Por Susana Lopes (cE3c, Faculdade de Ciências da Universidade de Lisboa).
Primary Ciliary Dyskinesia (PCD) is caused by mutations in genes involved in the formation and function of motile respiratory cilia. PCD results in chronic lung failure and clinical care is symptomatic and no causal treatment is available. Human PCD patients with CCDC40 mutations have more severe symptoms ending up needing lung transplantation more often than other patients with other mutations. Research using the zebrafish animal model allowed for in vivo assays on cilia function. We demonstrate how a novel mRNA based approach can restore the function of ciliary axonemes of live Ccdc40 homozygous mutant zebrafish. In these mRNA base protein replacement studies we used lipidoid nanoparticle formulated, codon-optimized, modified mRNA encoding human CCDC40 (Ethris GmbH). Upon treatment by injection at one-cell stage or by topic administration to fish larvae we achieved different levels of rescue in terms of motile ciliated area and flow generation as well as normalization of cilia beat frequency. We conclude mRNA-based protein replacement therapy in PCD has high potential as a future treatment option.
