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Cures are possible for many people with sickle cell disease (SCD) and β-thalassemia, according to preliminary results of a CRISPR-Cas9 gene-editing study.

Among three patients with SCD who had experienced numerous annual vaso-occlusive crises, none have occurred up to 16 months post-transplant, reported Haydar Frangoul, MD, of the Sarah Cannon Research Institute and HCA Healthcare TriStar Centennial Medical Center, both in Nashville.

Additionally, seven patients with β-thalassemia (TDT) who had required blood transfusions a median of 15 times a year were transfusion-free for as long as 20 months after being infused with their own modified blood cells, he stated during a press conference at the American Society of Hematology (ASH) virtual meeting. Some of the findings were simultaneously published in the .

"Here, we describe the first...patients who were infused with CTX001 (autologous CRISPR-Cas9-edited CD34+ HSPCs that were genetically edited to reactivate the production of fetal hemoglobin) and enrolled in CLIMB THAL-111 [for TDT] and CLIMB SCD-121 (for SCD]," Frangoul and co-authors wrote in the brief report.

"The first 10 patients treated with CTX001 have been followed for 3.8 months to 21.5 months and have stopped transfusions and are vaso-occlusive crisis-free," Frangoul said at the ASH meeting. "Clinical proof-of-concept for CTX001 has now been demonstrated for both β-thalassemia and sickle cell disease. These data demonstrate that CTX001 is a potential functional cure for the treatment of β-thalassemia and sickle cell disease."

"What we have shown here is proof of principle that CRISPR-CAS9 technology can work," he added. "Not only can it work, but it is safe and it can be delivered to humans. This is the first in human clinical trials. We are very hopeful that this technology can be used in multiple diseases to either target a gene or edit a gene. The future is very exciting for this technology."

Study Details

Several approaches to genome editing have been developed and reported on in previous. Frangoul's group shared data from and .

Frangoul explained that, after screening, a patient's stem cells are collected and shipped to a central manufacturing location. There, CD34-positive cells are isolated and edited using the CRISPR-Cas9 technology. The cells are frozen and undergo quality control testing before the cells are returned to the index facility for infusion. The patient then undergoes myeloablative conditioning with high-dose busulfan, followed by CTX001 infusion of the cells. The patient is then monitored for engraftment and hematopoietic recovery. The patient is discharged and followed.

Frangoul reported that five women and two men with β-thalassemia have been transplanted and are transfusion-free more than 3 months post-treatment. Patients received a median of 33 units of blood a year to combat anemia caused by the disease, and the median transfusion episodes a year was 15. Within 2 months of receiving the transplant, all seven patients have been transfusion-free for 1.8 to 20.5 months.

Also, two women and one man with SCD have gone at least 3 months since infusion and have not had characteristic painful vaso-occlusive crises, Frangoul said. These patients had between four and seven of the vaso-occlusive episodes in the 2 years prior to transplant.

All patients showed a substantial and sustained increase in the production of fetal hemoglobin, he noted.

"We have done many allogeneic transplant in patients with β-thalassemia and sickle cell disease," he said. "Unfortunately, less than 20% of patients have matched related donor. The results using unrelated donors for both sickle cell and β-thalassemia has been [fraught] with a lot of complications, including graft-versus-host disease; graft failure. So I think the approach using autologous cell actually has a huge advantage here because it makes it available to all patients."

As for the safety profile, Frangoul said it was "similar to using high-dose chemotherapy. Here we are using high-dose busulfan as a conditioning regimen. This approach definitely opens the door to many more patients who potentially can get curative therapy."

The authors reported in the journal that one patient had 32 adverse events (AEs), most of which were considered to be grade 1 or 2 in severity. Also, two AEs were classified as serious: pneumonia in the presence of neutropenia, and veno-occlusive liver disease with sinusoidal obstruction syndrome (VOD-SOS), both of which began on study day 13. While the pneumonia resolved on day 28, the VOD-SOS reached a severity of grade 3 in spite of defibrotide prophylaxis. The latter was continued "with therapeutic intent along with supportive care, and the VOD–SOS resolved on study day 39," they stated.

At the meeting, Frangoul reported four serious AEs that were related, or possibly related to, CTX001 in one patient with β-thalassemia: headache, hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and idiopathic pneumonia syndrome. The patients have now recovered.

Frangoul said that each of the CLIMB trials are set to accrue 45 patients each, and "We are accruing patients ages 12 to 35...I think we need to infuse more patients and follow them longer. The safety profile looks great but long-term follow-up is very important."

"Another Curative Option"

"I do think the results that [the authors] are showing in β-thalassemia and sickle cell disease are remarkable," said ASH press briefing moderator Catherine Bollard, MD, MBChB, of the Center for Cancer and Immunology at Children's National Research Institute and George Washington University in Washington.

"Given that the only FDA-approved cure for sickle cell disease -- a bone marrow transplant -- is not widely accessible, having another curative option would be life-changing for a large number of the sickle cell disease population," she said.

"While longer follow-up data are needed, this study is extremely exciting for the field," Bollard told 木瓜直播. "As a pediatric bone marrow transplant physician, who has certainly cured many children with these life-threatening blood diseases, the use of gene therapy like this opens up a curative approach for many patients who otherwise would not be cured because they couldn't cope with an allogeneic stem cell transplant, or were ineligible from the aspect of not being able to get a suitable donor."

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