Cerebral Hemodynamics Improve in Adults with Sickle Cell Disease after Gene Therapy

Introduction Two gene therapy products were approved by the FDA for individuals with severe sickle cell disease (SCD) in 2023. While these products have had an impressive impact on the reduction of acute vaso-occlusive crises, their effect on long-term organ function, especially cerebrovascular disease in individuals with SCD is unknown. In fact, individuals with history of overt stroke, or those at risk of stroke (having abnormal transcranial doppler) were noticeably excluded from most gene therapy clinical trials. Cerebral blood flow (CBF) is increased in SCD to compensate for chronic anemia, reduced oxygen carrying capacity and to maintain adequate oxygen delivery to brain tissue. Importantly, the high metabolic demand of the brain makes assessment of CBF a sensitive predictor of stroke risk in patients with SCD. An evaluation of cerebral hemodynamics may be the most direct physiological evidence of the impact of gene therapy on cerebrovascular disease progression in individuals with SCD. Methods We performed anatomical and hemodynamic magnetic resonance imaging (MRI) of the brain at baseline/screening, just prior to, and at 12 months and 24 months after infusion of hematopoietic stem cells (HSCs) CRISPR-Cas9 edited at the HBG1 and HBG2 promoters to raise fetal hemoglobin (HbF) in RBCs in adults with SCD on a clinical study (NCT04443907). All participants received conditioning with myeloablative busulfan prior to the cell infusion. Region of interest (ROI) analysis was performed on brain MRI diffusion and perfusion data from the 3 enrolled participants. Five large ROIs were analyzed: one of the whole brain, and one each of the left and right hemisphere white matter and cortical gray matter, respectively. The CBF map was derived from arterial spin labeling perfusion imaging, and the apparent diffusion constant map was derived from diffusion-weighted images. The results at different time points were compared within each participant and are being presented descriptively. Results Three participants (HbSS genotype) received the genetically modified cellular infusion and have been followed for 30 months, 24 months, and 18 months since the cell infusion. Preliminary results from the clinical trial have been reported previously (Sharma et. al. NEJM 2023). At the time of enrollment, participants were aged 22 years, 21 years, and 24 years. The first 2 participants were males, and both had a history of silent cerebral infarction. The third participant was a female with no known cerebrovascular disease at baseline. The first and the third participants were receiving chronic blood transfusions at study enrollment. All participants received routine blood transfusions from study enrollment until cellular product infusion. No participant has required further regular blood transfusions since their cell infusion. None of the patients had any clinical neurological complications or local imaging evidence of new infarcts or anatomical abnormalities in the follow up period. At baseline, the hemoglobin was 10.2 g/dL, 11.6 g/dL, and 10.2 g/dL with 1.4%, 0.2%, 1.0% HbF in participants 1, 2, and 3 respectively. At 12 months after cell infusion, in participants 1 and 2, the hemoglobin was 10 g/dL and 11.3 g/dL with 26.8% and 23% HbF, respectively. At 18 months after cell infusion, in participant 3, hemoglobin was 9.5 g/dL with 18.9% HbF. Calculated whole brain CBF was 46.7 mL blood/100 g tissue/min, 41.2 mL blood/100 g tissue/min, and 29.6 mL blood/100 g tissue/min in the 3 participants at baseline. Calculated whole brain CBF decreased to 26.2 mL blood/100 g tissue/min, 24.0 mL blood/100 g tissue/min, and 23.0 mL blood/100 g tissue/min at 12 months after infusion, representing a 43.9%, 41.7% and a 22.3% reduction in CBF from baseline, respectively. There were no geographic differences in the patients' brain, each having similar changes in white and gray matter in the right and left hemispheres. Conclusion Our preliminary results indicate that it is feasible to quantify CBF using MRI in patients with SCD before and after undergoing gene therapy. We demonstrate that cerebral hemodynamics improved after infusion of gene edited HSCs that raise HbF in adults with SCD, indicated by a large relative reduction in calculated CBF. Improved CBF is expected to reduce stroke risk and may also preserve or improve neurocognitive functioning. Prospective monitoring of these outcomes is underway.