S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)

Abstract

BackgroundS110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat β-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the γ-globin gene promoter in vivo were evaluated.MethodsThe effect of S110 on HbF and γ-globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model.ResultsS110 increased HbF and reduced DNA methylation of the γ-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA.ConclusionS110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

“…Comparison of the level of γ-globin synthesis in RN-1-treated baboons with previous results from our laboratory of baboons treated with DNMT inhibitors [3][4][5]12,38,[40][41][42] A. Rivers et al 694 haematologica | 2016; 101(6) …”

MIR29B mediates epigenetic mechanisms of HBG gene activation

“…Therapeutic interventions to decrease HBG gene methylation and reactivate transcription have proven beneficial in clinical studies. For example, SCD patients treated intravenously with the DNA methyltransferase (DNMT) inhibitor decitabine (Dec) demonstrated robust induction of HbF and total haemoglobin levels (Molokie et al , ; Akpan et al , ; Lavelle et al , ; Desimone et al , ). However, when administered by mouth, Dec is rapidly inactivated by cytidine deaminase.…”

The Application of Delivery Systems for DNA Methyltransferase Inhibitors

“…[127] In an attempt to improve the stability and reduce the cytotoxicity of decitabine, Yoo et al [117] generated a derivative of decitabine termed S110 by modification of the structure with the addition of short oligonucleotides. S110 is rapidly converted to decitabine after degradation of the oligonucleotide linkages by cellular phosphodiesterases, [117,128] and has shown in vivo demethylation potency similar to decitabine. [118] Although S110 did not improve the stability or reduce the cytotoxicity of decitabine, the use of S110 oligonucleotides was shown to protect decitabine from inactivation by cytidine deaminase in vivo.…”

“…[118] Although S110 did not improve the stability or reduce the cytotoxicity of decitabine, the use of S110 oligonucleotides was shown to protect decitabine from inactivation by cytidine deaminase in vivo. [128] Although treatments using demethylating cytidine analogs in combination with oligonucleotides and cytidine deaminase inhibitors (e.g. zebularine) are feasible approaches, there is still no strategy to overcome the therapeutic limitation of cytidine analogs caused by in vivo metabolism.…”