July 9, 2017

What Does Gene Therapy Mean to YOU?

Written by Laurie Kelley 
Originally published in PEN, May 2017  

Ladonna Pettus remembers the cover of Hemalog, a hemophilia magazine from 1990, promising “A Cure by the Year 2000?” It seemed at once like a vision and a done deal. Ladonna’s son with hemophilia was around two at the time. She recalls, “I had such hope. He is almost 30 now.”
Many parents who remember that magazine cover had those hopes. Their children are adults now, and although gene therapy trials are underway, it seems that the passion and dreams for a cure have been tempered. Alvin Luk, head of clinical research and operations at Spark Therapeutics, is working on hemophilia gene therapy. He offers, “We all underestimated the complexity of gene transfer.”
Maybe this is why, when I repeatedly asked 2,600-plus hemophilia “friends” on Facebook about their thoughts on gene therapy, only a handful of people replied. I’m sharing their comments here. Normally, the hemophilia community is vocal and active. Does this lack of response indicate that we are mostly unaware when it comes to gene therapy? Are we not sure what it is?
Defining gene therapy: A cure?
Parents and patients sometimes use the terms “gene therapy” and “cure” interchangeably. But the definitions aren’t the same. When we think of a cure, we think of eradicating the disorder or disease. In other words, a person with hemophilia no longer has it. In fact, a permanent cure for hemophilia already does exist. Steven Riedle notes that his brother with hemophilia had a liver transplant in October 2016, and is indeed cured of hemophilia. But a liver transplant is not a feasible option. 1 Many patients and caregivers are waiting—hoping—for a safe, widely available therapy that will cure hemophilia permanently. Yet we may need to adjust our definition of cure. Community members who responded to my questions seem to realize that most current gene therapy trials promise to make hemophilia less severe by increasing circulating levels of factor in the blood. Very few patients or parents understand gene therapy as thoroughly as Ray Stanhope, former National Hemophilia Foundation president, and person with hemophilia. He defines gene therapy as “the use of a viral vector to modify cells in the body to produce an additional specific protein which is either missing or produced at a lower than normal level in a person with hemophilia.”2 What Ray describes is not necessarily a cure, but an improved therapy.
What level of success?
If current gene therapy trials promise to increase circulating factor in the bloodstream, what level would be considered successful—a “cure”? Remember that severe hemophilia means less than 1% circulating factor, moderate means greater than 1% to 5%, and mild means 6% to 50%. Anything over 50% is considered in the normal range. 3 For Ray, levels of circulating factor would have to be well over 40% and closer to 50% (normal) to be considered a cure.
But others think that even converting someone from severe to mild hemophilia could be considered a success. Nichole Foley writes, “I think taking a person from severe to mild hemophilia is enough of an advantage for some of these kids that have constant challenges, and hopefully it will alleviate inhibitor issues.”
Bryce Loehrke says, “If gene therapy could permanently bring me to the levels of even mild hemophilia, I would consider myself cured for the most part. Having severe hemophilia A, I’ve often said that those with mild hemophilia don’t even have hemophilia. I don’t mean to diminish the fact that they still have issues from it periodically, but often with much less severity or frequency, sometimes to the point of not knowing they have it until later in life.” Tina Ruis takes this even further. “My 24-year-old son with severe hemophilia B—his left leg is unbearable. His calf is massive, and he can barely move without a walker. Levels of 11% to 15% would be worthwhile; over 25% would make me cry with joy.”
Stephen Brewer would be happy if gene therapy worked, even if it wasn’t permanent: “I would accept having mild hemophilia even if only for a few years.”
Chris Templin and his daughter both have hemophilia B. Chris notes that aiming for “mild” hemophilia is fraught with inconsistencies. “I think it’s interesting how people think all those with mild hemophilia bleed less then severe hemophilia patients. I know some milds who bleed more than some severe patients.”
The price of success
If gene therapy is successful and becomes available, how much would it cost? Some families think that because gene therapy trials are being held at university hospitals and hemophilia treatment centers, its cost may be lower than that of current commercial therapies. But this is not correct, because the trials are underwritten by pharmaceutical companies and the manufacturing process would ultimately need to be upscaled by a commercial pharmaceutical company.
    The issue of cost for a new therapy is complex, and includes these questions:
    • What is an acceptable therapeutic factor level: moderate, mild, normal?
    • How long will the treatment last: three years? permanently?
    • Will other factor products need to be used during the treatment period?
Ray estimates the cost of a one-time treatment of gene therapy at “close to $1 million, given the low number of patients, the cost of research and development, and assuming that the therapy is successful for four years.” He adds, “For the manufacturers, as much as they can charge; for the insurers, the least amount they have to pay.” Nichole Foley doesn’t care: “Cost-wise, I am sure it will be astronomical, but if [gene therapy] enables kids to live a normal life, I’d think it would be worth it!” Bryce believes, “If there’s an effective lifetime cure, $250,000 will be a lowball figure. We need to convince insurance providers of the long-term savings of a permanent or semipermanent cure.”
What if gene therapy is good for only a few years?
The term “cure” isn’t applicable at all if gene therapy—even if it brings your factor levels to normal—lasts for only a few years. This is a real concern.
Ray explains: “Given that the current vectors are viral and the immune system develops a response to that vector so that once used, it cannot be used again, this is problematic if the period of time that the treatment persists is short. There may not be time to develop an alternate type of vector. However, given the speed at which medical advances are occurring and accelerating, having the treatment persist for more than ten years might be enough to get you to the next vector, whatever that might be.”3
Amber Brandt, mother of a child with hemophilia, worries, “Regular factor is so expensive, I don’t see gene therapy being cheap by any means. And I’m sure it would be a huge struggle to get insurance to cover it. But if it only lasts a few years, I don’t even think it would be worth [trying] it at all.”
Wait-and-see approach
Patients who don’t see any solutions to these concerns may adopt a wait-and-see approach. Some are inherently mistrustful of playing with genes, or of the whole commercial industry of factor manufacturing. Some feel that current therapies are good enough for now.
Brandi Worthington admits, “I don’t know anything about gene therapy.” Amber adds, “It’s fascinating, but I would never choose that option for my son. He can choose that if he wants when he is an adult.” “I won’t be a first adopter for gene therapy by any means,” declares Bryce, “primarily due to distrust of the entire pharmaceutical industry for various legitimate and historical reasons. We need to know the consequences as well as benefits [of gene therapy].” Ray concludes, “Depending on the factor levels achieved and the duration of the treatment and the usable number of vectors…I might wait and see.”
Stepping-stone to a cure
Ray understands well the nuances and importance of educating the hemophilia community about gene therapy. Parents and patients will one day need to make an informed decision about whether to participate in it. “We as a community first need to define the parameters of what we would consider a cure,” says Ray. “I have always had a strict interpretation of this word. A cure would be a single treatment that provides normal hemostasis over the lifetime of the person living with hemophilia. Anything less than this should be considered a stepping-stone toward a cure.”
Stephen still has hope and carries the definition of cure even further. “Looking forward, a cure would include increasing circulating factor levels, [and] eliminate hemophilia from future generations [of a family].4 This is the ideal I hope for.”
1. Factors VIII and IX are produced primarily in the liver, although the cells lining the blood vessels also produce and hold reserves of factor VIII for release into the bloodstream when needed. Replacing the liver indeed cures hemophilia, but this is not deemed a viable option for treatment because it is too risky. Only patients with hemophilia who face liver failure are considered for this operation.
2.  A vector is a modified virus used by molecular biologists to deliver genetic material into cells.
3.  Among the general population, normal factor levels are between 50% and 150%, with most people being close to 100%.  
4.  Changing the genetics of future generations is not gene therapy, but human germline engineering. This practice is currently banned. It’s highly unpredictable, dangerous, and considered unethical.
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