Two trials using CRISPR-Cas9 to treat patients with sickle cell anemia and β-thalassemia have produced promising results. The patients have not had any vaso-occlusive crises following treatment and no longer require blood transfusions.
The companion trials used a form of CRISPR therapy called CTX001 to treat the two single gene disorders. Sickle cell anemia and β-thalassemia are inherited blood disorders involving abnormal hemoglobin, which limits the amount of oxygen that can be carried by the blood. While both disorders can be cured with a bone marrow transplant, many patients cannot undergo the treatment due to the problem finding a suitable donor.
CTX001 was used to edit the DNA to increase production of fetal haemoglobin in the patients’ red blood cells. Both trials targeted the BCL11A gene, which switches off production of fetal hemoglobin. By disabling the gene, fetal hemoglobin will continue to be produced.
Patient 1 had transfusion-dependent β-thalassemia and required an average of 34 units of blood a year, which equates to approximately 18 liters. After receiving the CRISPR treatment, the level of fetal hemoglobin increased rapidly within 6 months and the increased level was maintained for 18 months and the patient no longer requires blood transfusions. Patient 2 had sickle cell anemia and suffered an average of 7 crises each year, but experienced no crises in the 16.6 months following treatment.
The findings from the trials are certainly promising and suggest CTX001 can be an effective treatment for both blood disorders, although the treatment was not without side effects. The β-thalassemia patient experienced two serious events, including one pneumonia infection. This was attributed to a delay in immune system recovery after receiving the treatment. The second patient experienced a serious case of sepsis, which was similarly attributed to delayed immune system recovery. In both cases, the side effects were managed and the patients made a full recovery.
The side effects were not due to the CRISPR treatment itself, but the treatment required to prepare the bone marrow for the procedure, which involves removing blood stem cells from the bone marrow, modifying them in the lab, and ablating the remaining blood stem cells prior to reintroduction. The ablation is risky as the patients face a risk of infection while the bone marrow recovers. The treatment also carries a risk of fertility damage.
Since the initial results were announced by CRISPR Therapeutics and Vertex Pharmaceuticals the results from a further 6 β-thalassemia patients and 2 sickle cell anemia patients have been released and the results are consistent across all 10 patients, all of whom avoided vaso-occlusive crises following treatment and none required further blood transfusions.
While the findings of the trials are certainly promising, it is still too early to tell whether the treatment will prove to be safe and effective in the long term, and whether the treatment will be effective for treating a broader variety of patients. A safer and gentler way to prepare the bone marrow for treatment will need to be found, otherwise this treatment is only likely to be suitable for patients with severe disease that does not respond to other treatments.
You can read more about the results of the clinical trial in the paper – CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia – which was recently published in The New England Journal of Medicine. DOI: 10.1056/NEJMoa2031054