CRISPR-Cas9 gene editing for patients with haemoglobinopathies

Abstract

At the end of July, CRISPR Therapeutics announced that the first patient with sickle-cell disease had been treated by gene-editing CRISPR-Cas9 technology as part of a phase 1 trial in the USA. In an interview with National Public Radio, the patient, Victoria Gray, indicated that she had been considering a bone marrow transplantation when she heard about the study. The aim of this therapy is to increase the production of fetal haemoglobin, which can ameliorate the pathology of both sickle-cell disease and β-thalassaemia. Treatment with CTX001 involves isolating a patient's stem cells from peripheral blood and then editing the cells with CRISPR-Cas9 designed to disrupt BCL11A, resulting in an increase production of fetal γ-globin. The edited cells are then returned to the patient following myeloablative conditioning of the bone marrow. Compared with traditional gene editing techniques, which use viruses to deliver genetic material that will be randomly inserted in the genome, CRISPR-Cas9 can make precise, targeted changes to the genome of living cells. It will be many months, if not years, before it is clear whether this method is able to truly help patients with sickle-cell disease. However, early results are promising as the company also reported that a patient with transfusion dependent β-thalassaemia remained transfusion independent for over 4 months following engraftment of CTX001-treated cells. The newness of this technology in human clinical trials necessitates careful monitoring and observation. Several trials using non-targeted gene editing approaches took place in the 1990s, but clinical advancement stalled with the death of a patient due to an extensive immune response during a safety trial for ornithine transcarbamylase deficiency. Now, the ability of CRISPR-Cas9 technology to target very specific DNA sequences along with improvement in gene-transfer and gene-editing efficiencies has catapulted gene therapy forward. China was the first country to approve the commercial production of a gene therapy product in 2003 to treat head and neck squamous-cell carcinoma. Europe followed in 2012 with approval of gene therapy for the rare disease lipoprotein lipase deficiency. The approval of three gene therapy products—including two CAR T-cell products—by the US Food and Drug Administration (FDA) in 2017 demonstrates that gene therapy has evolved from beyond a theoretical exercise to providing real clinical benefit, with more therapies being approved around the world each year. Although a newcomer in human clinical trials, CRISPR-Cas9 technology has not been without controversy. Last November, He Jiankui announced that CRISPR-Cas9 had been used in germline editing of twin girls at risk of HIV transmission born earlier that month in China. This news was generally met with widespread criticism and condemnation for good reasons, including the lack of an unmet medical need in this setting and lack of adherence to existing research guidelines. From an ethical standpoint, the distinction between gene therapy for disease genes and gene therapy to enhance desired traits is not clear cut—there have been suggestions that He's experimentation with CCR5 could potentially enhance the twins cognitive abilities. Careful consideration will be required in the future regarding potential germline editing, and without knowledge of long-term effects, it is of utmost importance that there is sound medical rational for developing a gene therapy technique, even when the goal is only to treat somatic cells. In respect to CTX001, time will tell whether there is long-term efficiency and whether there are any off-target effects; in mice, Bcl11a is a common site of retroviral integration in myeloid leukaemia and can be downregulated in B-cell malignancies. Furthermore, gene therapy will be out of reach for many of those in the world who have sickle-cell disease. Nevertheless, this potential therapy for patients with sickle-cell disease is good news, and gene therapy holds real promise for improvements of patients' survival and quality of life. There are few drugs that effectively control symptoms in patients with sickle-cell disease, and stem-cell transplantation, although provided with curative intent, requires the availability of matched donors and carries a degree of risk and long-term adverse events. The potential for gene therapy to overcome the pain of a sickle cell-crisis and allow patients to lead a fuller life could be revolutionary. As Gray stated in her interview, “This gives me hope if it gives me nothing else”.