Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling

Daniel C. Souza, Nicolas Hebert, Erica B. Esrick, M. Felicia Ciuculescu, Natasha M. Archer, Myriam Armant, Étienne Audureau, Christian Brendel, Giuseppe Caprio, Frédéric Galactéros, Donghui Liu, Amanda McCabe, Emily Morris, Ethan Schonbrun, Dillon Williams, David K. Wood, David A. Williams (), Pablo Bartolucci () and John M. Higgins ()
Additional contact information
Daniel C. Souza: Massachusetts General Hospital
Nicolas Hebert: French Blood Establishment (EFS)
Erica B. Esrick: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
M. Felicia Ciuculescu: Harvard Medical School
Natasha M. Archer: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Myriam Armant: Harvard Medical School
Étienne Audureau: Paris-East Créteil University
Christian Brendel: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Giuseppe Caprio: Massachusetts General Hospital
Frédéric Galactéros: IMRB, Laboratory of excellence LABEX
Donghui Liu: Harvard Medical School
Amanda McCabe: Harvard Medical School
Emily Morris: Harvard Medical School
Ethan Schonbrun: Massachusetts General Hospital
Dillon Williams: University of Minnesota
David K. Wood: University of Minnesota
David A. Williams: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Pablo Bartolucci: IMRB, Laboratory of excellence LABEX
John M. Higgins: Massachusetts General Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT 03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT 03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects.

Date: 2023
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DOI: 10.1038/s41467-023-40923-5

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