Clinical Trial Aims to Treat Sickle Cell Disease with Genetic Therapy

By Jean Yaeger

Her whole life, 19-year-old Ashlynn Malone has struggled with fatigue, outbreaks of severe pain, and hospitalizations due to sickle cell disease (SCD). 

That’s why Ashlynn jumped at the chance to join a clinical trial designed to stop her SCD symptoms by modifying her blood stem cell genes. Ashlynn has early access to the treatment at Cook Children’s Medical Center – Fort Worth, the RUBY Trial’s only pediatric site in Texas.  

The RUBY Trial uses an experimental technology called EDIT-301 for editing genes. Cook Children’s hematologist Clarissa Johnson, M.D. said preliminary results show the EDIT-301 treatment provides long-lasting relief from the painful flare-ups and anemia that patients like Ashlynn experience when their blood flow is blocked by sickle-shaped red blood cells. 

“This is a more potent treatment than what we have been able to offer thus far,” said Dr. Johnson, who heads up the Sickle Cell Program at Cook Children’s, which serves about 400 patients. “It’s not a cure, but a transformative treatment.”

The first RUBY Trial transplant at Cook Children’s was done in January 2024. Ashlynn will be the second. Cook Children’s is now working to enroll qualified patients ages 12-17 because the enrollment for adults has closed.

“The trial was always planned to include adolescents,” Dr. Johnson said. “We were chosen because I pursued this for our patients, and we were able to demonstrate to the company that we had the expertise and resources to conduct this trial with great support from our research department.”

How does EDIT-301 work? Through technology that edits the genes involved in SCD to make them able to produce healthier blood cells. The RUBY Trial is a study that measures the safety and effectiveness of that treatment.

Gretchen Eames, M.D., serves as Medical Director of the Stem Cell Transplant Program at Cook Children’s. Dr. Eames said the program has an extensive track record since 1985 of providing leading-edge therapies and caring for patients with SCD. 

“Our outcomes as well as our superb and experienced research team are the reasons we have been chosen to participate in clinical trials such as the RUBY Trial,” she said. “We jumped at the chance to bring this transformative therapy to the patients of North Texas and beyond.”

Previously, the only definitive therapy for SCD was undergoing a stem cell transplant from a family member -- a much more intensive therapy, with greater risks. EDIT-301 eliminates the need for a matched donor since it uses the patient’s own cells.

“Now we have a gene therapy that can give hope to those patients who do not have a family bone marrow donor or who are ineligible to receive a traditional bone marrow transplant,” Dr. Eames said.

Ashlynn met the criteria to enroll in the RUBY Trial in 2023. Her stem cells were collected at Cook Children’s and shipped to the manufacturer’s lab. After about 12 weeks, the edited genes will be shipped back to Fort Worth and infused into Ashlynn’s blood. Then she’ll go through follow-up testing for at least two years.

She has confidence in her doctors -- and she’s hopeful that the treatment will end her SCD pain and exhaustion. Ashlynn knows she’ll need some chemotherapy before the infusion, and there are potential side effects, but she says the risks are worth the expected outcome.

“I can’t wait to be done with sickle cell,” she said. “I’m more excited than anything.”

Here’s a closer look at the potential for this treatment to expand the genetic therapy options for people living with severe SCD.

Three Treatment Phases

An estimated 100,000 people in the U.S. have sickle cell disease, an inherited disorder most common in people of African descent. A mutation in the patient’s genes causes the hemoglobin proteins – the body’s oxygen transporters -- to bend so that the red blood cells curve like crescent moons instead of round discs. Instead of flowing smoothly through the blood vessels, the sickle-shaped cells get clumped up. It causes pain and can lead to anemia, organ damage or stroke.  

Dr. Johnson said the EDIT-301 treatment targets the genes that makes fetal hemoglobin. Adults with healthy hemoglobin don’t usually need fetal hemoglobin. The treatment tweaks the genes so that they start producing very high levels of fetal hemoglobin to counteract effects of the sickled hemoglobin.  

The clinical trial spans about 2½ years and consists of three parts:

1. Phase One: Selected candidates are injected with a medication that moves their blood stem cells out of the bone marrow. An intravenous line collects the stem cells, which are sent to the Editas Medicine laboratory, where genes from those cells are edited via CRISPR technology.
2. Phase Two: After the cells are edited and shipped back to the trial site, the patient receives four days of chemotherapy to wipe out any remaining stem cells in their bone marrow. “Think of it like a garden,” Dr. Johnson said. “You have to clear out the garden to make room to plant something new.” Cells with the edited genes are transplanted into the body and travel to the bone marrow. The patient remains hospitalized until they can consistently create white blood cells to reduce risk of infection and are not needing frequent transfusions of red blood cells and platelets.
3. Phase Three: Follow-up tests check for any side effects and measure the impact of the treatment on the patient’s blood quality, heart and lungs.  

Results are encouraging from other sites nationally where the clinical trial started earlier, according to Dr. Johnson and Dr. Eames. The edited cells have increased the production of fetal hemoglobin in most participants in the study, leading to fewer SCD complication and improved quality of life.

Departments across Cook Children’s play a role in the RUBY Trial. The effort includes the research, apheresis, radiology, lab, pharmacy and hematology departments, along with the stem cell transplant physician and team. 

Ashlynn’s Perspective

Ashlynn was born with SCD because both of her parents carried the genetic trait. One cousin also has the disorder, but no one else in her family.  She’s a patient of hematology/oncology physician Timothy McCavit, M.D., who directs the Bleeding Disorder Program and Hemophilia Treatment Center at Cook Children's.

“I was never really able to do things other children were able to do because I had physical limitations,” she said. “When I was younger, I was prone to getting sinus infections because my immune system wasn’t as strong. If I push myself too hard, that could cause me to have a pain episode. So I always had to limit myself.” 

Hard exercise, stress or allergies can bring on an SCD pain episode for Ashlynn. She described the sensation as an aching in her back, head, arm … anywhere in her body. Sometimes the pain is sharp.

To control mild pain, she takes Tylenol. She’ll take a prescribed medication for moderate pain. And if that doesn’t work within a day or two, she goes to the Emergency Department. She estimates she’s been 50-100 times to different hospitals, including Cook Children’s Medical Center – Prosper, a short drive from her home in Little Elm.

“I have a natural high pain tolerance. If it gets to a point where I feel like I’m going to start crying, that’s when I know it’s getting bad,” Ashlynn said.

She first heard about the RUBY Trial during one of her hospitalizations last year, when Dr. Johnson brought it to her and her mom’s attention. Ashlynn was eligible because the medications she was taking for SCD didn’t stop her frequent pain episodes.

Optimistic that the clinical trial would help, she was screened and accepted. Her stem cells were collected in January 2024, placed in an ice chest, and shipped to the Editas Medicine lab.   

She has received regular transfusions of donated blood while waiting for her edited genes to be shipped back, likely by April. Ashlynn looks forward feeling well enough to reach her goals: Travel to Japan, start working out, and own a business. She’d like to spread awareness of SCD.

“If you know someone who has sickle cell disease, just know there are going to be some days when they’re not really going to want to hang out or do much physical activity,” she said. “Just be more understanding about it.”

Bringing Hope

SCD can complicate school, work, travel and other plans because a pain episode can happen at any time. That’s why a treatment like EDIT-301 gives hope to patients and families dealing with the interruptions and stress that chronic illnesses cause.

“Having a chronic illness is very consuming, not just for the child who's affected, but also for the family,” Dr. Johnson said.

Many parents tell her they’re excited about genetic therapy because of the prospect of making long-term plans without worrying about their child’s SCD flaring up on a trip, for instance. Some families, however, are more hesitant. 

“It's a big decision,” she said. “We know that not everybody's going to necessarily be first in line. But I think the longer we see this out there and see the difference it makes for people, that will be what encourages others to give it a try.”

After the RUBY Trial ends, the manufacturer may choose to submit the data to the U.S. Food and Drug Administration for approval of the treatment. 

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