Exploring Earlier Gene Editing For Children With Dr. Haydar Frangoul, Part 2

By Erin Harris, Editor-In-Chief, Cell & Gene
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In Part 1 of my conversation with Dr. Haydar Frangoul, medical director of the Pediatric Stem Cell Transplant Program at HCA Healthcare’s TriStar Centennial Children’s Hospital in Nashville, we discussed the potential of treating children with gene editing earlier in life, along with the risks families must weigh. In Part 2, we look at the questions that remain around long-term outcomes and what it takes to expand access to these therapies.

The efficacy results are encouraging, but what longer-term questions are most important to answer now around durability, safety, and patient follow-up?

Dr. Frangoul: The biggest question right now is how long these benefits will last. The results we’ve seen so far are very encouraging, but the median follow-up in these pediatric studies is about 16 months, and the number of patients is still relatively small. We want to know whether these benefits will hold up not just for a few years, but for decades. That’s why every child has the opportunity to participate in a 15-year follow-up study after treatment. We’ll be looking closely at whether fetal hemoglobin levels remain high and whether the proportion of edited cells in the bone marrow stays stable over time.

What gives me confidence is what we’ve already seen. We treated our first patient in 2019, and so far, we haven’t seen the benefits fade in any patient. In the adolescent and adult trial, editing levels remained stable for up to 4.8 years of follow-up, and no cancers were reported. We have 25 to 30 years from now, but everything we’ve seen so far suggests the treatment effect is lasting.

Safety is another important piece of the picture. We’re continuing to monitor patients closely, including those who are still within the first two years after treatment. In the pediatric trials, we haven’t seen any cases of graft failure, myelodysplasia, or other blood cancers. And if a blood cancer is ever suspected, the study protocol allows us to test for unintended genetic edits.

We also need to understand the longer-term effects of the chemotherapy used during treatment, particularly when it comes to fertility. These are important considerations, especially when we’re treating children who have their whole lives ahead of them.

Ultimately, our responsibility doesn’t end when a patient completes treatment. We need to keep following these children, learn from their experiences, and ensure the benefits we’re seeing today continue well into the future. That’s what the 15-year follow-up study will help us understand. There’s still more to learn, but the results so far give us a lot of reason to be optimistic.

Once a therapy is approved, what does it take for a pediatric health system to stand up a gene-editing program, (e.g., referral and patient selection, conditioning, transplant support, long-term monitoring)?

Dr. Frangoul: The foundation is having an established stem cell transplant program. Gene editing builds on much of the same infrastructure and expertise we already use for bone marrow transplants every day. That includes collecting stem cells through apheresis, having inpatient units equipped to care for patients receiving intensive chemotherapy, and having experienced teams who know how to manage potential complications.

One important consideration, especially with younger children, is stem cell collection. Mobilizing and collecting stem cells in children requires specialized skills, and some patients need more than one collection cycle.

Another critical piece is managing the chemotherapy used to prepare patients for treatment. Busulfan dosing must be carefully adjusted based on how each patient’s body processes the drug. That’s particularly important in younger children, where there can be greater variation. Programs need teams that can closely monitor drug levels, maintain a consistent dosing schedule and recognize serious complications, such as liver veno-occlusive disease.

There’s also a tremendous amount of coordination involved. The stem cells are sent to a central manufacturing facility for editing, and manufacturing slots are limited. Just securing a slot and coordinating collection can mean a two- to three-month wait. Patients then need about two months of transfusions before collection, three to four days in the hospital for collection, four to six months for manufacturing and quality testing, and approximately another month in the hospital for infusion. When you consider that entire process, health systems must be very intentional about planning staffing, hospital beds, and scheduling.

But building a successful program goes beyond the treatment itself. Education and outreach are just as important. Many eligible families, and even some of the physicians caring for these children, still don’t know this option is available. We must build strong referral pathways and make sure physicians and families understand who may be eligible and what treatment involves. Once that awareness grows, the demand is significant.

Programs grow by sharing experience. HCA Healthcare is helping establish a model for expanding access to this treatment. We’ve had physicians spend a week with our team in Nashville to learn the process and take that knowledge back to their own programs.

Ultimately, the goal is to make this treatment available to more patients who could benefit from it.