Potent and orally active purine-based fetal hemoglobin inducers for treating β-thalassemia and sickle cell disease

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

“…In leukemia cell lines, TN1 (100 nM) induced HbF more potently than HU [137]. However, another study conducted on human primary erythroid cells showed that this agent did not significantly increase γglobin gene expression [138]. These drawbacks limited the development of this compound and its capability of being used in clinical trials in patients with hemoglobinopathies.…”

“…These drawbacks limited the development of this compound and its capability of being used in clinical trials in patients with hemoglobinopathies. Lai et al then reported another potent and orally active purine-based HbF inducer known as Nethylpiperazine, or compound 13a [138]. In vitro assays demonstrated that in primary erythroid cells as well as in HU-resistant primary erythroid cells, compound 13a might efficiently induce γ-globin expression at a non-toxic concentration [138].…”

“…Lai et al then reported another potent and orally active purine-based HbF inducer known as Nethylpiperazine, or compound 13a [138]. In vitro assays demonstrated that in primary erythroid cells as well as in HU-resistant primary erythroid cells, compound 13a might efficiently induce γ-globin expression at a non-toxic concentration [138]. In a mouse model for SCD, compound 13a was safe and well tolerated with a dose-dependent beneficial effect on the hematologic SCD phenotype [138].…”

“…In vitro assays demonstrated that in primary erythroid cells as well as in HU-resistant primary erythroid cells, compound 13a might efficiently induce γ-globin expression at a non-toxic concentration [138]. In a mouse model for SCD, compound 13a was safe and well tolerated with a dose-dependent beneficial effect on the hematologic SCD phenotype [138]. Thus, compound 13a can be considered an interesting molecule to be further developed as an inducer of HbF.…”

Molecular genetics of β-thalassemia

“…HbF inducer Hydroxyurea Thalidomide, Lenalidomide, Sirolimus Inhibition of DNA analysis Histone acetylation at g-globin gene promotor [62,63] Activin receptor ligand traps Luspatercept, Sotatercept Inhibit effect of GDF-11 [53,54] JAK2 inhibitor Ruxolitinib, Pacritinib Inhibition of signal transducer of EPO [64] Iron restriction Hepcidin Hepcidin binds to ferroportin, leading to its endocytosis and degradation, thus preventing the entry of iron into plasma [65] Antisense therapy Oligonucleotide analogs Specifically modify RNA expression through multiple mechanisms including RNase H1-mediated degradation of RNA and modulation of RNA splicing [66] Gene insertion Vectors packaged with HBB gene and its promotor, enhancer, and parts of LCR Insertion of a vector that contains the whole regulatory machinery and the b-globin or g-globin producing genes into autologous HSPCs "ex-vivo," and then infusing these modified HSPCs back to the patient after myeloablation [44] Gene editing Different engineered nucleases-zinc-finger nucleases, transcription activator-like effector nucleases, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated-nuclease 9…”