Adenine Base Editor-Mediated Reactivation of Foetal Haemoglobin via BCL11A Erythroid Enhancer Disruption: Comparative Delivery by Lipid Nanoparticles and AAV9 in a Humanised Mouse Model of Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a monogenic haemoglobinopathy caused by a point mutation (p.Glu6Val) in the HBB gene, resulting in polymerisation of deoxyhaemoglobin S and chronic haemolytic anaemia with vaso-occlusive complications. Nigeria carries the world's highest burden of SCD, with approximately 150,000 affected births annually and over 4 million Nigerians living with the disease—yet access to curative therapies remains critically limited. This study, conducted as a collaborative research programme between the University of Lagos Sickle Cell Research Centre and Harvard Medical School, evaluated adenine base editor (ABE8e)-mediated disruption of the BCL11A erythroid enhancer as a strategy to reactivate foetal haemoglobin (HbF), comparing delivery by lipid nanoparticles (LNP) and AAV9 in a humanised SCD mouse model. Five base editor variants were assessed in HEK293T cells for on-target efficiency, off-target activity, and bystander editing by deep sequencing. LNP-delivered ABE8e achieved 52.1% HbF at day 56 post-treatment, while AAV9 delivery reached 50.9%, both substantially exceeding the 30% therapeutic threshold by day 21. Off-target editing was minimal (<0.31% across all editors). These results support the clinical translation of LNP-ABE8e for BCL11A enhancer disruption in SCD—a curative approach that could transform outcomes for millions of patients across sub-Saharan Africa.