CRISPR-based Tx brings hope to difficult-to-treat blood disorders

Preliminary results from the CRISPR-Cas9 gene editing study show that many people with sickle cell disease (SCD) and β-thalassemia can be treated.

Haydar Frangoul, MD of Sarah Cannon Institute and HCA Healthcare Tristar Centennial Medical Center in Nashville did not occur until 16 months after transplantation of 3 SCD patients who experienced numerous vaso-occlusive disorders each year. I reported that.

In addition, seven patients with β-thalassemia (TDT) who needed a median 15 transfusions a year had not been transfused for 20 months after being injected with their modified blood cells, he said at a news conference. ..Include American Society of Hematology (ASH) Virtual conference.Some of the findings were published at the same time New England Journal of Medicine..

“Here we describe the first patient to be infused with CTX001 (gene-edited autologous CRISPR-Cas9 edited CD34 + HSPC to reactivate fetal hemoglobin production) and enrolled in CLIMB THAL-111. [for TDT] And CLIMB SCD-121 (for SCD), ”Frangoul and co-authors wrote in a brief report.

“The first 10 patients treated with CTX001 were followed for 3.8 to 21.5 months, stopped transfusions and were not at risk of vaso-occlusive disease,” Frangoul said at the ASH conference. “The clinical proof of concept of CTX001 is currently demonstrated in both β-thalassemia and sickle cell disease. These data show that CTX001 is a potential functional treatment for the treatment of β-thalassemia and sickle cell disease. It shows that it is a law. “

“I’ve shown here a proof of the principle that CRISPR-CAS9 technology works,” he added. “Not only does it work, it is safe and can be delivered to humans. This is the first time in human clinical trials. The technology can be used to target and edit genes in multiple diseases. I am very much looking forward to it .. The future of this technology is very exciting. “

Details of the study

Several approaches to genome editing have been developed and previously reported CLIMB research.. Frangoul group shared data from CLIMB THAL-111 And CLIMB SCD-121..

After screening, Frangoul explained that the patient’s stem cells would be collected and shipped to a central manufacturing site. There, CD34-positive cells are isolated and edited using CRISPR-Cas9 technology. The cells are frozen, subjected to quality control tests, and then returned to the index facility for injection. The patient then undergoes myeloablative conditioning with high-dose busulfan, followed by a CTX001 injection of cells. The patient is then monitored for engraftment and hematopoietic recovery. The patient will be discharged and followed.

Frangoul reported that five women and two men with β-thalassemia had been transplanted and had not been transfused for more than three months after treatment. Patients received a median of 33 units of blood per year to combat the anemia caused by the disease, with a median transfusion episode of 15. Within two months of receiving the transplant, all seven patients have not been transfused for 1.8 to 20.5 months. ..

In addition, two women and one man with SCD were at least three months old after the infusion and did not develop the characteristic painful vaso-occlusive crisis, Frangoul said. These patients developed 4-7 episodes of vascular occlusion in the 2 years prior to transplantation.

All patients showed a substantial and sustained increase in fetal hemoglobin production, he said.

“We have done many allografts in patients with β-thalassemia and sickle cell disease,” he said. “Unfortunately, less than 20% of patients are consistent with associated donors. Results using donors not associated with both sickle cell disease and β-thalassemia [fraught] With many complications, including graft-versus-host disease; graft failure. So I think the autologous cell approach actually has a big advantage here as it is available to all patients. “

Regarding the safety profile, Frangoul said, “Similar to the use of high-dose chemotherapy. Here we use high-dose busulfan as a conditioning regimen. This approach is more than the potential for curative treatment. It will definitely open the door to many patients. “

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. Two AEs were also severely classified: pneumonia in the presence of neutropenia and venous obstructive liver disease (VOD-SOS) with sinusoidal obstruction syndrome, both day 13 of the study. It started in. Pneumonia resolved on day 28, but VOD-SOS reached grade 3 severity despite defibrotide prevention. The latter was “continued for therapeutic purposes with supportive care and VOD-SOS was resolved on day 39 of the study,” they said.

At the meeting, Frangoul reported four serious AEs associated with, or perhaps associated with, CTX001 in one patient with β-thalassemia: headache, hematopoietic lymphohistiocytosis, acute respiratory distress syndrome, And idiopathic pneumonia syndrome. The patient has now recovered.

Frangoul said that each CLIMB trial is set to have 45 patients each, “There are patients aged 12-35 years … Inject more patients and follow them longer. I think we need to. The safety profile is great, but it looks long-time follow-up is very important. “

“Another treatment option”

“I have the result [the authors] Is indicated by β-thalassemia, and sickle cell disease is noteworthy. ” ASH Press Conference Moderator Catherine Borard, MD, MBChB, National Institute of Pediatrics and George Washington University Cancer Immunology Center in Washington.

“Given that bone marrow transplantation, the only treatment for sickle cell disease approved by the FDA, is not widely available, alternative treatment options can affect the lives of large sickle cell populations. It will change, “she said.

“We need longer follow-up data, but this study is very exciting for this area,” Bollard said. Today’s MedPage.. “As a pediatric bone marrow transplant doctor who has certainly treated many children with these life-threatening blood disorders, many patients who have not been cured because the use of such gene therapy could not be addressed otherwise. Opened a therapeutic approach to allogeneic stem cell transplantation or was ineligible in terms of not being able to obtain suitable donors. “