Novel gene editing cell therapy shows curative potential in sickle cell disease
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An experimental gene editing cell therapy for sickle cell disease has shown encouraging early results in a phase 1/phase 2 multicenter clinical trial, according to researchers at Cleveland Clinic Children’s.
Preliminary data presented at European Hematology Association Hybrid Congress showed the first four trial participants who received EDIT-301 (Editas Medicine) had new white blood cells at about 4 weeks without any severe adverse effects. They also achieved normal hemoglobin levels and freedom from pain crises so far.
The clinical trial is the first in which CRISPR/Cas12, a novel CRISPR gene-editing technology, is being employed to edit human cells, according to a Cleveland Clinic Children’s press release.
“For me, the most exciting thing is that we’re starting to have so much research and so many potential cures for patients with sickle cell disease,” lead investigator Rabi Hanna, MD, director of pediatric bone marrow transplantation at Cleveland Clinic Children’s, told Healio. “This is just one of many that are in development. Some of them are in advanced stages and have applied for [biologics license applications] from the FDA. This adds to those options, and hopefully, we can continue to refine that.”
Hanna spoke with Healio about the trial, the promising results to date, and the need for equitable access to new sickle cell disease treatments.
Healio: What is this new treatment and how is it being evaluated in this trial?
Hanna: This is a phase 1/phase 2, multicenter international study. It uses a novel approach to gene editing — CRISPR with the use of Cas12. Cas12 has been shown in preclinical research to be more efficient for gene editing because it is a single RNA endonuclease compared with Cas9, which is a double-RNA endonuclease.
This study also added hemoglobin G1 and G2 directly instead of a different enhancer. Their goal is to make gene editing more precise, more efficient and targeted directly to the hemoglobin G1 and G2 so it mimics exactly what happens in nature with fetal hemoglobin.
Healio: How many patients have you studied so far, and what results have you observed?
Hanna: We publicly presented data on the first four patients infused as of the data cutoff in May. The four patients were able to proceed through all phases of the study, from mobilization to chemotherapy and infusion of the CD34 gene-edited cells. They subsequently engrafted and the patients are now able to be transfusion independent.
In terms of follow-up at that time, the longest was around 11 months. All four patients had no pain crises so far, and any side effects they noticed were related mostly to the busulfan used in the chemotherapy regimen. So, we are happy to see that it is comparable to what we would expect with autologous transplant. We’re also excited about the clinically robust and seemingly meaningful improvement in fetal hemoglobin. All four patients were able to achieve fetal hemoglobin above 40% within around 3 to 4 months. They all had hemoglobin in a normal range starting at about 3 months after transplant. Even their hemolysis markers are becoming normalized, which is an important finding.
Healio: What do you expect to be the long-term implications of this study?
Hanna: I think this has promise as another treatment option, but I want to highlight the importance of access to care. That is really going to be the essence of this improvement. It will mean nothing if we potentially have this great therapy and people don’t have access to care. This is a great clinical trial of a medication that can hopefully help these patients, but the challenge in sickle cell disease treatment remains the health disparities and the inability to access high-quality care for most of the adult patients with sickle cell disease. I think that is going to be the most important factor in advancing the care.
Also, not everyone will need this. We know sickle cell disease is heterogenous; some of the patients have very severe phenotypes, some have mild phenotypes, and it can be debilitating for those with severe disease. This can potentially offer them a functional cure, because this is not going to change their body. It’s only going to change the stem cells in their bone marrow to prevent further complications and allow them the freedom to explore their life goals.
One patient, anecdotally, had six admissions to the hospital per year on average for pain crises and spent more than 80 days in the hospital. Now, with this therapy, he has gone almost 11 months with no admission. He is able to explore, go to college without interruption and finish his semester. He said, “I am free.” I think this is what this curative therapy could offer if the long-term results show continuous safety and efficacy.
Healio: Is there anything else you’d like to mention?
Hanna: This is an early study and we presented data on only the first four patients. I want to be cautious as we await the long-term results.
For more information:
Rabi Hanna, MD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; Twitter @RabiHannaMD.
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Novel gene therapy shows positive initial results in sickle cell patients treated in clinical trial at Cleveland Clinic Children’s (press release). Available at: https://newsroom.clevelandclinic.org/2023/06/09/novel-gene-therapy-proving-safe-and-successful-in-sickle-cell-patients-treated-at-cleveland-clinic-childrens/. Published June 9, 2023. Accessed June 23, 2023.
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