Karen Weintraub Contributor GEN

Gene Therapy Allows Hemophilia Patients to Give Up Medication, Avoid Bleeds; but More Improvements Are Needed

A new gene therapy trial in hemophilia B patients is the most successful so far, allowing all 10 participants to give up regular use of their medication, and 9 out of the 10 to avoid spontaneous bleeding altogether. The participants, all men, saw dramatic increases in their blood levels of clotting factor IX, the absence of which causes their disease and can make even minor injuries life-threatening.

“It’s definitely the best thing I’ve seen so far in terms of consistency of responses in patients, in terms of minimal side effects, in terms of overall efficacy—there’s no doubt about it,” said Thierry VandenDriessche, Ph.D., director of the department of gene therapy and regenerative medicine at the Free University of Brussels and deputy European editor of the journal Human Gene Therapy, who was not involved in the research.

Hemophilia A and B are X-linked diseases, meaning that men who inherit the defective gene—and only have one copy of the X chromosome—develop the disease, while women normally inherit only one copy and are carriers since their other X chromosome is usually normal.

The therapy, delivered to the liver via a viral vector, inserts a variant factor IX gene containing a mutation called Padua. In 2009, Italian researchers discovered a young man in Padua with a genetically sky-high level of clotting factor activity. The mutation was terrible for him—triggering blood clots while he was still in his teens—but gave hemophilia researchers an idea.

Scientists, including Dr. VandenDriessche, showed that in animals bred to have hemophilia B, turning up the Padua gene mutation increased levels of factor IX in the blood and reversed the symptoms of hemophilia. The human study, published yesterday in the New England Journal of Medicine, showed the same benefits.

The trial participants’ factor IX blood levels increased to 34% of normal on average—compared with levels of no more than 5% in previous gene therapy trials, and natural levels below 1% in the most severely affected hemophilia patients. The higher clotting factor levels have lasted for an average of about a year so far.

Patients typically need to inject clotting factor as often as every other day to reduce incidents of spontaneous bleeding. Being able to stop their medication without triggering bleeds makes a big difference in their quality of life, Dr. VandenDriessche told GEN.

The treatment is still not a cure and doesn’t bring clotting factor levels up to 100%. “We’re not quite there yet. It’s not yet normal. But it’s certainly a very significant improvement,” he said.

Two patients experienced a temporary immune reaction in their livers, which was treated with steroids. A previous trial had led to liver reactions in four out of six trial participants. Fewer patients reacted in this trial because the effectiveness of the Padua gene allowed researchers to provide a four-times-lower dose of the therapy—while still achieving a seven-fold improvement in clotting factor levels, said Katherine A. High, M.D., the paper’s senior author, and president and head of research and development at Spark Therapeutics, a Philadelphia-based biotechnology company that ran the study in collaboration with pharmaceutical giant Pfizer.

It’s also unclear how long the improvements will last. A previous gene therapy study in people shows that the clotting factor boost lasts for at least three years, and data in dogs shows a 10-year benefit, Dr. High said.

But liver cells turn over, and while the virus inserts the new gene inside the nucleus, the gene does not stably integrate into the chromosomes. It’s possible then that the new genes won’t survive cell division, or that their presence will be diluted over time as the cells divide, Dr. VandenDriessche said.

That’s also why the therapy was tested in adults although it is an inherited condition whose symptoms appear early in life, said Lindsey George, M.D., the paper’s first author. Babies’ liver cells divide rapidly, so the gene would be in fewer and fewer of them as the liver grew, she said.

The immune system develops resistance to the virus that delivers the gene therapy, so the treatment can currently be used only once in a lifetime, added Dr. George, who is also a hematologist at the Children’s Hospital of Philadelphia and an instructor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Researchers introduced the Padua gene into the liver cells using an adeno-associated viral (AAV) vector. They had to turn away about 30% of patients who wanted to participate in the trial, but who already had immunity to AAV, Dr. High said, meaning their immune systems would immediately neutralize the vector. AAV is different from the adeno viruses used in early gene therapies, which sparked dramatic—and sometimes deadly—immune reactions. AAV has never triggered such a strong immune response, Dr. VandenDriessche said.

In the future, Dr. VandenDriessche said, researchers may consider using lentiviral vectors, which integrate the gene into the nuclear genome, making a more permanent change—for better and worse. Fewer people have natural immunity to lentivirus, said Dr. VandenDriessche, who is now using this approach to test gene therapy in mice with hemophilia.

Dr. High, an emeritus professor of pediatrics at Penn, said her team was able to get a better result than in previous trials because they focused on many aspects simultaneously: designing a careful trial, improving the gene target, using a strong promoter, and a good capsid, which directs the treatment into the liver where factor IX is made. “There’s no single magic bullet,” Dr. High said. “It’s important to think seriously about everything that can affect the clinical outcome and try to address all of those.”

The research team is already planning a larger Phase III trial of the therapy, Dr. High said, which will be run in partnership with Pfizer. The researchers are also working on a trial using gene therapy to treat patients with hemophilia A, which affects at least four times more patients than hemophilia B. Most researchers have started with hemophilia B because factor IX is easier to fit into an AAV vector than the factor VIII gene that is involved in hemophilia A.

Gene therapy has been tested in hemophilia since the late 1990s, but progress was slow until recently. There have been eight or nine trials in the last three years—making it an exciting but also a confusing time to be a patient, said Michelle Witkop, who holds a doctorate of nursing practice and is the head of research at the National Hemophilia Foundation.

Because if today’s gene therapies can only be used once, some patients are reluctant to try the approach until it is further advanced. But even small increases in clotting factor levels can mean big improvements in quality of life, Dr. Witkop said.

The National Hemophilia Foundation has been working with gene therapy researchers to develop consistent standards for evaluating all the gene therapy trials, she added.

Life expectancy for people with hemophilia used to be just 30 or 40 years, said Witkop said. When the AIDS epidemic hit, many hemophilia patients were infected by using blood products.

With current treatments, most patients now have a normal lifespan, she said, though they do suffer frequent bouts of severe pain from bleeding in joints.

There will be a lot more gene therapy advances to come, Dr. George promises. “The hope is that lessons that are learned from this trial as well as other gene therapy trials could be translatable for other patients who have disorders that originate from abnormalities in a single gene,” she said.

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