Imagine giving birth to a child, only to learn that they’d face a life of chronic, often debilitating pain — and a life expectancy of at least 20 years less than their peers.
That’s been the reality for any parents of a child with sickle cell disease (SCD) — the genetic condition that predominantly affects people of African descent — for as long as scientists have known of the illness.
In the U.S. alone, about 1 in every 365 Black or African American births result in the disorder, in which red blood cells — normally round — are shaped like sickles, microscopic crescents that die early, restricting blood flow and causing complications like stroke; kidney, liver, and heart disease; pneumonia; and more.
But Children’s Hospital of Philadelphia (CHOP) has always prided itself on changing the human condition for the better — on improving the lives of children in Philadelphia, and around the world. Famously, back in 2012, CHOP made history in collaboration with Penn Medicine for treating Emily Whitehead, then a 7-year-old patient with acute lymphoblastic leukemia (ALL), the most common childhood cancer, with her own genetically modified cells. Called CAR-T therapy, it made headlines around the world; all these years later, Whitehead is a thriving college sophomore (at Penn, no less).
But for all of the headlines gene therapy made for its potential to cure certain cancers, little had been known — outside of the worlds of biotech and academia, at least — about the potential for gene therapy to cure non-cancerous diseases. That is, until last December, when the FDA approved “two milestone treatments,” Casgevy and Lyfgenia, the first gene therapies for the treatment of SCD in patients 12 years and older. Within months, CHOP became the first children’s hospital to treat a patient outside of a clinical research setting. (They already had seven patients enrolled in the trial, even before FDA approval.)
The doctors at the forefront of Philly’s revolution in SCD treatment are Alexis A. Thompson, MD, MPH, and Dr. Stephan A. Grupp, MD, PhD. For their commitment to helping patients with SCD — a population that has for years been overlooked and stigmatized — the doctors are this year’s Disruptors of the Year. They will be honored alongside their fellow Citizens of the Year at a dinner celebration on February 25 at The Fitler Club Ballroom. (You can read about all of this year’s winners here, and find out about tickets and sponsorships for the star-studded event here.)
Driven by intrigue
To talk to Grupp is to realize immediately that he is the ultimate polymath. An MD / PhD who’s as committed to leading groundbreaking work in the lab as he is to delivering it to patients, he essentially runs a startup within CHOP — overseeing the science and delivery of care, first and foremost, but also the finances and insurance coverage and policy implications around treatment. In 2018 and 2019 alone, he spent 415 hours in the air, flying around the world teaching other clinicians how to administer CAR-T.
But as cancer treatment advanced by leaps and bounds and spread around the world, Grupp and his colleagues were left treating patients with SCD as they had been for years: namely, with bone marrow transplants, typically between siblings, a grueling process that left patients who didn’t have suitable donors in the shadows, suffering.
When gene therapy — the process of taking a person’s defective cells, modifying them in the lab, and then infusing them back into the patient — became a possibility for SCD, Grupp knew it would be a game-changer. With gene therapy, no donors are needed — each patient is, in effect, their own donor. The process would still be challenging: from gaining insurance approval and reimbursement on the one hand, to requiring patients to undergo chemotherapy to prepare their body for the reinfusion of their own modified cells.
Grupp knew he couldn’t do it alone.
“We come in with a potentially curative therapy that’s very exciting but very complicated and brand-new to everybody, including the sickle cell community,” Grupp says. “You have to explain it — and does that work without a trusted hematology physician that patients and their families have known their whole lives? Absolutely not. All of the technical stuff is on us [the oncology team], but it continues to be a collaboration [with the hematology team] throughout — and nobody starts the journey without the blessing of the hematologist who’s taking care of them.”
And no one is a more trusted hematologist than Thompson. The former President of the American Society of Hematology, Thompson was mentored by the late Kwaku Ohene-Frempong, a giant in the field of sickle cell disease, who pioneered newborn screening for SCD and was as committed to treatment as he was to the democratization of it, transforming care in sub-Saharan Africa, where the burden of the disease is highest. When Frempong, affectionately called “KOF” by friends, died in 2022, there was an outpouring of devastation — and gratitude — from around the world.
“KOF was an amazing pediatric hematologist who was so inspiring and intrigued me with possibilities,” Thompson says. “My interests globally very much mirror his inspiration.”
From Philly to the world
CHOP’s extensive experience and leadership in CAR-T paved the way for it to become the first pediatric institution to administer SCD gene therapy to a patient outside of the clinical setting. Now, in addition to that first patient and the seven who were enrolled in clinical trials before FDA approval, CHOP currently has six additional patients in the process to receive Casgevy, all at different stages. But as transformational as Casgevy and treatments like it may be, Thompson and Grupp acknowledge that there is still so much more work to be done.
“There are things we can do to improve this process. To hopefully, for instance, get rid of chemotherapy altogether, and all of the toxicities and side effects that come with it,” Thompson says. “We think that there’s also a possibility of doing this in what we call in vivo gene therapy, where the cells are not taken out of the body, and the correction is made inside a patient’s own system.”
Thompson and Grupp would both like to see the process in some way automated, so that it can reach more people in more places throughout the world. “If we’re thinking about delivering these transformational therapies to places like sub-Saharan Africa, there’s not a CHOP in sub-Saharan Africa — but if we can find a way to deliver something like this kind of therapy with less dependence on technology, that really holds a tremendous promise to the areas of the world where there’s the highest burden of this disease,” Thompson says.
Grupp says that, as fast as the technology is advancing, we’re still in early days.
“The thing is, this is Model-T Ford time,” he says. “We’re barely doing this. If we can make it work right — and that includes getting the economics and the finances right — you can imagine the most amazing things, you can imagine them coming to fruition within your own career, and you can have the sense that what you did really made a lot of difference.”
Both doctors agree that while “disruption” can have a negative connotation, when it comes to changing lives for good, nothing is more meaningful.
“It’s often very easy to see what’s right in front of you and to make a difference in the space where you currently live,” says Thompson. “But if we’re able and willing to step out just a little bit and to see that we are global citizens, that we have the possibilities of having an impact in our lifetime around the world, perhaps in the lives of [those] we’ll never meet — to be daring enough and bold enough to actually think that we can do that is a real privilege.”
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