Agents and targets for inducing HbF expression
| Agent/target . | Mechanism . | Status . |
|---|---|---|
| Metformin | Enhanced FOXO3 expression. | Two- to threefold increase in F-cells in vitro91 ; small increment in HbF in vivo in 3 of 6 patients92 ; in an administrative database, patients with diabetes treated with metformin had fewer medical encounters; no HbF data.93 |
| Pomalidomide | Alters erythroid maturation.94 | HbF increased in 2 of 4 patients in phase 1 study. Myeloma patients treated with pomalidomide had increased γ-globin in RBC precursors95 and increased F-cells in vitro.43 |
| Tranylcypromine, RN-1, other LSD1 inhibitors | Inhibition of lysine-specific demethylase 1 via demethylation of H3K4.96 | Mouse, primate, and in vitro studies.96-99 |
| Decitabine/other demethylating agents | DNA methyltransferase depletion, histone methyltransferase inhibition decreases H3K9Me2 and increases H3K9Ac at the γ-globin gene locus.100 | Phase 1 trial of oral tetrahydrouridine + decitabine, HbF increased 4-9%, F-cells 40-80%, hemoglobin 1-2 g/dL in 3 patients with highest baseline HbF at highest drug dose.101 Methyltransferase (EHMT1/2) inhibition studied only in vitro. |
| PDE9 inhibitors | Inhibition of PDE9, increases cGMP and protein kinase G that increased HbF. | HbF increased in CD34+ cells. Sickle mice had greater than threefold increase in HbF and decrease in sickle cells and hemolysis.102 In phase 1B trial (NCT02114203), no effect on HbF or hemoglobin; decreased soluble E-selectin and WBC-platelet aggregates.103 |
| IGF2BP1 | mRNA-binding protein. Lentivirus delivery of IGF2BP1 to CD34+ cells increased HbF, fetal γ-globin mRNA and decreased β-globin mRNA. Contacts between the LCR and γ-globin genes increased. | Cell-based studies only.104 |
| LCR-promoter facilitation | Zinc finger-ldb1-facilitated looping of LCR to γ-globin gene promoters; increased γ-globin mRNA 40-fold in HUDEP-2 and CD34+ cells. | Cell-based studies only.105,106 |
| Dimethyl fumarate (DMF) | Through a Nrf2-mediated pathway, increased HbF in sickle CD34+ cells, sickle mice and primates. | Preclinical studies only.107 |
| BCL2LI | Overexpression in CD34+ cells increased HBG expression 11-fold. | Cell-based studies only.108 |
| SIRT1 agonists | Ectopic expression and SIRT1 agonists promote LCR-HBG interaction and increased HBG expression. | Cell-based studies only.109,110 |
| EIF2AK1 | EIF2AK1, the heme-regulated inhibitor, promotes the translation of ATF4, activating BCL11A transcription and silencing HBG. Inhibition of EIF2AK1 reduces BCL11A increasing HbF.111 | Cell-based studies only.112 |
| MBD2-NuRD | Knockdown of methyl-CpG binding domain protein 2 (MBD2) increased γ/γ+β mRNA > 30-fold and γ globin 10-fold. | Cell-based studies only.113 |
| Agent/target . | Mechanism . | Status . |
|---|---|---|
| Metformin | Enhanced FOXO3 expression. | Two- to threefold increase in F-cells in vitro91 ; small increment in HbF in vivo in 3 of 6 patients92 ; in an administrative database, patients with diabetes treated with metformin had fewer medical encounters; no HbF data.93 |
| Pomalidomide | Alters erythroid maturation.94 | HbF increased in 2 of 4 patients in phase 1 study. Myeloma patients treated with pomalidomide had increased γ-globin in RBC precursors95 and increased F-cells in vitro.43 |
| Tranylcypromine, RN-1, other LSD1 inhibitors | Inhibition of lysine-specific demethylase 1 via demethylation of H3K4.96 | Mouse, primate, and in vitro studies.96-99 |
| Decitabine/other demethylating agents | DNA methyltransferase depletion, histone methyltransferase inhibition decreases H3K9Me2 and increases H3K9Ac at the γ-globin gene locus.100 | Phase 1 trial of oral tetrahydrouridine + decitabine, HbF increased 4-9%, F-cells 40-80%, hemoglobin 1-2 g/dL in 3 patients with highest baseline HbF at highest drug dose.101 Methyltransferase (EHMT1/2) inhibition studied only in vitro. |
| PDE9 inhibitors | Inhibition of PDE9, increases cGMP and protein kinase G that increased HbF. | HbF increased in CD34+ cells. Sickle mice had greater than threefold increase in HbF and decrease in sickle cells and hemolysis.102 In phase 1B trial (NCT02114203), no effect on HbF or hemoglobin; decreased soluble E-selectin and WBC-platelet aggregates.103 |
| IGF2BP1 | mRNA-binding protein. Lentivirus delivery of IGF2BP1 to CD34+ cells increased HbF, fetal γ-globin mRNA and decreased β-globin mRNA. Contacts between the LCR and γ-globin genes increased. | Cell-based studies only.104 |
| LCR-promoter facilitation | Zinc finger-ldb1-facilitated looping of LCR to γ-globin gene promoters; increased γ-globin mRNA 40-fold in HUDEP-2 and CD34+ cells. | Cell-based studies only.105,106 |
| Dimethyl fumarate (DMF) | Through a Nrf2-mediated pathway, increased HbF in sickle CD34+ cells, sickle mice and primates. | Preclinical studies only.107 |
| BCL2LI | Overexpression in CD34+ cells increased HBG expression 11-fold. | Cell-based studies only.108 |
| SIRT1 agonists | Ectopic expression and SIRT1 agonists promote LCR-HBG interaction and increased HBG expression. | Cell-based studies only.109,110 |
| EIF2AK1 | EIF2AK1, the heme-regulated inhibitor, promotes the translation of ATF4, activating BCL11A transcription and silencing HBG. Inhibition of EIF2AK1 reduces BCL11A increasing HbF.111 | Cell-based studies only.112 |
| MBD2-NuRD | Knockdown of methyl-CpG binding domain protein 2 (MBD2) increased γ/γ+β mRNA > 30-fold and γ globin 10-fold. | Cell-based studies only.113 |
Agents and pathways studied in preclinical and early-phase clinical studies to stimulate increased HbF.