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In vitro and in vivo induction of fetal hemoglobin with two potent and orally bioavailable LSD1 inhibitors

ABSTRACT: Pharmacological small molecules that target fetal hemoglobin (HbF) repressors serve as potent, cost-effective, and accessible therapeutic strategies to β-globinopathies such as sickle cell disease (SCD). LSD1 inhibition has been shown to induce HbF levels both in vitro and in vivo. However, all potent LSD1 inhibitors in HbF induction in vivo are covalent irreversible compounds, which can cause some adverse effects. In this study, we utilized structure-aided drug design based on the scaffold of a reversible LSD1 inhibitor GSK-690, and developed potent new reversible LSD1 inhibitors that induce robust γ-globin expression in human primary erythroid differentiation culture. Moreover, in a transgenic mouse model of SCD, oral administration of the novel LSD1 inhibitors induces significant elevation of HbF levels and alleviates the disease pathologies resulted from SCD. In addition, combined treatment of an BRD4 degrader, BD-9136 with the LSD1 inhibitors represses the induction of RUNX1 and PU.1, therefore rescues the yield of erythroid cells caused by LSD1 inhibition. Our data indicate that our novel LSD1 inhibitors can effectively induce HbF levels and reduce disease pathologies in SCD mice, and are well-tolerated by oral administration. We anticipate that these new compounds will offer new therapeutic possibilities for treating SCD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275880 | GEO | 2025/05/15

REPOSITORIES: GEO

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AMPK-beta1 Activation Induces Fetal Hemoglobin

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Project description:Genetic manipulations to increase fetal hemoglobin (HbF, α2γ2) in postnatal red blood cells (RBCs) can alleviate β-thalassemia and sickle cell disease. We compared five strategies in CD34+ hematopoietic stem and progenitor cells, using either Cas9 nuclease, which creates uncontrolled indel mixtures, or adenine base editors (ABE), which generate more precise nucleotide changes. The most potent modification was ABE generation of γ-globin (HBG1/HBG2) −175 A>G, which creates a promoter binding motif for the transcriptional activator TAL1. In erythroid colonies with >87.5% on-target edits, those with −175 A>G expressed 81 ± 7% HbF, versus 17 ± 11% in unedited controls. In comparison, HbF levels were lower and more variable in erythroid cells modified with either of two Cas9 nuclease strategies with similar editing efficiencies, being 32 ± 19% when a BCL11A repressor binding motif in the γ-globin promoter was targeted and 52 ± 13% when the +58 BCL11A erythroid enhancer was targeted. Contrary to currently accepted models of γ-globin regulation, HbF levels varied significantly with different Cas9 indels that disrupted the γ-globin promoter BCL11A binding motif. The −175 A>G base edit also induced HbF more potently than did the Cas9 nuclease approaches in RBCs generated after transplantation of modified normal or SCD patient CD34+ cells into mice. Our data suggest a strategy for potent, uniform induction of HbF and provide insights into γ-globin gene regulation. More generally, we demonstrate that diverse indels generated by Cas9 nuclease can cause unexpected variations in biological outcomes that can be circumvented by base editing, with important implications for therapeutic gene editing efforts.

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2016-01-15 | E-GEOD-74977 | biostudies-arrayexpress

Identification and characterizaton of RBM12 as a novel regulator of fetal hemoglobin expression [eCLIP-Seq]

Project description:The fetal-to-adult hemoglobin transition is clinically relevant as reactivation of fetal hemoglobin (HbF) significantly reduces morbidity and mortality associated with sickle cell disease (SCD) and b-thalassemia. Most studies on the developmental regulation of the globin genes, including genome-wide genetics screens, have focused on DNA binding proteins including BCL11A and ZBTB7A/LRF and their cofactors. Our understanding of RNA binding proteins (RBPs) in this process is much more limited. Two RBPs, LIN28B and IGF2BP1 are known post-transcriptional regulators of HbF production but a global view of RBPs is still lacking. Here, we carried out a CRISPR/Cas9-based screen targeting RBPs harboring RNA methyltransferase and/or RRM domains and identified RBM12 as a novel HbF suppressor. Depletion of RBM12 induced HbF expression and attenuated cell sickling in erythroid cells derived from SCD patients with minimal detrimental effects on cell maturation. Transcriptome and proteome profiling revealed that RBM12 functions independently of major known HbF regulators. Enhanced crosslinking and immunoprecipitation followed by high throughput sequencing (eCLIP-Seq) revealed strong preferential binding of RBM12 to 5’UTRs of transcripts, narrowing down the mechanism of RBM12 action. Notably, we pinpointed the first of five RRM domains as essential, and, in conjunction with a linker domain, as sufficient for RBM12-mediated HbF regulation. Our characterization of RBM12 as a negative regulator of HbF points to an additional regulatory layer of the fetal-to-adult hemoglobin switch and broadens the pool of potential therapeutic targets for SCD and b-thalassemia.

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