BCL11A as a novel target in gene therapy for sickle cell disease

Three adult patients (ages ranging from 21-26 years) with sickle cell disease received an infusion of their own stem cells that were genetically engineered ex vivo to induce them to stop producing harmful sickle haemoglobin and start producing the healthy foetal form of haemoglobin. All 3 patients are doing well and the gene therapy pilot study is extremely promising for future development.

Dr David A. Williams (Boston Children’s Hospital, USA) said that the 3 patients, who are now 18, 10, and 9 months post-infusion, are all producing significantly increased amounts of the healthy form of haemoglobin and have so far shown no therapy-related adverse effects beyond those expected with autologous haematopoietic stem cell transplantation [1].

Dr Williams and colleagues hypothesised that knocking down BCL11A with RNA interference would re-induce foetal gamma-globulin expression. They genetically engineered a virus to deliver a gene that blocks the BCL11A protein in red blood cells using microRNA to simultaneously increase foetal haemoglobin and decrease sickle haemoglobin. Preclinical work in mice has shown that erythroid-specific expression of microRNA-adapted short hairpin RNAs (shRNAmiR) targeting BCL11A effectively induced foetal haemoglobin in human erythroid cells derived from transduced haematopoietic stem cells, mitigating the haematologic effects of sickle cell disease while avoiding negative effects in the stem cells and B lymphocytes.

Post-treatment follow-up shows that all 3 adult patients now have normal or near-normal haemoglobin levels and are producing foetal haemoglobin in quantities that should be sufficient to prevent sickling of red blood cells. One patient continues to receive planned blood transfusions due to extensive pre-existing blood vessel damage in the brain to reduce any risk of stroke, but the patient now needs fewer transfusions than before receiving the investigational gene therapy.

Two adolescents aged 16 and 12 years old have also received the gene therapy, at 5 months and 1 month post-treatment. Similarly, these patients are benefitting from the gene therapy. For all patients, the hope is that increasing foetal haemoglobin levels enough to prevent sickling will decrease their pain, as well as their long-term risk for sickle cell disease-related complications such as organ damage, strokes, and lung disease. Long-term follow up is needed.

1. Esrik EB, et al. LBA-5, ASH 2019, 7-10 December, Orlando, USA.

Posted on 5 March, 202025 March, 2024