{"doi":"10.1002/ajh.27757","title":"Normalization of Cerebral Hemodynamics After Gene Therapy in Adults With Sickle Cell Disease","abstract":"Two autologous gene therapy (GT) products to treat severe sickle cell disease (SCD) are now commercially available, and several other similar products are under development. Pivotal clinical trials have demonstrated a dramatic reduction in acute vaso-occlusive crises in patients receiving these GTs, but their impact on long-term organ function and especially on cerebrovascular disease in individuals with SCD is unknown [1]. In fact, individuals with a history of overt stroke or those at risk for stroke (with abnormal transcranial doppler ultrasound findings) were noticeably excluded from most clinical trials of GT [1]. Validated biomarkers that act as sensitive surrogates of ischemic brain injury and, therefore, predict long-term irreversible anatomic central nervous system (CNS) damage and neurocognitive defects are needed to evaluate the response to GT in these patients. Several studies have shown quantitative improvement (reduction) in cerebral blood flow (CBF) in patients who have received various disease-modifying therapies and allogeneic hematopoietic cell transplantation (HCT) [2, 3]. In SCD, CBF increases to compensate for chronic anemia and reduced oxygen-carrying capacity and to maintain adequate oxygen delivery to brain tissue [2, 3]. Importantly, the high metabolic demand of the brain makes CBF a sensitive predictor of ischemic stroke risk in patients with SCD—it may be the proverbial “canary in the coal mine” for SCD-associated ischemic injury. Thus, cerebral hemodynamics evaluations may provide the most direct physiological evidence of the impact of GT on CNS disease progression in individuals with SCD. To our knowledge, no such assessment in individuals undergoing autologous GT has been reported thus far. In this prospective cohort study, we quantified the effects of fetal hemoglobin (HbF) induction by GT on CBF, as measured by magnetic resonance imaging (MRI). Anatomical and hemodynamic MRI of the brain was performed at baseline/screening, just before, and at 12 and 24 months after infusion of autologous hematopoietic stem cells (HSCs) that were CRISPR-Cas9 edited at the HBG1 and HBG2 promoters to raise HbF in red blood cells (RBCs) in adults with SCD enrolled on a clinical study (NCT04443907) [4]. The study protocol was IRB approved at each participating center. All patients provided written informed consent in accordance with the Declaration of Helsinki. All brain images were acquired on a 3 T MRI scanner (Siemens Prisma or Philips Ingenia). Standard clinical sequences included three-dimensional T1-weighted and T2*-weighted scans, fluid-attenuated inversion recovery, diffusion weighted imaging, and time-of-flight magnetic resonance angiography. The study sequence consisted of a multi-slice, three-dimensional pseudocontinuous arterial spin labeling (PCASL) sequence (echo time/repetition time = 15/5000 ms; labeling duration = 1800 ms; post-labeling delay = 2000 ms; slice thickness = 3–4 mm) acquired with background suppression. CBF maps were created from MRI scans by using the PCASL technique. These maps were aligned with the Montreal Neurological Institute's 152 brain template (MNI-152) through a series of image registration processes. Five large regions of interest (ROIs) were analyzed for each participant (Figure S1A): two ROIs for lateralized white matter, two for lateralized cortical gray matter, and one of the whole brain, including the deep gray matter (shown in dark green in Figure S1A). The ROIs were derived from one of the Harvard–Oxford segmented population probability maps (specifically HarvardOxford-sub-maxprob-thr25-1 mm-ROIs from neurovault.org) by eroding the original ROIs by 2 mm to minimize misregistration effects. The software used for analysis was 3D Slicer. The median CBF from the ROIs, calculated at different time points, was compared within each participant and is presented descriptively. Statistical comparisons were not performed because of the small sample size. Original data may be mad","journal":"American Journal of Hematology","year":2025,"id":532590,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":320683,"name":"Jane S. Hankins","orcid":"0000-0003-4439-7321","position":1,"is_corresponding":false},{"id":297903,"name":"Jaap Jan Boelens","orcid":"0000-0003-2232-6952","position":2,"is_corresponding":false},{"id":327028,"name":"Maria Cancio","orcid":"0000-0003-4430-6290","position":3,"is_corresponding":false},{"id":1267979,"name":"Radhika Peddinti","orcid":null,"position":4,"is_corresponding":false},{"id":1414153,"name":"Lawrence Rispoli","orcid":null,"position":5,"is_corresponding":false},{"id":1414154,"name":"Sarah Sloan","orcid":null,"position":6,"is_corresponding":false},{"id":1414155,"name":"Sarah DiDominick Costa","orcid":null,"position":7,"is_corresponding":false},{"id":1072070,"name":"Sharon Peled","orcid":"0000-0002-2980-3005","position":8,"is_corresponding":false},{"id":1414156,"name":"Andrea J. Wiethoff","orcid":null,"position":9,"is_corresponding":false},{"id":1249862,"name":"Ranganatha Sitaram","orcid":"0000-0002-8577-8035","position":10,"is_corresponding":false},{"id":687814,"name":"James L. LaBelle","orcid":"0000-0001-6776-4695","position":11,"is_corresponding":false},{"id":313730,"name":"Akshay Sharma","orcid":"0000-0003-3281-2081","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40576267","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}