Products Cited in Publications Worldwide Effect of antivirals on clinical and lab-adapted human cytomegalovirus strains using induced Pluripotent Stem Cell-derived human neural models

Effect of antivirals on clinical and lab-adapted human cytomegalovirus strains using induced Pluripotent Stem Cell-derived human neural models

Mulder, Lance; da Sá, Renata Vieira; Korsten, Joep; Freeze, Eline; Schotting, Amber J; Koen, Gerrit; Molenkamp, Richard; Van Kampen, Jeroen; Cornelissen, Marion; Zorgdrager, Fokla

DOI: PMID:

Abstract

Human cytomegalovirus (CMV) infections can cause severe neurological complications, particularly in newborns and immunocompromised patients. Children affected with congenital infection may develop long-term neurological damage and intellectual disabilities. Currently, postnatal therapies are limited and there are no prenatal options available. Research on against congenital infections is, at least partly, restricted due to the lack of physiologically relevant models and the use of lab-adapted strains with limited clinical relevance. In this study, we evaluated the toxicity and efficacy of three FDA-approved anti-CMV drugs against two strains, a clinical and a lab-adapted strain, using two human induced pluripotent stem cell (iPSC-)derived central nervous system models, viz. neural progenitor cells (NPCs) and dorsal forebrain regionalized neural organoids (RNOs). We found iPSC line-dependent differences in toxicity. We observed that treatment restored NPCs and RNOs gene expression after infection and reduced copy numbers. Infection of NPCs and RNOs with the clinical strain, but not with the lab-adapted strain, led to an impaired expression of cortical development markers. Our findings highlight the value of using physiologically relevant human models and clinical strains to understand the neuropathogenesis of congenital and to test therapeutic strategies.

Keywords

congenital ; neural organoids ;

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