Gene Therapy for Sickle Cell Disease Offers Patient New Lease on Life

By Lauren Ingeno

Since she was a child, Marie-Chantal Tornyenu, now 23, was plagued by a "hollow burning" in her chest, which landed her in the hospital nearly every month by the time she entered high school.

"And then you can't breathe on top of it," she said. "It felt like ice almost. I would wake up, and I couldn't move."

Tornyenu is among the 100,000 Americans — most of them African American — who are affected by sickle cell disease, a lifelong genetic disorder. Patients have a single gene mutation that prevents the body from making normal hemoglobin, the protein in red blood cells responsible for delivering oxygen throughout the body. The mutation causes hemoglobin molecules to stick together, hardening red blood cells into C-shaped "sickles," which can clog blood vessels and lead to intense pain episodes.

While a bone marrow transplant is one potential cure, Tornyenu didn't have a matching donor. But her life changed in 2021, when she enrolled in a clinical trial at Children's Hospital of Philadelphia.

The trial tested a new gene therapy called exa-cel (Casgevy®, Vertex and CRISPR Therapeutics) — the first-ever treatment to use the Nobel Prize-winning CRISPR technology to edit a patient's DNA as a potential cure for disease.

"Gene therapy allows us to treat patients in a completely different way," said Stephan Grupp, MD, PhD, Section Chief of Cellular Therapy and Transplant, who led the exa-cel trial at CHOP. "We take their own cells, fix the problem, and give their cells back, without the significant risks of donor transplant."

Simultaneously, CHOP also served as a clinical trial site for lovo-cel (Lyfgenia®, bluebird bio), a gene therapy that treats sickle cell by delivering a modified hemoglobin gene into the body via a viral vector. That trial was led by Janet Kwiatkowski, MD, MSCE, Director of CHOP's Thalassemia Center and Clinical Director of the Comprehensive Center for the Cure of Sickle Cell Disease and Other Red Blood Cell Disorders (CuRED) Frontier Program.

During clinical trials for both gene therapies, more than 90% of patients had no debilitating pain episodes for at least one year, and the treatments had positive safety profiles.

In early December 2023, the U.S. Food and Drug Administration approved both gene therapies — exa-cel and lovo-cel — for patients 12 years and older with recurrent vaso-occlusive crises.

The approval of the revolutionary treatments marked a turning point for an underserved patient population and could revolutionize the future of treatment for numerous other medical conditions. As CHOP and other centers bring these new approaches to the bedside, the hope is their experiences will inform how to offer the treatments to more U.S. communities, and potentially, throughout the world.

For patients like Tornyenu, having access to a curative treatment could be life-changing, said Alexis Thompson, MD, MPH, Chief of the Division of Hematology at CHOP. Living with sickle cell disease often means dealing with the unpredictability of symptoms while taking frequent trips to the emergency room and managing other chronic complications.

"When we think about an option that is curative, it really has two important considerations," Dr. Thompson said. "One is the possibility that the individual will be freed of the burden of this disease. The other is the hope that these individuals no longer require the degree of care and the expenses related to that care, and instead can look forward to having more full lifespans where they finish their educations, have jobs, raise families, and live the lives that they want."

“Now, I can see myself living into my 80s or 90s," said Tornyenu, who graduated from Cornell University in the spring and has plans for law school. "I can imagine the life I'll have for myself. ”

While the approvals of both exa-cel and lovo-cel offer new possibilities to a patient population that previously had few treatment options, gene therapy is not a quick and easy fix. The process can take up to a year from start to finish and comes with many complexities.

Helping CHOP patients navigate the arduous gene therapy process are specialists in the CuRED Frontier Program who support the patient and family through a streamlined care model. The Center offers a multidisciplinary clinic for evaluation and treatment of children with sickle cell disease, beta thalassemia, and other red cell disorders.

For decades, CHOP researchers have been at the forefront of developing therapies for sickle cell and other genetic disorders. More work toward cell and gene therapy solutions is ongoing at laboratories at CHOP, as researchers continue to search for red blood cell disease treatments that are safer, easier to administer, and cost-effective for a large and diverse patient population.

Since receiving the exa-cel therapy three years ago, Tornyenu has remained pain-free. She said the treatment has given her a new outlook on a future she didn't think was possible just a few years ago.

"Now, I can see myself living into my 80s or 90s," said Tornyenu, who graduated from Cornell University in the spring. "I can imagine the life I'll have for myself."