Ever since its discovery in 2012, the CRISPR/Cas9 gene-editing system has promised to "revolutionize" modern medicine and transform the lives of patients suffering from incurable genetic diseases. The world has waited patiently for it to deliver on such promise. However, this wait has been necessary to ensure that CRISPR therapies are safe. Behind the scenes, scientists have worked extensively to ensure that CRISPR technology can be delivered to humans without dangerous off-target effects on the genome.
In January of this year, CRISPR Therapeutics and Vertex Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) had granted fast track designation for an investigational, autologous, gene-edited hematopoietic stem cell therapy for patients suffering from hemoglobinopathies. The therapy is known as CTX001. Now, the companies have announced positive safety and efficacy interim data from the first two patients with severe hemoglobinopathies treated with the CRISPR/Cas9 gene-editing therapy CTX001 in ongoing Phase 1/2 clinical trials.
The enrolled patients suffer with two different hemoglobinopathies: transfusion-dependent beta thalassemia (TDT) and sickle cell disease (SCD).
What is transfusion-dependent beta thalassemia?
Beta thalassemia is a genetic blood disorder, characterized by either reduced or no production of β-globin, a component of hemoglobin, the oxygen-carrying protein. Beta thalassemia is a result of mutations in the beta-globin (HBB) gene, and severity of the disorder is dependent on whether an individual carries a mutation in one HBB gene, or both. Patients with the most severe forms of beta thalassemia, TDT, experience severe anemia, and unfortunately have to rely on red blood cell transfusions throughout their lives, which can have iron toxicity implications.
The TDT patient received CTX001 in early 2019, and so the data announced represents nine months of safety and efficacy follow-up.
What is sickle cell disease?
SCD is a group of disorders that also affect hemoglobin. In SCD, the hemoglobin molecules are atypical, and are known as hemoglobin S. They can distort red blood cells into a sickle shape causing them to break down prematurely and results in anemia. The subsequent symptoms of anemia include shortness of breath, delayed growth and development in children, and fatigue. Pulmonary hypertension also occurs in approximately one-third of adults with sickle cell disease. Unfortunately, this can lead to heart failure.> The SCD patient received CTX001 in mid-2019, and so the data for this patient is reflective of four months of safety and efficacy follow-up.
CRISPR/Cas9 as a therapeutic
If you've been keeping up with Technology Networks Explores the CRISPR Revolution, you may be quite familiar with CRISPR and its application as a gene-editing tool. If not, check out Jennifer Doudna's comprehensive TED talk below. You can also catch our interview with her, where we discuss the latest advancements and ethical conversations surrounding CRISPR, here.
Video credit: TED.
What is CTX001?
CTX001 is an ex vivo CRISPR gene-edited therapy that is being evaluated in the TDT and SCD patients. In this therapy, patient's hematopoietic stem cells are genetically edited to produce high levels of fetal hemoglobin (HbF) in red blood cells. By elevating levels of HbF, CTX001 offers the potential for TDT patients to live a life without being dependent on blood transfusions and alleviate the debilitating and painful symptoms of SCD.
How is the gene-editing therapy delivered? Patients that enroll in the CTX001 study will have their hematopoietic stem cells and progenitor cells collected via a blood draw. These cells will then undergo gene-editing using CRISPR/Cas9, before being infused back into the patient via a stem cell transplant
Interim results from the TDT and SCD patients
“The data we announced today are remarkable and demonstrate that CTX001 has the potential to be a curative CRISPR/Cas9-based gene-editing therapy for people with sickle cell disease and beta thalassemia,” said Jeffrey Leiden, M.D., Ph.D., Chairman, President and Chief Executive Officer of Vertex. “While the data are exciting, we are still in the early phase of this clinical program. We look forward to continuing to work with physicians, patients, caregivers and families over the coming months and years to bring forward the best possible therapy for these two serious diseases and to continue to accelerate our gene-editing programs for other serious diseases such as Duchenne muscular dystrophy and myotonic dystrophy type 1.”
The results show that the TDT patient achieved neutrophil and platelet engraftment 33 days after CTX001 infusion. Two serious adverse events (SAEs) occurred, but the principal investigator (PI) did not consider these to be related to CTX001. Nine months after CTX001 infusion, the patient was transfusion independent, and had total hemoglobin levels of 11.9g/dL, 10.1g/Dl fetal hemoglobin, and 99.8% F cells (erythrocytes expressing fetal hemoglobin).
The SCD patient originally experienced seven vaso-occlusive crises (VOCs) per year before enrolling in the clinical trial. This is where the circulation is obstructed by sickled red blood cells, resulting in lack of oxygen supply to the organs and subsequent pain. The patient achieved neutrophil and platelet engraftment 30 days after CTX001 infusion. Whilst three SAEs occurred, the PI did not consider any of these to be related to CTX001, and all events resolved. Four months post-CTX001 infusion, the patient had a total hemoglobin level of 11.3g/dL, 46.6% fetal hemoglobin, and 94.7% F cells. Four months post CTX001 infusion, the patient was free of VOCs.
“We are very encouraged by these preliminary data, the first such data to be reported for patients with beta thalassemia and sickle cell disease treated with our CRISPR/Cas9 edited autologous hematopoietic stem cell candidate, CTX001,” saidSamarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. “These data support our belief in the potential of our therapies to have meaningful benefit for patients following a one-time intervention. We continue to enroll these studies as we drive forward to develop CRISPR/Cas9 therapies as a new class of transformative medicines to treat serious diseases.”
Forward-thinking in CRISPR gene-editing therapy
Of course, whilst the results look promising, the small sample size cannot be ignored. However, the Phase 1/2 study in TDT will eventually enroll up to 45 patients with TDT and will follow the patients for approximately two years after infusion. Forty-five patients will also be recruited to the SCD Phase 1/2 study in the future, and these patients will receive long-term follow up.
Only a few years ago, the prospect of conducting gene editing in patients to cure debilitating genetic disorders seemed a far-away dream. But the results of these studies argue that CRISPR gene-editing is far from a futuristic fantasy – it's here, and it's now.
Is the world ready? Let us know what you think.