Telomerase RNA (TERC) has a non-canonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. Aptamers, short single-stranded oligonucleotides that bind to specific target molecules, are considered promising alternatives to antibodies for use as high affinity agents in disease treatment.

In this study, we report that two aptamers based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full Terc; that is, they increased the expression of master myeloid genes, independently of endogenous Terc, by interacting with RNA Pol II and with the Terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in preclinical zebrafish models of DC (Terc deficiency) and poikiloderma with neutropenia (Usb1 deficiency). Finally, the corresponding human aptamers restored defective myeloid gene expression and myeloid differentiation in human induced pluripotent stem cells (iPSC) from DC patients harboring a mutation in the CR4/CR5 domain of TERC.

The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.