The small molecule agonist of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) called ZLN005 may improve the production of fetal γ-globin levels and fetal hemoglobin (HbF) in patients with sickle cell disease (SCD), as published in the British Journal of Haemotology.

The results showed that treatment of human primary erythroid progenitor CD34+ cells with ZLN005 induced the production of fetal γ-globin mRNA and protein as well as increased the percentage of cells expressing HbF (F cells). These increases were achieved without significantly affecting the proliferation and differentiation of the cells.

Levels of γ-globin and the number of F cells could be further increased in the cultured CD34+ cells through the combination treatment of both ZLN005 and hydroxyurea.

“A small-molecule like ZLN005, with oral bioavailability and effects additive to [hydroxyurea] and possibly other HbF inducers, might have more therapeutic potential where SCD is most prevalent,” the authors said.

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The in vivo impact of ZLN005 was tested in a mouse model with SCD. Intraperitoneal administration of ZLN005 resulted in a slight increase in γ-globin but a large increase in murine endogenous embryonic βh1-globin mRNA expression.

The study also found that overexpression of PGC-1α through infection with a lentivirus carrying the full-length cDNA for PGC-1α resulted in similar increases in fetal γ-globin and HbF in CD34+ cells.

“This study constitutes firm evidence that PGC-1α is a novel molecular target for HbF induction and that ZLN005 exerts potential therapeutic effects for treating SCD,” the authors concluded.

ZLN005 is a small molecule designed to increase the expression of PGC-1α in skeletal muscle cells through activation of the adenosine monophosphate-activated protein kinase pathway. Activation of this pathway can also lead to post-translational modification through phosphorylation of the PGC-1α, increasing both the expression of itself and its downstream targets.

It is still unclear whether ZLN005 activates PGC-1α through the same mechanism or a novel one in erythroid cells.

Reference

Sun Y, Habara A, Le CQ, et al. Pharmacologic induction of PGC-1α stimulates fetal haemoglobin gene expression. Br J Haematol. Published online February 4, 2022. doi:10.1111/bjh.18042