Replace broken

Giving hope to hemophilia | Efforts

Brent Harrison enjoys a beautiful day at Sandling Beach at Falls Lake State Park in Wake Forest. (photo by Alyssa LaFaro)

June 14, 2022

Brent Harrison hates going to the beach.

Well he used at. But not because of sunburn or sips of salt water or shorts full of sand. He hated the beach because he had hemophilia.

Hemophilia is a genetic blood clotting disorder that affects 400,000 people worldwide. It often causes spontaneous bleeding into soft tissues, such as muscles or joints. If a bleed is severe enough, a joint can swell up to the size of a watermelon. Thus, people with hemophilia often develop arthritis. They self-administer injections filled with clotting factor when bleeding occurs and undergo regular treatments for the disorder. Harrison has spent most of his life infusing himself with clotting factor intravenously three times a week.

So every time Harrison went to the beach, he worried about rolling his ankle walking on the sand.

Brent Harrisson

Brent Harrison (photo by Alyssa LaFaro)

“I would actually look for compacted sand because it hurts so much to walk on it,” he shares. “I would go out, find a place, put my blanket or my chair down, then my wife would go play in the water and I would sit there. And I would dread the thought of having to get up to use the bathroom or pack my bags to get out of there.

Today, Harrison stresses a lot less. In 2018, he began participating in a clinical trial at UNC-Chapel Hill for a gene therapy treatment from pharmaceutical company BioMarin. Harrison was given a four-hour infusion of the drug – and hasn’t had a bleed or an infusion since. That was nearly four years ago.

Harrison is one of 134 people from around the world who took part in the BioMarin clinical trial – the largest Phase 3 gene therapy study ever for adults with severe hemophilia A. If the company receives FDA approval for the treatment later this year, it will be the first hemophilia gene therapy to be licensed.

“Gene therapy has had a huge effect on these patients,” says Nigel Key, UNC BioMarin clinical trial lead and director of the UNC Blood Research Center. “It changes people’s lives.”

Before the 1960s, the average life expectancy of a person with hemophilia was 11 years. Today, that number has risen to 68 – just 10 years less than the average life expectancy for men in the United States. This is partly due to the work of UNC researchers who have dedicated their lives to the disease, unpacking how it occurs, developing treatments that could be administered at home, and creating drug delivery systems that could lead to a potential cure.

Make a disease manageable

Carolina’s commitment to the field of hemophilia goes far beyond her participation in clinical trials. UNC researchers have worked diligently to treat the disease since 1947, leading to incredible advancements in the field.

Kenneth Brinkhous and his lab were instrumental in this work. In 1953, they developed the first test, called the partial thromboplastin time test, to identify hemophilia – hundreds of which are now performed every day at UNC hospitals alone. Other milestones include the discovery of clotting factor X in 1955 and the development of the first factor VIII concentrate in the 1960s, which was later licensed and marketed by Baxter-Hyland.

Kenneth Brinkhous

Kenneth Brinkhous (right) began studying the first known canine carriers of hemophilia in 1947. His research on dogs led to the establishment of a blood laboratory, known today as the Research Laboratory on Francis Owen blood, which led to many advances in the field of hemophilia, including testing, treatments and knowledge of the disease.

When scientists in Boston and San Francisco discovered how to genetically modify the missing clotting factor for people with hemophilia A, UNC researchers took the opportunity to participate in the clinical trial and administered the world’s first dose ever administered to a human. The treatment, called recombinant factor VIII, was licensed by Baxter and Bayer in 1992.

Carolina researchers have also been instrumental in developing treatments for people with hemophilia B, von Willebrand’s disease and hypercoagulation – when the blood clots too much.

Using genes as a cure

At the end of the 20e century, gene therapy research began to attract medical attention as an innovative treatment option for many people. The technique introduces healthy genes to replace or repair broken ones to ultimately treat or cure disease.

Sounds simple enough, right? But finding a tool to deliver the genes was not easy. Enter Jude Samulski.

Samulski came to UNC in the early 1990s to direct the new gene therapy center, which opened in 1993. At the time, he was just 39 years old. But he had already made a huge discovery.

More than a decade earlier, while a doctoral student in Nicholas Muzyczka’s lab at the University of Florida, Samulski began searching for a virus that could be turned into a gene delivery system. That’s when he and his lab colleagues came across the adeno-associated virus (AAV), which met three important criteria: it infects humans, it doesn’t cause disease, and its genetic payload can persist in cells, meaning it stayed in the body. indefinitely. Samulski’s work? Manipulate it so it can deliver genes.

Samulski moved on to Princeton, where he continued to work with AAV as a postdoctoral researcher. There, he and his lab removed 96% of the virus’s genome, giving it enough space to carry potentially therapeutic genes. and be packaged in the virus envelope which acts as the gene delivery vehicle. This form of AAV continues to be one of the most successful gene delivery systems in the world – and it is what BioMarin’s gene therapy treatment for hemophilia uses. But getting the AAV right took 20 years.

Samulski was recruited to Carolina to perfect the basic science behind gene therapy, which ultimately cemented the university’s position as a leader in genetics. His lab focused on hemophilia B, a bleeding disorder caused by a shortage of factor IX protein. About 20% of people with hemophilia have type B. The rest, like Brent Harrison, have type A, caused by a deficiency in factor VIII.

In the mid-1990s, under Samulski’s leadership, UNC pediatrician Paul Monahan began experimenting with AAV as a gene therapy tool for hemophilia B. The goal: to get AAV to deliver factor IX to the liver, where most of the body’s clotting factors are synthesized. .

“AAV is kind of a Trojan horse that we load with Greek soldiers, which is Factor VIII or IX DNA,” says Key, who has spent 30 years studying bleeding and bleeding disorders and has worked in collaboration with Samulski and Monahan. to Carolina.

When it came time to test Monahan’s viruses, biologist Darrel Stafford developed a mouse model of hemophilia B and Tim Nichols provided access to the established – and incredibly successful – canine laboratory that Brinkhous started in the late 1940s. .

Eventually, Monahan’s research was part of the science that helped launch Samulski’s spin-off company, AskBio, in 2001.

The development of AAV for gene therapy not only formed the basis of a Phase III clinical trial for a gene therapy treatment for hemophilia B led by CSL Behring, but also led to therapy programs genes for hemophilia from pharmaceutical giants like Sangamo Therapeutics, Pfizer, Spark Therapeutics and Freeline Therapeutics. CSL Behring’s therapy is being reviewed by the FDA alongside BioMarin’s hemophilia A treatment, both of which could be approved in 2022.

Additionally, AAV has been instrumental in gene therapy for hundreds of diseases. It also led to the approval of two commercially available treatments, one for a form of retinal blindness called Leber’s hereditary optic neuropathy and the other for spinal muscular atrophy.

To look forward

Key believes the next step in Carolina’s involvement in the hemophilia world is to create a physical place where patients can receive gene therapies — and other innovative treatments, such as protein therapies — as they come. as they become available to the public.

“I think UNC has a hemophilia tradition here that we need to keep going,” Key says. “Translating these therapies into actual treatment centers is the next step.”

As for Harrison, he has already volunteered to participate in BioMarin’s follow-up study of the gene therapy clinical trial, which involves a liver biopsy to see how AAV persists in liver cells and produces the clotting factor – essential information to continue improving treatments.

“It takes a lot of altruism on the part of the patient to participate in these clinical trials,” Key shares. “It’s not just self-interest; it’s for the next generation of hemophilia patients. And Brent is a good example of that.

Harrison found nothing but benefits from participating in the clinical trial. He “prays and hopes” that the BioMarin gene therapy lasts a long time.

“If I have to start treating again and giving injections, that’s not a problem. I’m old hat about it,” he admits. “But I really wish I didn’t have to. I’ve had a taste of the good life.

So good, in fact, that he and his wife are looking to Aruba for retirement. It seems he really don’t hate the beach anymore.