Gene therapy comes of age to staunch hemophilia B

How often does a person fall in a year? Most would forget a minor trip within a few minutes, but for people with hemophilia B, even a minor fall can have major consequences. The genetic disorder, which leads to prolonged bleeding events even for minor incidents, has a storied history. In the early 1900s, before the advent of blood storage, the life expectancy of someone with hemophilia B was 13 years. Early treatment for the inherited disorder, which included diluted viper venom discovered to clot blood, had limited effect, and by 1960, the life expectancy had barely risen, still less than 20 years. 

The publication of the “clotting cascade” in 1964, the series of factors which participate in blood clotting, set change in motion. With the advent of safer blood product synthesis and administration practices throughout the 1980s and ’90s, missing factors could begin to be safely given prophylactically, significantly improving survival rates and quality of life for people with hemophilia B. Along with prophylactic treatments, patients can take clotting factors on-demand in response to a bleeding event, but either way has drawbacks; it can be expensive, invasive and a significant burden, especially over the course of a lifetime. 

Adrian was born with hemophilia B, induced by a missing or defective gene responsible for blood-clotting factor IX. “I was fairly active as a kid and teenager, so I had quite a number of bleeds into my joints, especially my ankles and my elbow,” Adrian explained. “I never felt like they were particularly debilitating, but then in my 30s, I started having a lot of trouble with my knees.” Adrian underwent two different surgeries on his knees, which had limited effect. The root of the issue remained his factor IX deficiency.

In search of a more permanent solution, Adrian’s hematologist came across a clinical trial that was recruiting at St. Jude. It was for a different kind of therapy — one that would address the problem at its genetic root. 

Tunable viruses offer reliable vehicle for gene therapy

Gene therapy involves modifying or replacing defective genes in the body. The trial Adrian joined in 2012, led by Andrew Davidoff, MD, and the late Arthur Nienhuis, MD, at St. Jude, and Amit Nathwani, PhD, of University College London Cancer Institute, was for a novel gene therapy aimed at replacing the lost factor IX gene. The study was recruiting 10 men because hemophilia B is an X-linked recessive disorder, meaning the defective gene is on the X chromosome and thus predominantly affects men. Adrian was one of the 10 selected for the trial.

A trained scientist, Adrian naturally began digging into the details of the study. Like many gene therapies, it all began with a virus, in this case, the adeno-associated virus (AAV). AAV is a naturally occurring virus within humans, and in the early 1990s, scientists began recognizing its potential for introducing genetic material into human cells. Decades of optimization and maturation produced a highly effective gene transport vehicle. By adding in a genetic “payload” designed to replace nonoperational genes, gene therapy was ready to revolutionize the medical world. 

The significance of being involved in this trial was not lost on Adrian. “I obviously wanted to improve my own situation, but I was also considering my two daughters, who have a 50% chance for each of their sons to have hemophilia, as well as other parents with hemophilia and their kids,” he said. “This is simply how science and progress work. You need volunteers to enroll in trials so that you can figure out if this is a groundbreaking new treatment that is going to help a lot of people down the road.” 

Therapies which can impact everyone

A three-year follow-up study published in 2014 in The New England Journal of Medicine led by Davidoff, Nathwani and Ulrike Reiss, MD, St. Jude Department of Hematology, demonstrated the long-term safety and efficacy of the gene therapy, with no late toxic events reported. Still, the real test of gene therapy is efficacy over decades. Now, 13 years after his enrollment, Adrian can reflect on the trial as a profound success. However, he did not need that long to make that conclusion. 

“Amazingly enough, there hasn’t been a difference between short-term and long-term results,” he said. “I was diagnosed as having severe hemophilia, which means I had bleeds much more often, but the treatment immediately changed me from severe to mild hemophilia.” This change means that rather than needing factor IX injections every two weeks to address bleeds, Adrian is down to injections as little as twice a year. Importantly, he has seen no waning in this effect since receiving treatment.

With the publication of the 13-year follow-up of the trial in The New England Journal of Medicine, the long-lasting benefits and safety of gene therapy for treating hemophilia B were validated, signaling a new paradigm for the disorder. Adrian is hopeful of the continued progress to be made using gene therapy. 

“All the studies on these viruses and how they can be used in gene therapy have all come from basic science research, which we need to have to be able to make this amount of progress,” he said. “It’s really amazing to see how pushing science on all different fronts can lead to therapies that have the potential to impact everyone.”