Gene therapy changes what it means to inherit hemophilia B

A bump, a fall or an injury that might have been quickly forgotten by another child could have been a crisis for Alexei Romanov. Born in 1904 as heir to the Russian throne, Alexei had hemophilia B, an inherited bleeding disorder caused by mutations in the F9 gene, which provides instructions for making the clotting protein Factor IX. The condition occurs predominantly in males, while women can carry the mutation and pass it to their children. Romanov’s great-grandmother, Queen Victoria, carried the mutation associated with hemophilia, which traveled through her descendants into royal families across Europe.

A royal title offered little protection from hemophilia B.

Romanov’s blood did not clot normally because his body could not produce enough functional Factor IX, a protein essential to the clotting process. An injury could lead to prolonged bleeding, which could cause severe pain and lasting damage if it occurs inside the body.

Advances in medicine eventually transformed hemophilia B care. First available in the 1960s, Factor IX replacement therapy gave patients the clotting protein their bodies lacked, helping prevent or control bleeding. For many decades, it stood as the best option for patients with hemophilia B, but there were still issues. 

“The challenge is that the protein doesn’t last very long, so patients need frequent intravenous infusions,” explained Andrew Davidoff, MD, St. Jude Department of Surgery chair. “It’s an effective treatment, but it’s also very expensive for something that has to be given so frequently.”

Changing the instructions

Researchers at St. Jude saw an opportunity to move beyond repeatedly replacing the missing protein. Building on the institution’s expertise in translational research, they began exploring whether they could provide a more lasting source of Factor IX.

For Davidoff, hemophilia B was well suited for a treatment that would address its root cause. “These individuals are missing one protein in the blood-clotting process,” Davidoff said. “Replace that one protein, and their blood can essentially clot normally.” 

Davidoff and his colleagues pursued gene therapy, an approach that introduces, modifies or replaces genetic material to treat disease. For hemophilia B, the therapy uses a modified virus to deliver a working F9 copy to cells in the liver, where Factor IX is normally produced. With those new instructions, the liver cells can produce Factor IX and release it into the bloodstream. 

In theory, a single treatment could turn the liver into a lasting source of the clotting protein patients had previously needed to receive repeatedly. The concept was straightforward. Getting it to patients was not. 

“It’s not a simple or short effort to get a clinical trial approved and going,” Davidoff said. “We did a lot of preclinical studies in the lab showing that it was safe and effective.” 

Putting gene therapy to the test  

Years of that work eventually led to a clinical trial conducted by St. Jude and University College London collaborators. Between 2010 and 2012, 10 adults with severe hemophilia B received a single infusion of the gene therapy. Davidoff and Ulrike Reiss, MD, Hemophilia Treatment Center director, Department of Hematology, co-led the effort, with Davidoff driving much of the scientific development and Reiss leading the clinical work that brought the gene therapy to patients. 

The trial tested whether an idea developed in the laboratory could work in the clinic. “We didn't know how long the treatment would last,” said Reiss. “But for many patients, the improvement was life-changing. They could live with far fewer concerns about their hemophilia.”

The participants began producing Factor IX. Bleeding episodes fell, and many were able to reduce or stop the regular infusions that had long been part of managing their disease. The results offered early evidence that gene therapy could do more than temporarily replace the missing clotting protein. It could give the body a lasting source of its own. A follow-up study published in The New England Journal of Medicine in 2014 reported results showing that a single infusion could produce sustained Factor IX levels and significantly reduce both bleeding and the need for Factor IX replacement therapy.

But what “lasting” meant was something researchers could not yet define. Gene therapy was still relatively new, and no one knew how long the liver cells would continue producing Factor IX from the genetic instructions they had received. 

There was only one way to find out: time.

A therapy that stands the test of time

Thirteen years later, researchers had an answer. The benefits had endured.

A long-term follow-up study published in the New England Journal of Medicine in 2025 showed that all 10 participants continued to produce Factor IX at stable levels years after receiving gene therapy. Their annualized bleeding rates had fallen nearly tenfold, and most no longer needed regular Factor IX replacement therapy. Researchers observed no long-term side effects or toxic events related to the treatment.

In addition, the impact extended beyond what could be measured in Factor IX levels or bleeding rates. Before gene therapy, living with hemophilia could mean constantly planning around the possibility of a bleed, preparing for an injury, knowing where to seek treatment and considering the risks of everyday activities. Years after receiving gene therapy, one participant emailed Davidoff: “Honestly, I’ve sort of forgotten that I have hemophilia.” For Davidoff, knowing the disease no longer shaped the patient’s everyday life was simply amazing.

However, as gene therapy moves forward, the question of who will have access to it is becoming increasingly important.

Expanding access around the world

For many patients around the world, reliable access to preventive hemophilia B treatment remains out of reach. In lower-resource settings, the cost of Factor IX and the need for frequent intravenous infusions can make regular replacement therapy difficult or impossible to sustain. Instead, some patients receive Factor IX only after a bleed has already begun, leaving them without the protection that preventive treatment provides.

“We know gene therapy for hemophilia B works, and now the question is how to bring those benefits to patients in countries where access to standard hemophilia treatment remains limited,” said Reiss. “We want more patients to have the opportunity to benefit from these advances.” 

Through the Global Hemophilia B Gene Therapy Trial, St. Jude and the World Federation of Hemophilia are working to determine not only whether gene therapy can be delivered safely and effectively in resource-limited countries, but also what it takes to establish programs in places that may not have the resources to develop them independently.

Doing so requires more than making the treatment available. Patients, caregivers and health care providers need education to understand the potential benefits and risks of gene therapy. A 2026 study published in Haemophilia found that although patients, caregivers and health care providers are hopeful about gene therapy for hemophilia B, concerns about safety and long-term effectiveness highlight the importance of clear communication and informed decision-making.

Participating centers also need technical and logistical support to deliver the therapy safely and monitor patients. To help build this capacity, eligible participants will initially receive treatment at St. Jude then return home for follow-up care at their local centers. The goal is for those centers to eventually provide the gene therapy and monitor patients themselves.

The potential is especially significant for patients who have never had reliable access to preventive Factor IX replacement. “They will benefit the most because many people cannot afford the recombinant protein,” said Davidoff. “The one-time administration that potentially helps them make protein for life is extremely practical.” 

A legacy redefined

For Romanov, born more than a century ago, hemophilia B was an inheritance physicians had few tools to change. The threat of a serious bleed followed him throughout his life.

Today, that inheritance does not have to dictate the same future.

Instead of waiting for a bleed or repeatedly replacing the Factor IX the body cannot make, gene therapy gives cells the instructions to produce it themselves. More than a decade after the first participants received those instructions, their bodies are still following them. 

Hemophilia B may still be written into a person’s genes, but advances in treatment are changing what it means to inherit the disease.