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Patient-derived cellular models of primary ciliopathies
  1. Lidia Pollara1,
  2. Virginie Sottile1,
  3. Enza Maria Valente1,2
  1. 1 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  2. 2 Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
  1. Correspondence to Dr Virginie Sottile, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy; virginie.sottile{at}unipv.it; Professor Enza Maria Valente; enzamaria.valente{at}unipv.it

Abstract

Primary ciliopathies are rare inherited disorders caused by structural or functional defects in the primary cilium, a subcellular organelle present on the surface of most cells. Primary ciliopathies show considerable clinical and genetic heterogeneity, with disruption of over 100 genes causing the variable involvement of several organs, including the central nervous system, kidneys, retina, skeleton and liver. Pathogenic variants in one and the same gene may associate with a wide range of ciliopathy phenotypes, supporting the hypothesis that the individual genetic background, with potential additional variants in other ciliary genes, may contribute to a mutational load eventually determining the phenotypic manifestations of each patient. Functional studies in animal models have uncovered some of the pathophysiological mechanisms linking ciliary gene mutations to the observed phenotypes; yet, the lack of reliable human cell models has previously limited preclinical research and the development of new therapeutic strategies for primary ciliopathies. Recent technical advances in the generation of patient-derived two-dimensional (2D) and three-dimensional (3D) cellular models give a new spur to this research, allowing the study of pathomechanisms while maintaining the complexity of the genetic background of each patient, and enabling the development of innovative treatments to target specific pathways. This review provides an overview of available models for primary ciliopathies, from existing in vivo models to more recent patient-derived 2D and 3D in vitro models. We highlight the advantages of each model in understanding the functional basis of primary ciliopathies and facilitating novel regenerative medicine, gene therapy and drug testing strategies for these disorders.

  • genetic research
  • genetics
  • medical

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Footnotes

  • Contributors All authors jointly contributed to the elaboration of the manuscript. VS and EMV are both corresponding authors for the manuscript.

  • Funding JS research in the Valente Lab is supported by grants from the European Research Council (StGrant 260888), the Italian Ministry of Health (Ricerca Corrente 2021, Ricerca Finalizzata RF-2019-12369368), Telethon Foundation (grant GGP20070), Fondazione Pierfranco and Luisa Mariani (PADAPORT project). VS is supported by a grant from the Italian Ministry of Education, University and Research (MIUR) to the Department of Molecular Medicine of the University of Pavia under the initiative ’Dipartimenti di Eccellenza (2018–2022)’.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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