CRISPR Gene-Edited Therapy CTX001 Raises Hopes for Sickle Cell Disease and β-Thalassemia Cures

The 62nd American Society of Hematology Annual Meeting & Exposition (ASH 2020) witnessed pathbreaking results from two pioneering early-stage clinical studies that utilized the power of CRISPR-based genome editing to treat two inherited blood disorders, potentially revolutionizing the field of therapeutics for monogenic disorders. A handful of patients with severe forms of β-thalassemia or sickle cell disease (SCD) that required frequent blood transfusions saw their condition improve after receiving an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy, CTX001.

“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,” said press briefing moderator Catherine Bollard, MD, of Children’s National Research Institute. “While longer follow-up data are needed, this study is extremely exciting for the field.”

CTX001 Shows Promise

CRISPR Therapeutics and Vertex Pharmaceuticals tested a one-time infusion of CRISPR-modified hematopoietic stem cells (CTX001) in patients with either β-thalassemia (CLIMB 111 trial) or SCD (CLIMB 121 trial) to see if their conditions improved and no longer required blood transfusions.

Both monogenic disorders are caused by mutations in the beta-globin gene, the product of which forms part of adult hemoglobin (HbA). In either disease, individuals cannot produce healthy HbA, which leads to anemia and a variety of other health problems. Patients with transfusion-dependent thalassemia (TDT) require blood transfusions from early childhood. On the other hand, SCD patients suffer from painful episodes called vaso-occlusive crises (VOC), organ damage, and strokes due to their misshapen RBCs obstructing the blood vessels,

CTX001 consists of stem cells from a patient’s bone marrow, which are edited using CRISPR to increase the production of fetal hemoglobin (HbF). The gene-edited cells are then infused back into the body, where they home into the bone marrow and produce sufficient HbF. Unlike the warped RBCs, which form abnormal HbA, increased amounts of HbF produce healthy RBCs in patients.

Trial Results

Results reported at the meeting showed all 7 patients with TDT who received the CRISPR altered stem cells showed a consistent and sustained response to treatment, meaning they all produced normal to near normal total hemoglobin and fetal hemoglobin. The total hemoglobin levels were from 9.7 to 14.1 g/dL, and fetal hemoglobin levels were from 40.9% to 97.7% in all patients. Before the treatment, TDT patients in the CLIMB 111 trial required blood transfusions approximately every three to four weeks (median of 15 infusions per year). However, during the entire time of follow up since the treatment, from 3 months all the way up to 18 months, patients became transfusion independent.

In the CLIMB-121 trial, a total of six patients with SCD were dosed with CTX001. The three SCD patients reported at the meeting did not experience episodes of severe and debilitating sickle crises (VOC) for at least three months and as long as about 15 months of follow up. They had hemoglobin levels in the normal to near normal range, including total hemoglobin from 11.5 to 13.2 g/dL and fetal hemoglobin levels from 31.3% to 48.0%. A report on the first two patients receiving CTX001 was published in the New England Journal of Medicine on December 5th.

“There is a great need to find new therapies for β-thalassemia and sickle cell disease,” said Haydar Frangoul, MD, Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcare’s TriStar Centennial Medical Center. “What we have been able to do through this study is a tremendous achievement. By gene editing the patient’s own stem cells, we may have the potential to make this therapy an option for many patients facing these blood diseases.”

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: ASH2020: Incyte Presents Positive Phase 3 Data for cGVHD Drug, Ruxolitinib

References

1. https://ash.confex.com/ash/2020/webprogram/Paper139575.html
2. http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-present-new-data-investigational
3. https://www.nejm.org/doi/full/10.1056/NEJMoa2031054
4. https://www.prnewswire.com/news-releases/genome-editing-and-cellular-therapies-show-promise-for-treating-blood-disorders-cancers-301186839.html

Author

Sangeeta Chakraborty