ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 14.4 | DOI: 10.1530/ey.18.14.4

N Engl J Med 2021; 384:252–260

In the Yearbook, we have been following the CRISPR story since its very beginning. Last year, Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry for discovering the CRISPR-Cas9 gene editing tool. Here, scientists have published the first successful treatment (as distinct from reports of using CRISPR-Cas9 to correct inherent mutations in patients), providing proof-of-principle that CRISPR-Cas9 gene editing is effective in human hematopoietic stem cells and capable of providing a cure for some of the most common and potentially fatal diseases in humans.

Patients with sickle cell disease (SCD) suffer from vaso-occlusive crises, while patients with transfusion-dependent thalassemia (TDT) exhibit chronic complications of iron overload, such as heart and liver failure, and several endocrinopathies. The only curative option for SCD and TDT is a stem cell transplant, which is available only for a minority of patients.

Here, Frangoul et al report a CRISPR-Cas9 approach that targets the BCL11A erythroid-specific enhancer, a transcription factor that represses expression of γ-globin (the structural subunit that is characterizes fetal hemoglobin) in erythroid cells and is responsible for the natural suppression of fetal hemoglobin beyond infancy. After myeloablation, two patients, one with SCD and one with TDT, received autologous (their own) CD34+ cells with genetically edited BCL11A. After > 1 year follow-up, both patients maintained high levels of edited alleles and several clinical improvements, including higher fetal hemoglobin levels, transfusion independence, and cessation of vaso-occlusive episodes.

These results represent an impressive proof-of-principle, opening the door not only for hemoglobinopathies but for a plethora of genetic diseases awaiting cure.

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