Gene Therapy: The New Reality

After decades of research, gene therapy for hemophilia is here—but several questions about the treatment remain
Author: Linda Marsa

In December 2015, Ryan Hallock did something that changed his life: He became the first patient treated in a gene therapy trial at the University of Mississippi Medical Center, in Jackson. Hallock, 27, has severe hemophilia B and is a nurse. He joined the trial because the treatment promised to release him from the worries and inconveniences of controlling his bleeding. For years he spent upward of 30 minutes a day, two or three times a week, on factor infusions. He suffered from joint pain, and he felt his career options were limited.

“I couldn’t play sports,” he says. “I had to be careful all the time, and there was no way I could do 12-hour shifts as a nurse. Having hemophilia was so much a part of my identity.”

The actual gene therapy treatment was surprisingly routine, as simple as getting a blood transfusion. The tough parts were before and after. The initial steps involved clearing strict eligibility requirements to become part of the clinical trial, and lengthy discussions with his doctors to understand the science and what to expect. Afterward there was rigorous follow-up, to ensure he didn’t experience any unexpected complications. “The screening process went on for six to eight months before the infusion itself, which took about four hours,” Hallock says. “I even took a nap and felt perfectly fine afterward. I spent the next couple of days doing follow-up with the labs.”

In the nearly five years since his treatment, Hallock’s quality of life has vastly improved. He hasn’t needed infusions, and his factor levels have consistently been in the 30% range. “I still see a hematologist, and I still have factor in the house and carry it with me when I travel, just in case,” he says. “But I’m not hurting anymore, I no longer worry about having a breakthrough bleed at work, and I can enjoy outdoor activities like kayaking and biking with my friends. It’s not necessarily a cure, but it is a viable treatment option.”

A Long Road

For decades, gene therapy has been one of the most sought-after treatments for hemophilia. A one-shot procedure that could fix the inherited condition at its source, it involves replacing a defective gene with a functional one to produce enough clotting factor to short-circuit bleeds. Now that the treatment is poised to become reality—several companies expect to receive US Food and Drug Administration approval to market gene therapy in the near future—it’s important to evaluate its potential risks and benefits.

The pluses seem obvious: potentially liberating patients from spontaneous bleeding episodes, expensive and time-consuming treatments, and joint degeneration. Several clinical trials encompassing about 100 patients over nearly a decade have yielded strong evidence that the experimental treatment is safe and effective. “It can be a transformative treatment for patients and lift the burden of what it takes to manage their condition,” says Steven Pipe, MD, a principal investigator on hemophilia A and B gene therapy clinical trials, professor of pediatrics and pathology at the University of Michigan in Ann Arbor and chair of the National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council.

Still, for each patient, there are many unknowns. While test results have been promising, there are no guarantees. “Gene therapy is a one-shot deal—you can’t stop gene therapy once you’ve done it, and it’s a very different treatment paradigm,” says Brendan Hayes, director of external affairs at NHF and head of NHF’s Gene Therapy Initiative. “It’s really important for people to understand the pros and cons of existing therapies in addition to future treatment options that are in the pipeline that may be worth waiting for.”

Gene Therapy Basics

Hemophilia A and B are caused by a single gene mutation. Gene therapy inserts a functional version of the defective gene—the factor VIII gene in hemophilia A, the factor IX gene in hemophilia B—into the liver, where the FVIII and FIX proteins are made, triggering clotting factor production. Copies of the healthy gene are placed into a vector, or tiny cargo ship, to transport the genetic payload to cells in the liver. A common vector used in gene therapy is AAV (adeno-associated virus), a non-disease-causing virus, modified as a delivery vehicle. The modified virus vector, which is injected intravenously, is used to ferry the fragments of DNA because the virus is taken up directly by certain cells. AAV is a popular choice because it especially targets the liver.

The hope is that enough working copies of the genes are delivered to the liver so that patients no longer have to rely on treatment with clotting factor therapy.

That was the case for Adrian Rothenfluh, PhD, a genetics professor at the University of Utah School of Medicine in Salt Lake City. Rothenfluh, 52, has severe hemophilia B and says he suffered more than 1,000 bleeds and needed infusions at least two or three times a month. As a scientist married to a physician, his decision to participate in a gene therapy trial was easy: He understood the importance of contributing to science, and he immersed himself in the scientific literature to quell any lingering doubts. “I wanted to drive the science forward, and I’m able to understand it,” he says.

In 2012, Rothenfluh participated in gene therapy tests at St. Jude in Memphis, and the treatment increased his clotting factor from less than 0.5% to between 5% and 6%. “Five percent is a big difference from less than 1%,” he says. He now has bleeds maybe once or twice a year. “So far, in eight years there has not been a decline in my factor levels. For me, it has been as good as I hoped for.”

Enrolling in a Clinical Trial

Biotech companies and academic centers that are conducting trials have strict eligibility requirements, mainly for safety reasons, to ensure participants don’t have any underlying medical conditions that could trigger an adverse reaction or that could introduce confounding variables that can muddy test results. To date, all trial candidates must be men ages 18 and older with severe hemophilia A or moderate to severe hemophilia B. Other than their hemophilia, they must be healthy, without diabetes, heart disease, a history of cancer, high blood pressure, HIV, hepatitis or liver problems.

In addition, potential candidates can’t have a history of inhibitors. Most trials also exclude patients who have antibodies to AAV, because these antibodies can block the AAV from efficiently delivering the replacement genes.

After receiving gene therapy treatment, participants are intensively monitored for the first 20 weeks. Typically two times a week they have blood tests as well as a weekly physical exam at an authorized clinical trial center.

“You can’t just go to your primary care physician or the ER around the corner,” says Ulrike Reiss, MD, director of the Hemophilia Treatment Center at St. Jude and a lead investigator in gene therapy trials. “All trials monitor the vector excretion in bodily fluids until it disappears.

In about half the patients, we do see liver inflammation by blood tests, but patients don’t have symptoms of liver disease. That is an immune reaction against the liver cells that have taken up the vector with the new gene—the immune system recognizes the viral particles and tries to fight it. But it is typically treated easily with steroids.”

Potential Risks?

Deciding whether to undergo gene therapy can be difficult. Aside from insurance questions, perhaps the biggest barrier is that results aren’t guaranteed and if it doesn’t work, you won’t get another chance using the same or a similar vector for re-treatment. “Like with any virus, you make antibodies to the AAV virus,” Reiss says. “Right now, we don’t know how to do a second infusion using an AAV-type vector.”

Unfortunately, scientists can’t predict whether the transmitted gene copy or the expressing cells will be stable and the results will endure, or if they may be lost or inactivated, which means a person is back to square one. Clinical trial candidates “have to be willing to accept an outcome across the spectrum,” Pipe says.

For people like Garrett Hayes, whose severe hemophilia A is well controlled, gene therapy isn’t something that he’s ready to pursue yet. A distance runner who trains at least five times a week, the 22-year-old Plano, Texas, resident considers himself quite healthy. He controls his condition with three weekly infusions of a recombinant factor VIII product. “It’s an old product—its early version was released in the 1990s—but it works well for me, and I’ve been using it for over a decade,” he says. “I can do the infusions at home, and they’re pretty quick—it takes about 10 minutes.”

So far, gene therapy has an excellent safety profile, but only about 100 people who have undergone treatment have had their results reported. Adverse reactions might emerge when thousands of people are using the therapy, which is one reason Hayes is hesitant. “I feel like there are many steps between what I do now, in terms of treatment options, and gene therapy,” he says. He doesn’t rule out gene therapy in the future but wants it to have a longer track record. “It isn’t like taking an allergy pill,” he adds. “You want to be really sure and confident.”

Frequently Asked Questions

Gene therapy can be daunting because it is based on complex science. Following are answers to some common questions about the treatment. If you’re thinking of enrolling in a clinical trial or you’re interested in undergoing gene therapy once it is available on the market, discuss your options and concerns with your healthcare team.

What will my factor levels be after gene therapy?

Responses to gene therapy are likely to vary. Based on clinical trials to date, we don’t know how durable the treatment will be. Factor levels may be in the moderate, mild or normal hemophilia range and may fluctuate over time. Whether you will still need factor if you have an accident, injury or require surgery will depend on your factor level and is a question best discussed with a healthcare provider.

Once I receive gene therapy, will I still need annual checkups at my hemophilia treatment center?

Yes, you still need to follow up at least yearly with your healthcare team after completing gene therapy. It will be important to continue to be monitored to assess any changes in overall health, including emotional health, as well as factor levels. Any underlying issues you had before gene therapy (e.g., joint issues) will need to be monitored as well. Your HTC will be an important partner in your follow-up care after gene therapy. People who receive gene therapy can also help researchers learn about its safety and efficacy by signing up for long-term observational research studies. Currently, one is in development within the HTC system. Sponsored by the American Thrombosis and Hemostasis Network, it will capture data on people who receive commercialized gene therapy products.

Can I stop or turn off gene therapy?

No, it is a one-time intravenous infusion that cannot be reversed or undone.

Can I pass the effects of gene therapy to my children?

No. Gene therapy for hemophilia corrects the genetic defect only in the person who receives it. It does not correct the genes that are passed on to the next generation.

Will gene therapy affect my ability to have children?

No. However, because the vector is found in semen for some time after the infusion, you will need to use a barrier contraceptive (such as condoms) until it is safe not to. If you are considering having a baby in the near future, it might be reasonable to think about banking sperm before undergoing gene therapy.

The Future of Gene Therapy

FDA has promised to expedite reviews of gene therapies for hemophilia A and B. Industry analysts predict these therapies could have a $2.5 million to $3 million price tag, making them the most expensive drugs ever to reach the market. NHF’s Brendan Hayes believes that “financing these one-time high-cost durable therapies could prove to be an obstacle to patient access.”

The hope is that with more research, inclusion parameters can be broadened and gene therapy will be available to people with less severe disease. Scientists are looking at other viral vectors, including a type of virus called a lentivirus, which would open up gene therapy to people who have antibodies to AAV. “But what we’ll see first is a drift down in age requirements—some 17-, 16- or even 15-year-olds will be admitted to trials,” Pipe says.

There are many questions when it comes to gene therapy, ranging from insurance coverage to eligibility and durability. But judging from the results of trials so far, for many the treatment has the potential to radically alter what it means to live with hemophilia. “We are looking at a functional cure,” Pipe says. “Gene therapy patients tell me how good they feel. They’re not bleeding anymore, spontaneity has returned to their lives and they really don’t talk about hemophilia issues anymore."

Learn more: hemophilia.org/Bleeding-Disorders/Future-Therapies