First Two Gene Therapies for Sickle Cell Disease Supported by CHOP Clinical Research

By Lauren Ingeno

The approval of two gene therapies for sickle cell disease marks a turning point for an underserved patient population and could revolutionize the future of treatment for numerous other medical conditions. As Children’s Hospital of Philadelphia and other centers prepare to bring these new approaches to the bedside, the hope is their experiences will inform how to bring the treatments to more U.S. communities, and potentially, throughout the world.

In early December, the U.S. Food and Drug Administration greenlit the therapies — exa-cel (Casgevy®, Vertex and CRISPR Therapeutics) and lovo-cel (Lyfgenia®, bluebird bio) — for patients 12 years and older with recurrent vaso-occlusive crises.

Exa-cel is the first-ever treatment to use the Nobel Prize-winning technology called CRISPR to edit a patient’s DNA as a potential cure for disease. Lovo-cel introduces a new gene through a modified virus vector for a form of hemoglobin that is resistant to sickling.

CHOP, which served as a clinical trial site for both therapies, will be one of a few Qualified Treatment Centers for lovo-cel and hopes to offer exa-cel later this year.

For patients with sickle cell disease, whose pain is often “indescribable,” having access to a curative 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 often debilitating complications.

“When we think about an option that is curative, it really has two important considerations. One is the possibility that the individual will be freed of the burden of this disease,” Dr. Thompson said. “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.”

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

The FDA approval of multiple curative therapies “can only be good for patients,” said Janet Kwiatkowski, MD, director of CHOP’s Thalassemia Center and clinical director of the CuRED Clinic, who led the hospital’s lovo-cel trial. Dr. Kwiatkowski also served as a principal investigator for the trials of beti-cel (Zynteglo®, bluebird bio), the first curative gene therapy for beta thalassemia, which was approved in 2022. 

“There are many factors we will take into account when choosing which product to offer to an individual patient,” Dr. Kwiatkowski said. “These include product availability as well as patient characteristics that might make one a better choice than the other.”

An Alternative to Conventional Donor Transplants

Sickle cell disease is a lifelong disorder that affects 100,000 Americans, most of them African American. Patients diagnosed with the disease have a 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 offers one potential cure, this carries the high risk that the donor’s cells will attack the patient’s tissues, causing serious complications. Both exa-cel and lovo-cel work by altering the genetic makeup of a patient’s own cells, making this therapy inherently much safer. To deliver the therapies, a patient’s stem cells are removed, transformed in a manufacturing lab, and injected back into the body after a round of chemotherapy to make room for the new cells. 

“In our clinic, more than half of the patients who we treat are getting conventional bone marrow transplants from another person to try to fix some well-defined genetic disorder,” said Stephan Grupp, MD, PhD, section chief of Cellular Therapy and Transplant at CHOP.

Dr. Grupp, who also is inaugural director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy and medical director of the Cell and Gene Therapy Laboratory, cared for the world’s first pediatric patient to receive CAR T-cell therapy in 2012. He served as a principal investigator on the exa-cel trial at CHOP and leads the Vertex steering committee for the international registration trial. 

“Gene therapy allows us to treat them in a completely different way,” Dr. Grupp said. “We take their own cells, fix the problem, and give their cells back, without the significant risks of donor transplant.”

An ‘Elegant’ Edit Advances the CRISPR Revolution

It was just 10 years ago that a group of scientists published a landmark paper on CRISPR — the technique that promised to accelerate biomedical research at lightning speed. Like an editor scanning for typos in a draft of text, CRISPR uses “molecular scissors” to snip out and replace spelling errors in the human genome with healthy DNA. 

To treat sickle cell disease, scientists could have targeted the gene mutation that causes faulty adult hemoglobin production. Exa-cel, by contrast, uses CRISPR technology to edit a key region of the gene BCL11A that controls fetal hemoglobin production, a form of the molecule that humans have in the womb but lose as adults. Rather than turning on the broken hemoglobin gene, the exa-cel therapy is created by turning off the gene that blocks fetal hemoglobin — a sort of double-negative approach.

“In biology, it’s often easier to break something than to fix it,” said Stephan Kadauke, MD, PhD, associate director of the Cell and Gene Therapy Laboratory at CHOP. “You don’t just turn the therapeutic gene on, you also turn the pathogenic gene off. It’s very elegant and makes a lot of biological sense.”

Increasing Access to a Life-Changing Treatment

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 by no means a quick and easy fix. The process can take up to a year from start to finish and comes with many complexities.

“It takes a village,” Dr. Grupp said. “There are so many people involved to make it work right. This is all hands on deck, which is what CHOP does best.”

The first step in the process is to prepare a patient for stem cell retrieval by giving a drug that moves stem cells from the marrow to the blood. When the stem cells are mobilized into the bloodstream, a clinician performs a procedure called apheresis to remove them. At CHOP, a team at the Gene and Cell Therapy Laboratory performs quality control tests and then ships the cells to a manufacturing site. 

Once at the manufacturing site, scientists modify genes in the cells to fix the patient’s genetic mutation. The FDA then requires that the modified stem cells are put through more quality control tests, which can take from three to six months to complete. After the cells are ensured to be pure, safe, and potent, they are sent back to the hospital and prepared to be infused back into the patient.

Before the patient can receive the gene therapy, their bone marrow must be cleared out with high doses of chemotherapy. “This is the most intense part of the process,” Dr. Kadauke said. Once the bone marrow is cleared, a clinician injects the modified cells into the patient, and then, the patient must wait. For six weeks, the patient remains in the hospital while their edited stem cells start making new red blood cells.

“During that time, the patient is admitted on the cell therapy service and will need to be in isolation while receiving transfusions, because they won’t have enough white blood cells to defend from infections,” Dr. Grupp said.

If all goes well, the patient begins to make new red blood cells from the new marrow, and their sickle cell disease symptoms will improve.

Helping CHOP patients navigate the arduous gene therapy process are specialists in the hospital’s CuRED program (short for Comprehensive Center for the Cure of Sickle Cell Disease and Other Red Blood Cell Disorders). The program, which was designed to support the patient and family through a streamlined care model, offers a multidisciplinary clinic for evaluation and treatment of children with sickle cell disease, beta thalassemia, and other red cell disorders.

“CHOP takes incredibly good care of people,” Dr. Thompson said. “Gene therapy requires specialized centers, and thanks to the work being done in our CuRED Program, CHOP is one such center where we not only have incredible expertise in taking care of patients with sickle cell disease, but also outstanding transplant specialists and others who help us meet the needs of patients and their families.”

Future Ways to Lower Gene Therapy Costs

Still, the hefty price tag attached to the newly approved gene therapies means that the treatment is likely out of reach for the uninsured. One solution for the high price of gene therapy? CHOP is investing in future infrastructure to manufacture the cells in-house.

An on-site clean room facility at CHOP’s Cell and Gene Therapy Lab has the machinery and resources to allow CHOP researchers to potentially manufacture gene therapies at a significantly lower cost than commercial products.

“I’m positive we could do this much cheaper,” Dr. Kadauke said. “We really see it as a patient-access solution.”

For almost two decades, CHOP has been at the forefront in the treatment of sickle cell disease as well as multiple gene therapies to treat other rare and complex diseases. 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.

Researchers from CHOP and the University of Pennsylvania, for instance, are using the same lipid nanoparticle technology used in COVID-19 vaccines to develop a system for in vivo modification of blood stem cells. CHOP researchers are also assessing the regulation of fetal hemoglobin to find potential dugs that could improve oxygen transfer.

“I think that that as extraordinary as these approvals are, and as excited as I am for the patients to see this happen, the pathway for additional approaches to therapy for sickle cell disease is wide open,” Dr. Thompson said. “CHOP is the kind of place where we really embrace that. And so, while we are going to be a major site for delivering these commercial products, I foresee CHOP continuing to be an institution that focuses on innovation.”

Read more about the FDA approvals in this CHOP press release and watch a video with patient Marie-Chantal’s story.