Three people with inherited diseases successfully treated with CRISPR

By Michael Le Page

Sickle cell disease can distort red blood cells

Stocktrek Images, Inc/Alamy

Two people with beta thalassaemia and one with sickle cell disease no longer require blood transfusions, which are normally used to treat severe forms of these inherited diseases, after their bone marrow stem cells were gene-edited with CRISPR.

Result of this ongoing trial, which is the first to use CRISPR to treat inherited genetic disorders, were announced today at a virtual meeting of the European Hematology Association.

“The preliminary results… demonstrate, in essence, a functional cure for patients with beta thalassaemia and sickle cell disease,” team member Haydar Frangoul at Sarah Cannon Research Institute in Nashville, Tennessee, said in a statement.

Beta thalassaemia and sickle cell disease are conditions caused by mutations that affect haemoglobin, the protein that carries oxygen in red blood cells. Those with severe forms require regular blood transfusions.

However, a few people with the disease-causing mutations never show any symptoms, because they keep producing fetal haemoglobin in adulthood. Normally, fetal haemoglobin stops being produced soon after birth.

This discovery has inspired the development of treatments based on boosting fetal haemoglobin. In this trial, run by collaborating companies CRISPR Therapeutics and Vertex, bone marrow stem cells are removed from people and the gene that turns off fetal haemoglobin production is disabled with CRISPR.

The remaining bone marrow cells are killed by chemotherapy, then replaced by edited cells. This is done to ensure that new blood cells are produced by the edited stem cells, but the chemotherapy can have serious side effects including infertility.

The first two patients with beta thalassaemia no longer need blood transfusions since being treated 15 and five months ago. Nor does the patient with sickle cell disease, nine months after treatment.

The results are excellent, says Marina Cavazzana at the Necker-Enfants Malades Hospital in Paris, France, whose team has treated a 13-year-old boy with sickle cell disease using a different approach.

Although the three patients did experience some adverse effects due to the chemotherapy, the CRISPR gene editing appears safe. However, the patients may need to be monitored for the rest of their lives to be sure it has no adverse effects, says Cavazzana.

Altogether five people have now been treated. The trial was put on hold because of the coronavirus pandemic, but has now resumed.

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Are patients with thalassemia more susceptible to serious COVID-19 disease?

COVID-19 and Thalassemia: Frequently Asked Questions

(last updated June 8, 2020)

Input from Drs. Maria Cappellini, Antonio Piga, Janet Kwiatkowski and Alexis Thompson

Note: Please review ASH's disclaimer regarding the use of the following information.

Are patients with thalassemia more susceptible to serious COVID-19 disease? Does splenectomy confer a higher risk?

Thalassemia patients, especially young adults/adults, have a chronic condition which may be associated with several co-morbidities linked to the underlying disease as well as complications of chronic transfusions, including heart failure, pulmonary hypertension, and diabetes. Thus, it seems possible that there could be an increased risk of more severe COVID-19 disease in some patients. Nonetheless, outcomes were recently reported from a small cohort of Italian patients followed in the northern part of Italy, where the pandemic has been the most widespread, showing most experienced relatively mild to moderate COVID-19 disease.¹ The number of infected thalassemia patients was lower than expected, likely due to earlier and more vigilant self-isolation compared to the general population.

Splenectomy is not known to increase the general risk of viral infection or severe viral disease, but no specific data exists for SARS-CoV-2. Splenectomized patients who develop fever should be evaluated for possible bacterial infection and should receive antibiotics to cover secondary bacterial infections.

Should any changes in transfusion schedules or thresholds be made in the context of the COVID-19 pandemic?

At present there is no evidence that the SARS-CoV-2 virus may be transmitted through donated blood. It is advisable to maintain the individual’s chronic transfusion regimen. Clinics and infusion centers should offer patients the safest possible environment for receiving transfusions, in areas free of COVID-19 patients or those being screened for respiratory symptoms and providing health care personnel protective equipment.

Hematologists and other thalassemia care providers should continue to follow local and national developments related to possible blood shortages related to COVID-19. Clinical sites and blood banks should develop contingency plans for adjusting transfusion regimens and obtaining appropriate donor units for individuals with alloimmunization in the event a significant shortage develops. 

Should thalassemia patients continue iron chelation if they are exposed to or have confirmed COVID-19 disease?

No data are available regarding iron chelation and susceptibility to COVID-19 or severity of infection. If a patient is exposed but asymptomatic there is no reason to interrupt iron chelation. If a patient becomes symptomatic, particularly with moderate to severe disease, then interruption of iron chelation is advisable, with ongoing communication between the treating physicians and the hematologist.

Many comorbidities in thalassemia are related to iron overload. Patients should be reminded that adherence to the iron chelation dose and schedule recommended by their thalassemia care provider will reduce organ injury and thalassemia complications.

What about treatment with the recently approved disease-modifying drug luspatercept during the COVID-19 pandemic?

Luspatercept has been approved for adults with transfusion dependent beta thalassemia and has been shown to significantly reduce transfusion burden in this population. No data are available to date on luspatercept and COVID-19. If patients are currently taking luspatercept, there are no theoretical reasons to stop treatment. If the drug has decreased transfusion frequency, then continuing treatment would be beneficial in terms of avoiding prolonged clinic visits for transfusions and decreasing utilization of a limited blood supply.

What are the recommendations for stem cell transplantation or gene therapy for thalassemia during the COVID pandemic?

Due to high risk of infection in hospital settings and the risk of myeloablation, most allogeneic stem cell transplantation and gene therapies were postponed during the initial phases of the pandemic. In localities with a fall in COVID-19 hospitalizations, patients and their physicians can begin to discuss moving forward with planned procedures, particularly in patients with gene therapy cell products already prepared or with limited allogeneic donor availability. There is no evidence that SARS-CoV-2 can be transmitted via hematopoietic stem cell grafts.

References

1. Motta et al, Am J Hematol, 2020 SARS‐CoV‐2 infection in beta thalassemia: preliminary data from the Italian experience. https://doi.org/10.1002/ajh.25840
2. Karimi M, et al. Prevalence and Mortality due to Outbreak of Novel Coronavirus Disease (COVID-19) in β-Thalassemias: The Nationwide Iranian Experience. Br J Haematol. 2020 Jun 2.
3. Roy NBA, et al. Protecting vulnerable patients with inherited anaemias from unnecessary death during the COVID-19 pandemic. Br J Haematol. 2020 May;189(4):635-639.

For additional information, see:

• Resources for providers to share with their patients
  • Cooley Anemia Foundation
  • Thalassemia International Federation

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Public Health Webinar Series on Blood Disorders

CDC’s Division of Blood Disorders (DBD) is proud to offer its Public Health Webinar Series on Blood Disorders. The purpose of this series is to provide evidence-based information on new research, interventions, emerging issues of interest in blood disorders, as well as innovative approaches in collaborations and partnerships. We invite you to join us in this series.

Archives for 2020

Sujit Sheth, MD
Harold Weill Professor, Chief of Pediatric Hematology and Oncology, and Vice Chair for Clinical Research, Department of Pediatrics, Weill Cornell Medicine

Director, New York Comprehensive Thalassemia Center, New York-Presbyterian Hospital/Weill Cornell Medical Center

Overview of Novel Thalassemia Treatments

The thalassemia syndromes are among the most common genetic disorders. Homozygous or compound heterozygotes have a wide spectrum of clinical severity, with the most severe requiring regular blood transfusions to maintain health and prevent morbidity. Transfusion-associated iron overload and its complications result in significant morbidity and mortality, thus disease-modifying treatments are a major unmet need in the management of these individuals.

During the past five years, novel approaches to treatment have been possible with advances in technology. In this webinar, Dr. Sheth will discuss the basic pathophysiology of the disease and specific targets for novel therapies. He will review data from trials of the newer agents aimed at reducing or abolishing the transfusion burden and mention additional strategies that are in early stage development that have the potential to completely change the landscape of thalassemia care.