoglobin, the protein in red blood cells that carries oxygen to organs and tissue. Beta-thalassemia and sickle-cell disease are related disorders—both hamper hemoglobin production and can have lifelong repercussions.

From toddlerhood on, people with the most severe forms of beta-thalassemia require monthly blood transfusions to replenish their red blood cell supplies along with iron chelation to remove extra iron from the body.

As a postdoctoral fellow at Massachusetts Institute of Technology, Leboulch began researching a therapeutic approach to compensate for the genetic mutations that lead to both sickle-cell disease and beta-thalassemia. In the 1990s, Leboulch joined HMS and Brigham and Women’s, where he continued his work to develop a viral carrier, or vector, that could insert genetic instructions into a patient’s own blood stem cells and restore hemoglobin production.

Leboulch and colleagues hoped that introducing the altered stem cells back into people would allow the cells to make enough hemoglobin, eliminating the need for blood transfusions.

Leboulch and colleagues studied the vector, LentiGlobin, in pre-clinical models, publishing results from mouse studies in Science. In 2010, Leboulch and his collaborator, Marina Cavazzana of University Paris-Descartes, published a paper in Nature detailing the success of using LentiGlobin to genetically correct cells and transplant them into a single beta-thalassemia patient. Last year, they published in NEJM on a successful gene therapy of the first sickle-cell anemia patient using the same vector.

Blood transfusions no more

In the newly published NEJM study, Leboulch, Cavazzana and their colleagues teamed up with a second group of U.S. and international clinical investigators in Australia and Thailand to share data and results from their respective phase II clinical trials.

In total, the two teams treated 22 patients at six different sites around the world. Among nine patients with the most severe form of beta-thalassemia, the one-time treatment reduced the need for red-blood cell transfusions by 73 percent. Three of the nine subsequently discontinued transfusions altogether. Twelve of the 13 patients with a slightly less severe form of the disease no longer needed any blood transfusions after treatment.

The team reports no safety concerns—treatment-related adverse effects were typical of those seen in patients who receive transplants of their own stem cells.

“When you have an anecdote of a single patient, you never know if it will be confirmed. Here, with a multi-center trial in a larger number of patients, we see a convergence of results, and we can measure the magnitude of the therapeutic effect,” said Leboulch.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” he added. “But there is also hope with protocol modifications we have introduced in our phase III trials.”

Based on these results, two pre-drug marketing phase III clinical trials have begun.

Patents on the LentiGlobin BB305 vector are owned by Bluebird Bio, which also sponsored the study. Leboulch is one of the co-founders of Bluebird Bio.

Gene Therapy for Severe Hemophilia A

A family medicine physician cares for a family in which both the grandfather and young grandson have hemophilia A. Recently, the grandfather came for a check-up on his arthritis and asked the physician, “Is there anything new for hemophilia that can help my grandson avoid what I’ve been through over the years? I wish there was some way he could avoid all those factor VIII infusions, the breakthrough bleeding, and all the painful joint damage.”

Patients with hemophilia A require frequent prophylactic infusions of factor VIII — on average 3 times per week — to prevent bleeding in joints, soft tissue, and the central nervous system. Unfortunately, breakthrough bleeding with progressive joint destruction and pain is common and can further impair quality of life. In addition, approximately one-third of patients develop antibodies to factor VIII that block its therapeutic effects. Gene transfer first showed promise in the treatment of hemophilia B, but the large size of the factor VIII gene has delayed the development of gene therapy for hemophilia A.

In this week’s issue of NEJM, Rangarajan et al. report the results of a single intravenous infusion of adeno-associated virus (AAV) factor VIII in nine adult men with severe hemophilia A. Patients were enrolled sequentially to low-dose (1 patient), intermediate-dose (1 patient), or high-dose (7 patients) cohorts and were followed for 52-weeks. Patients who received lower doses were escalated to a higher dose if their factor VIII levels were inadequate and safety requirements were maintained. High-dose patients were also treated with a short course of glucocorticoids to minimize liver toxicity from the virus.

In the low- and intermediate-dose cohorts, factor VIII levels remained low (≤3 IU/dL). However, in all seven patients in the high-dose cohort, the factor VIII level increased to the cut-off level for mild-to-moderate hemophilia (>5 IU/dL) between weeks 2 and 9; the factor VIII level in six patients increased to a normal value (>50 IU/dL) that was maintained at 1 year. In the high-dose cohort, the median annualized bleeding rate decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for bleeding ceased in all the participants in this cohort by week 22. Adverse events related to the gene therapy were considered minor. Seven patients experienced mild elevation in serum alanine aminotransferase (ALT) levels that resolved without sequelae. One patient experienced progression of pre-existing chronic arthropathy.

The authors concluded that in this small study of nine patients with severe hemophilia A, a single infusion of the high-dose vector-encoded factor VIII led to sustained normalization of factor VIII activity, with significant reduction in bleeding events and additional factor VIII use. Although no serious adverse events were reported during the 1-year study, further testing in more patients with longer follow-up is needed to determine the efficacy and safety of this novel treatment.

Returning to the patient’s question, although research on gene therapy for hemophilia A requires further study before it becomes widely available, hope is on the horizon that the patient’s grandson will be able to receive treatment to prevent the complications of hemophilia A and significantly improve his quality of life.

Another Gene Therapy Breakthrough Against Hemophilia

Coming just days after reports of a gene therapy that pushed the bleeding disorder hemophilia B into remission, new research suggests the same could be true for adults with the “A” form of the disease.

That’s significant because, due to the complexities of the gene responsible for hemophilia A, experts had thought it might be far more resistant to gene-based treatment.

But in the new British trial, all 13 adult patients with hemophilia A were able to go without preventive injections of a blood-clotting factor that they’d needed almost weekly, researchers report. The study was led by Dr. K. John Pasi, hemophilia clinical director at Barts Health NHS Trust in London.

Ten of the 13 patients experienced no bleeding incidents requiring transfusion, the team said. And that improvement began a month after the one-time gene therapy and continued over 18 months of follow-up.

Pasi’s group was scheduled to report the findings Saturday at the American Society of Hematology annual meeting, in Atlanta. Hemophilia A affects over 20,000 Americans; it is the more common form of hemophilia.

 The results “exceeded our expectations,” Pasi said in a meeting news release. He explained that people with hemophilia have a genetic flaw that renders them incapable of producing a key blood-clotting factor, called factor VIII.

However, after receiving the new therapy, “many clinical trial participants have seen factor VIII levels at or close to normal,” Pasi noted.

The breakthrough — if it lasts over the long-term — could be a game-changer, he said.

The treatment “has the potential to improve the lives of patients who must now infuse themselves with factor VIII as often as every other day,” Pasi explained.

 If the results bear out in larger, longer trials, he said, “it may be possible for hemophilia A patients to reduce or eliminate factor VIII treatment over an extended timeline.”

One hematologist agreed that the technique could be groundbreaking.

“This strategy promises to be the only ‘cure’ for hemophilia A patients who can hope to be free of their bleeding symptoms without the use of clotting protein replacement into their veins,” said Dr. Suchitra Acharya, who directs the Hemophilia Treatment Center at Long Island Jewish Medical Center, in New Hyde Park, N.Y.

The findings follow news of another study, published on Wednesday, that found a similar approach helped 10 men with hemophilia B go without standard treatments. That study was led by Dr. Lindsey George, of the Children’s Hospital of Philadelphia.

Both studies were published in the New England Journal of Medicine.

In both trials, doctors used a harmless virus to introduce into the patient’s body a functional copy of the gene responsible for producing factor VIII — a gene that’s defective in people with the disease.

In the hemophilia A study, the men received either a high- or low-dose of the gene therapy.

Five months after receiving the treatment, people who got the higher dose achieved factor VIII levels that settled out at the normal range; while three of the patients who got the lower dose achieved that level by 8 months after treatment, the findings showed.

And while other gene therapy trials have sometimes been plagued by adverse immune system reactions in recipients, there was no evidence of that in this trial, Pasi’s group noted.

Still, the researchers stressed it’s too soon to draw conclusions about the long-term safety of the treatment.

This DNA-tweaking approach likely won’t be cheap, either. The few gene therapies in use around the world typically cost between $400,000 to $1 million for each treatment.

The hemophilia A study was funded by drug company Biomarin Pharmaceuticals.

In another potential breakthrough, researchers also plan to report at the hematology meeting on Saturday that a drug called emicizumab appears to free children with hemophilia A from serious “bleeding events” requiring treatment. Young people with the disease often experience painful bleeds, especially within the joints.

That trial was led by Dr. Guy Young, of Children’s Hospital Los Angeles and the University of Southern California. His team tracked outcomes for 60 kids, all between the ages of 1 and 12, for an average of nine weeks.

The researchers reported that only three of the children experienced a bleeding episode that required standard treatment after receiving emicizumab via injection.

“Before this drug, we didn’t have very effective ways to prevent joint bleeding in these patients,” Young said in a meeting news release. But the new medicine has “been life-changing for the children I’ve treated,” he added.

No safety issues were observed, but because longer-term safety concerns can’t be ruled out, his group plans to follow the children’s progress for another year.

The study was funded by emicizumab’s co-developers, Roche and Genentech. Research presented at meetings is considered preliminary until published in a peer-reviewed journal.

New Gene Therapy May Be Cure for ‘Bubble Boy’ Disease

Babies born with the immune-system ravaging “bubble boy” disease have had to spend their too-often-short lives in germ-free isolation, lest something as simple as a common cold virus fell them with a fatal infection.

But after decades of research, doctors now believe they have created a cure for severe combined immunodeficiency (SCID).

Six out of seven infants treated using a newly crafted gene-based therapy already are out of the hospital and leading normal childhoods at home with family, said lead researcher Dr. Ewelina Mamcarz, an assistant member of the faculty in the Bone Marrow Transplant Department at St. Jude Children’s Research Hospital in Memphis, Tenn.

“They left the hospital after four to six weeks and we’re following these babies on an outpatient basis,” Mamcarz said. The last infant is barely six weeks past treatment, and his immune system is still in the process of constructing itself.

  The results so far indicate that Mamcarz and her colleagues have cured these infants, said Jonathan Hoggatt, an assistant professor of stem cell research at Harvard Medical School.

“If they get all of their immune cells and the stem cells are lasting long-term, this is for all intents and purposes a cure,” said Hoggatt, who was not involved with the study. “This isn’t a repeated treatment. You do this once and you’re done.”

The new therapy focuses on X-linked SCID, the most common type of the disease. It only affects males because it is caused by a genetic defect found on the male X chromosome. It occurs in 1 out of every 54,000 live births in the United States, Mamcarz said.

 SCID was first brought to public attention after the release of “The Boy in the Plastic Bubble,” a 1976 movie about the true-life story of a child born with the disease.

Boys born with X-SCID cannot produce any of the immune cells that defend the body against infection: T-cells, B-cells and natural killer (NK) cells.

Without treatment, these babies typically die by age 2, researchers said. About one-third of those who receive the best available treatment, a stem cell transplant, wind up dying by age 10.

The new treatment uses an inactivated form of HIV to introduce genetic changes into the patient’s bone marrow cells. These changes fix the bone marrow so it starts doing its job, pumping out all three types of immune cells, explained senior researcher Dr. Brian Sorrentino, director of the Experimental Hematology Division at St. Jude Children’s Research Hospital.

Researchers chose HIV as their vehicle because the virus naturally evolved to effortlessly infect human immune cells, “so we’re co-opting this property for our own purposes,” Sorrentino said.

Previous versions of this gene-based cure used a different mouse-derived virus, which tended to activate cancer-causing cells and produce leukemia in patients. The new HIV-based version does not have this effect, Sorrentino said.

But the virus is only part of the solution. Babies given this treatment also underwent “conditioning” using the chemotherapy drug busulfan to prepare their bone marrow to accept the genetic changes, researchers said.

People undergoing bone marrow transplants often receive chemo or whole-body radiation to kill off their damaged immune system, so it won’t interfere with the new healthy immune cells being introduced, Hoggatt explained.

Previously, research teams had been reluctant to use chemotherapy in treating SCID because of the potential damage it could do to newborns, Hoggatt said. Doctors also believed the babies probably didn’t need it.

“The thought was for SCID patients, they don’t really have any immune cells so we don’t need to do that,” Hoggatt said.

However, X-SCID babies only achieved a partial cure when they received the viral treatment without chemo. Their T-cells came back, but not their B-cells or NK-cells, Sorrentino said.

“The B-cells wouldn’t come back, and as a result many if not all these initial gene therapy babies would require a lifelong supplementation with antibody therapy, sometime every month or every six weeks, which is very expensive,” Sorrentino said.

Computer-guided infusions allowed the researchers to give babies individual doses of busulfan that were just strong enough to prepare them for gene therapy, Sorrentino said.

The combination of the gene therapy with mild chemo appears to have restored all three types of immune cells in the babies, the researchers said.

The virus also appears to be successfully infiltrating the immune system. In some cases, more than 60 percent of all bone marrow stem cells carried the new corrective gene introduced by the virus, researchers say.

The researchers emphasize that the babies still need to be tracked, to make sure the treatment remains stable with no side effects. They’ll also need to see how the babies respond to vaccination.

“Our oldest patient is now at about 15 months, and our youngest one is just several months,” Sorrentino said. “We definitely need more follow-up time, to understand more about them. But based on what we’re seeing at this early point, we think it’s got a good chance of being a permanent fix.”

The researchers were to present the findings Saturday at the American Society of Hematology’s annual meeting, in Atlanta. Research presented at meetings is considered preliminary until published on a peer-reviewed journal.


FDA Okays Gene Therapy for Rare Form of Blindness


Hemophilia – Gene Therapy .

uniQure has built an exciting portfolio of clinical and pre-clinical programs focused on hemophilia.

uniQure has built an exciting portfolio of clinical and pre-clinical programs focused on hemophilia. This overall effort is well supported by uniQure’s proprietary position with our AAV5 viral vector, which has shown particular affinity for reaching the liver. AAV5 has the benefit of a low prevalence of pre-existing anti-AAV5 antibodies in patients screened to date in uniQure’s clinical trials and as indicated in medical literature. uniQure also has gained extensive experience in the development and regulatory approval of the first gene therapy approved in the Western world: Glybera.

Hemophilia B

uniQure is developing a gene therapy for hemophilia B, a severe orphan blood clotting disorder. The program’s gene therapy product candidate consists of an AAV5 vector carrying a therapeutic human Factor IX, or FIX, gene cassette that uniQure has exclusively licensed from St. Jude Children’s Research Hospital in Memphis, Tennessee. uniQure is currently conducting a Phase I/II study of AMT-060 in patients with severe hemophilia B and advanced joint disease.

In December 2016, the Company presented updated clinical data from our Phase I/II trial (view press release).  In January 2017, AMT-060 received Breakthrough Therapy designation from the U.S. Food and Drug Administration in January 2017 based on results from this ongoing, dose-ranging study (view press release).

The data from our Phase I/II study demonstrate AMT-060 is delivering sustained and significantly improved clinical benefits to patients suffering from severe hemophilia B by enabling them to discontinue bi-weekly infusions of FIX replacement therapy and to essentially eliminate the risk of spontaneous bleeding. We are observing a therapeutic benefit from AMT-060 that is clearly superior to their  previous prophylactic FIX  replacement therapy regimen, even in patients with advanced joint disease who still experienced many bleeds despite prophylaxis with FIX.

At both doses evaluated, AMT-060 appears to be safe and well-tolerated with no loss of FIX activity, no activation of T-cell response and no development of inhibitors for any of the 10 patients in the study.

The data from this ongoing study demonstrate clinically significant and sustained increases in FIX activity, substantial reductions in FIX replacement usage and a near cessation of spontaneous bleeding episodes.

AMT-060 has demonstrated a very low screening failure rate, with all patients screened in the study testing negative for pre-existing anti-AAV5 NABs, which suggests that a large proportion of the hemophilia patient population may be eligible for treatment with AMT-060.   The proprietary elements of AMT-060, including our fully-humanized FIX gene cassette and AAV5 vector, are the only gene therapy components clinically demonstrated in hemophilia B to be safe, effective, and durable for up to six and a half years.  These factors, along with our commercial-scale manufacturing capabilities, differentiate AMT-060 from other hemophilia gene therapies in development, and we look forward to advancing our program into a late-stage clinical study.


Hemophilia A

As another indication important to uniQure’s efforts in liver/metabolism, the Company is in pre-clinical evaluation for a gene therapy to treat hemophilia A.  We expect to provide an update on this program sometime in the first half of 2017.

New find offers hope for some Hemophiliacs

The human factor VIII (hFVIII) gene therapy has been improved to identify the exact virus to take the treatment forward
These design improvements are crucial as the practical application of gene therapy for hemophilia progresses. (Photo: Pixabay)

 These design improvements are crucial as the practical application of gene therapy for hemophilia progresses.

A team of researchers has improved the vectors for delivering human factor VIII (hFVIII) gene therapy to treat Hemophilia A.

The University of Pennsylvania study examined 42 combinations of promoters and enhancers for hFVIII gene expression to identify the optimal adeno-associated virus (AAV)-based gene therapy delivery vector constructs to take forward into development.

Evaluation of the different combinations in mice that lack factor VIII demonstrated the significant and differing effects the vector components had on liver-specific expression of the hFVIII transgene.

Researcher James M. Wilson and coauthors developed and compared the different AAV vectors to overcome the challenge of delivering the relatively large hFVIII gene and to achieve therapeutic levels of factor VIII gene expression. They also compared the levels of antibody generated against the various AAV transgene delivery vectors.

“Dr. Wilson’s group and their colleagues at Dimension Therapeutics continue to improve the design of AAV vectors designed to treat the more common form of hemophilia, hemophilia A,” said Editor-in-Chief Terence R. Flotte. “These design improvements are crucial as the practical application of gene therapy for hemophilia progresses.”The study appears in the journal Human Gene Therapy.



Blind British man in world’s first operation to deliver modified DNA to his eyes

Eye surgeons carry out the operation 
A 29-year-old man with an inherited form of blindness has become the first in the world to receive groundbreaking gene therapy  

Thousands of people born with a faulty gene which makes them go blind have been offered new hope after a British man underwent the world’s first operation to deliver new DNA to his eyes and restore his sight.

Around 15,000 people in Britain suffer from x-linked retinitis pigmentosa, a deteriorating condition which brings a slow and irreversible loss of vision, and which is the leading cause of blindness in young people.

Loss of sight occurs because a gene responsible for maintaining the light sensitive cells at the back of the eye is missing half of its DNA code.

 But scientists can now replace the code using a groundbreaking technique which reprogrammes the gene in the lab, then delivers the healthy DNA into the eye, via a harmless virus.
Scientists used a harmless virus to transport the modified DNA to the man's eyes 
Scientists used a harmless virus to transport the modified DNA to the man’s eyes  

Last Thursday, a 29-year-old man became the first person in the world to undergo the procedure at Oxford Eye Hospital and is now recovering.

Robert MacLaren, Professor of Ophthalmology at the University of Oxford, who is leading the trial said: “He is doing well and now at home, but we will have to wait a few years to know if it has stopped his retina from degenerating.

“The effect of disease on families with retinitis pigmentosa is devastating and we have spent many years working out how to develop this gene therapy.

“Changing the genetic code is always undertaken with great caution, but the new sequence we are using has proven to be highly effective in our laboratory studies.

“The genetic code for all life on Earth is made up of four letters – G, T, A and C. In retinitis pigmentosa, however, half of the RPGR gene comprises only two letters – A and G.

“This makes the gene very unstable and prone to mutations, making it a lead cause of blindness in patients with retinitis pigmentosa. RPGR is vital for the light sensitive cells at the back of the eye.”

Robert MacLaren, Professor of Ophthalmology at the University of Oxford
Robert MacLaren, Professor of Ophthalmology at the University of Oxford

Retinitis pigmentosa affects 1 in 4000 people, with symptoms that typically appear between age 10 and 30. Night vision and peripheral vision go first, as the photoreceptors active in low light – the ‘rods’ – start to degenerate.

Eventually the condition affects the ‘cones’ – the photoreceptors responsible for central, detailed, colour vision, causing complete sight loss.

Doctors want to enroll at least 24 more patients in the trial to find out if the technique is safe and effective.

The combined NHS, University of Oxford and Nightstar gene therapy team
The combined NHS, University of Oxford and Nightstar gene therapy team

CRISPR Gene Editing Has Repaired a Blood-Borne Disease

  • Researchers from Stanford have used the CRISPR-Cas9 gene editing technique to fix the gene defects that cause sickle cell disease.
  • Approximately 70,000 – 100,000 individuals in the United States have sickle cell disease and 3 million have sickle cell trait.


Gene editing remains a widely controversial topic due to the large potential for both benefit and “accidents.” Despite this, scientists are still hard at work developing gene edits that can solve a wide variety of diseases.

A new study may have found the key to solving a painful, and potentially fatal, genetic defect. Researchers from Stanford used the CRISPR-Cas9 gene editing technique to fix the gene defects that cause sickle cell disease.

Sickle cell disease is actually a group of related diseases that cause the formation of hemoglobin S, or sickle-shaped hemoglobin. That shape results in red blood cells becoming tangled in each other. Enough tangling, and blood vessels could be blocked, causing pain and even death.

To correct the issue, one has to repair the genes that code for abnormal hemoglobin. Using CRISPR, the researchers were able to do this. They took hematopoietic stem cells from patients that have the disease and edited them to repair their genome.

After, the repaired stem cells are concentrated and injected to healthy mice. Once there, the stem cells find their way into bone marrow and start producing more of their healthy variants. Sixteen weeks after injection, the researchers found healthy red blood cells thriving in the bone marrow.


This is just one of the increasing number of diseases that have met their match thanks to CRISPR. The gene editing technique is composed of an enzyme that can splice DNA sequences and guide RNA that take them to the specific sequences that need splicing.

“There’s already a lot of active research going on using the CRISPR technology to fix diseases like Duchenne muscular dystrophy or cystic fibrosis or Huntington’s disease,” says Jennifer Doudna, a pioneer of the technology, to CNBC.

But even if ways to cure using CRISPR are abound, researchers are treading lightly on implementation, since editing genes is risky and can have disastrous consequences. Ultimately, we will need to have a serious debate on how to go about the changing the very blueprint of our bodies.

Ageing process may be reversible, scientists claim.

New form of gene therapy shown to produce rejuvenating effect in mice, although scientists say human clinical applications are decade away

Discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.
Discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.

Wrinkles, grey hair and niggling aches are normally regarded as an inevitable part of growing older, but now scientists claim that the ageing process may be reversible.

The team showed that a new form of gene therapy produced a remarkable rejuvenating effect in mice. After six weeks of treatment, the animals looked younger, had straighter spines and better cardiovascular health, healed quicker when injured, and lived 30% longer.

Juan Carlos Izpisua Belmonte, who led the work at the Salk Institute in La Jolla, California, said: “Our study shows that ageing may not have to proceed in one single direction. With careful modulation, ageing might be reversed.”

The genetic techniques used do not lend themselves to immediate use in humans, and the team predict that clinical applications are a decade away. However, the discovery raises the prospect of a new approach to healthcare in which ageing itself is treated, rather than the various diseases associated with it.

The findings also challenge the notion that ageing is simply the result of physical wear and tear over the years. Instead, they add to a growing body of evidence that ageing is partially – perhaps mostly – driven by an internal genetic clock that actively causes our body to enter a state of decline.

The scientists are not claiming that ageing can be eliminated, but say that in the foreseeable future treatments designed to slow the ticking of this internal clock could increase life expectancy.

“We believe that this approach will not lead to immortality,” said Izpisua Belmonte. “There are probably still limits that we will face in terms of complete reversal of ageing. Our focus is not only extension of lifespan but most importantly health-span.”

Wolf Reik, a professor of epigenetics at the Babraham Institute, Cambridge, who was not involved in the work, described the findings as “pretty amazing” and agreed that the idea of life-extending therapies was plausible. “This is not science fiction,” he said.

On the left is muscle tissue from an aged mouse. On the right is muscle tissue from an aged mouse that has been subjected to “reprogramming”.
On the left is muscle tissue from an aged mouse. On the right is muscle tissue from an aged mouse that has been subjected to “reprogramming”. Photograph: Salk Institute

The rejuvenating treatment given to the mice was based on a technique that has previously been used to “rewind” adult cells, such as skin cells, back into powerful stem cells, very similar to those seen in embryos. These so-called induced pluripotent stem(iPS) cells have the ability to multiply and turn into any cell type in the body and are already being tested in trials designed to provide “spare parts” for patients.

The latest study is the first to show that the same technique can be used to partially rewind the clock on cells – enough to make them younger, but without the cells losing their specialised function.

“Obviously there is a logic to it,” said Reik. “In iPS cells you reset the ageing clock and go back to zero. Going back to zero, to an embryonic state, is probably not what you want, so you ask: where do you want to go back to?”

The treatment involved intermittently switching on the same four genes that are used to turn skin cells into iPS cells. The mice were genetically engineered in such a way that the four genes could be artificially switched on when the mice were exposed to a chemical in their drinking water.

The scientists tested the treatment in mice with a genetic disorder, called progeria, which is linked to accelerated ageing, DNA damage, organ dysfunction and dramatically shortened lifespan.

After six weeks of treatment, the mice looked visibly younger, skin and muscle tone improved and they lived 30% longer. When the same genes were targeted in cells, DNA damage was reduced and the function of the cellular batteries, called the mitochondria, improved.

“This is the first time that someone has shown that reprogramming in an animal can provide a beneficial effect in terms of health and extend their lifespan,” said Izpisua Belmonte.

Crucially, the mice did not have an increased cancer risk, suggesting that the treatment had successfully rewound cells without turning them all the way back into stem cells, which can proliferate uncontrollably in the body.

The potential for carcinogenic side-effects means that the first people to benefit are likely to be those with serious genetic conditions, such as progeria, where there is more likely to be a medical justification for experimental treatments. “Obviously the tumour risk is lurking in the background,” said Reik.

The approach used in the mice could not be readily applied to humans as it would require embryos to be genetically manipulated, but the Salk team believe the same genes could be targeted with drugs.

“These chemicals could be administrated in creams or injections to rejuvenate skin, muscle or bones,” said Izpisua Belmonte. “We think these chemical approaches might be in human clinical trials in the next ten years.”

The findings are published in the journal Cell.

  • This article was amended on 16 December 2016. A previous version erroneously gave Wolf Reik’s affiliation as the University of Cambridge. This has now been corrected to the Babraham Institute, Cambridge.

Listen to the video discussion. URL:https://youtu.be/h56hDCji1QM