Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model

Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
Nature medicine (Impact Factor: 27.36). 09/2012; 18(9). DOI: 10.1038/nm.2860
Source: PubMed


Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88(Tg737Rpw) mice, also known as ORPK mice) have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.

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    • "Treatment of anosmia due to ciliary defects in olfactory sensory neurons is a potential target for gene delivery, via intranasal injection. AV-mediated IFT88 transduction in fully differentiated olfactory sensory neurons in Ift88 mutant mice saw restoration of ciliary structures and rescue of olfactory function (McIntyre et al., 2012). Lentivirus has recently been proven beneficial for gene therapy against childhood lysosomal disorders (Aiuti et al., 2013; Biffi et al., 2013); however, lentivirus has not yet been widely utilized for gene delivery in ciliopathies except for in vitro studies. "
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    • "On neurons, disruption of the primary cilium or ciliary proteins revealed that they have an important role in regulating satiation and object recognition through unknown mechanisms [16-18]. In addition, cilia are known to be important for sight and smell [16,19-21] and recently it was demonstrated that they regulate pathways involved in adult neurogenesis and migration of newborn neurons [22]. However, the ubiquitous nature of primary cilia on most neurons in the central nervous system (CNS) was unexpected [23]. "
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    • "Overall, our findings implicate the role of IFT80 in chondrocyte differentiation and provide direct evidence for IFT80 regulation in the Hh and Wnt/b-catenin signaling pathways. Most recently, McIntyre [69] et al. found that adenoviral-mediated expression of IFT88 can restore ciliary structures and rescue olfactory function in IFT88 mutant mice. This study provides a proof and an effective therapeutic option by using IFT proteins to rescue of the complex ciliary organelle in IFT/Cilia and Hh signaling related human diseases. "
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