Long-term stability of posttranscriptional genetic silencing of BCL11A using a shmiR vector in Sickle Cell Disease
Abstract
Sickle cell disease (SCD) is characterized by chronic hemolysis, painful vaso-occlusive episodes (VOE) and end organ damage. High levels of fetal hemoglobin (HbF) attenuate the disease phenotype. We used a lentivirus vector (LVV) expressing an shRNA embedded in a microRNA (shmiR) targeting BCL11A in erythrocytes to induce HbF in a first-in-human pilot study in SCD. The purpose of the study was to assess hematopoietic stem/progenitor cells (HSPCs) collection, transduction parameters, safety, HbF induction and durability. Eleven eligible patients with SCD had HSC collection. Plerixafor-mobilized peripheral blood HSCs required for manufacturing were obtained in one mobilization cycle for 10/11 subjects and 11/11 patient products were successfully manufactured with a median time to release of product of 39 days. Ten patients were infused with autologous HSCs transduced with the shmiR vector. Engraftment occurred in all 10 patients. With a median follow-up of 58 months (range: 35-82) after infusion, no adverse events attributed to the gene vector have occurred. Transduction efficiency was 93.1%. One patient demonstrated low engraftment of transduced cells and had suboptimal HbF induction. In the remaining 9 patients, at 2 years post-treatment peripheral blood demonstrated 71% F cells with 11.9 pg HbF/F cells, both stable in 9 patients with ≥48 months follow-up. All patients who had VOEs prior to gene therapy demonstrated sustained mitigation of pain events. These data demonstrate excellent manufacturing efficiency and safety, with efficacy of targeting BCL11A using a shmiR LVV, and long-term durability of the shmiR vector, leading to a pivotal multi-site phase 2 trial currently underway (NCT05353647).
Article Details
Authors (27)
Erica B Esrick
Boston Children's Hospital, Boston, Massachusetts, United States
Leslie Lehmann
Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
Amy Federico
Boston Children's Hospital, Boston, MA, Boston, Massachusetts, United States
Helene Vincon
Boston Children's Hospital, Boston, Massachusetts, United States
Boya Liu
Heather Daley
Colleen Dansereau
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Satiro De Oliveira
Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles
John K. Everett
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
Pei-Chi Kao
Boston Children's Hospital/Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Theodore B Moore
UCLA, Los Angeles, CA, California, United States
Emily Morris
Dana-Farber Cancer Institute, Boston, Massachusetts, United States
Helene Trebeden-Negre
CellforCure, Les Ulis, France
Kit L. Shaw
Gavin D Roach
Seattle Children's Hospital, Seattle, Washington, United States
Jerome Ritz
Dana–Farber Cancer Institute, Boston
Aoife M Roche
University of Pennsylvania, Philadelphia, Pennsylvania, United States
Olivia Silva
Boston Children's Hospital, Boston, Massachusetts, United States
Patricia Ellen Grant
Fetal Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School
Frederic D Bushman
University of Pennsylvania, Philadelphia, Pennsylvania, United States
Donald B. Kohn
Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles
Akshat Jain
Loma Linda University, Redlands, California, United States
Wendy B. London
Boston Children's Hospital, Boston, Massachusetts, United States
David G Justus
Boston Children's Hospital, Canton, Massachusetts, United States
Myriam Armant
John P Manis
Boston Children's Hospital, Boston, Massachusetts, United States
David A Williams
Boston Children's Hospital, Boston, Massachusetts, United States