A team at Boston Children’s Hospital have reported on the success of their virus gene therapy in six sickle cell disease patients treated for at least 6 months.
Sickle cell disease
Sickle cell disease is a common inherited blood disorder. It affects approximately 100,000 individuals in the United States. Mutations in the β-globin gene (HBB) result in a variant of normal adult haemoglobin (HbA) – sickle haemoglobin (HbS). The standard curative treatment for sickle cell disease is allogeneic haematopoietic stem-cell transplantation. Matched sibling donor transplantation is curative in over 90% of patients. However, limitations include a higher risk of complications in older patients, risk of graft-versus-host disease and lack of a matched sibling donor. For patients with β-hemoglobinopathy who are without a matched sibling donor, transplantation of genetically modified autologous hematopoietic stem cells is an attractive alternative.
Infants with sickle cell disease are typically free of clinical symptoms. This is due to a phenomenon known as haemoglobin switching. In utero and during infancy, HbS protein is produced at very low levels. This is because the erythrocytes have not yet shifted from expression of the γ-globin gene (HBG) to expression of the HBB gene. HBG encodes the developmentally regulated component of foetal haemoglobin (HbF). In older children and adults, a higher level of HbF associates with lower disease severity in sickle cell disease. Researchers have validated the transcription factor BCL11A as a repressor of HbF levels in model systems. Down regulation of BCL11A thus represents a promising therapeutic strategy for induction of HbF.
In a study, published in the NEJM, researchers enrolled six patients with sickle cell disease to treat with BCH-BB694 gene therapy. Specifically, the therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector. This vector encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR). This allows erythroid lineage-specific knockdown. Researchers assessed patients for points of engraftment and safety as well as for clinical responses to treatment.
The team found that all patients had engraftment and adverse events were consistent with effects of preparative chemotherapy. Patients achieved robust and stable induction, with HbF broadly distributed in red blood cells. Most importantly, the team found that clinical manifestations of sickle cell disease reduced or were absent during the follow-up period.
This study validates inhibition of BCL11A as an effective target for HbF induction. It also highlights the potential of shmiR-based gene knockdown as an approach to prevent chronic complications of sickle cell disease. This development also has potential implications for other diseases that could benefit from downregulation of gene expression.
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