Repurposing small molecules for nephronophthisis and related renal ciliopathies

Benmerah, Alexandre; Briseño-Roa, Luis; Annereau, Jean‐Philippe; Saunier, Sophie

doi:10.1016/j.kint.2023.04.027

Cited by 6 publications

(4 citation statements)

References 67 publications

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“…Chemicals to regulate these ciliary genes could be generated using technologies that lead to targeted protein degradation, such as proteolysis-targeting chimeras and small-molecule hydrophobic tagging ( Bhole et al, 2023 ; Xie et al, 2023 ). In vitro phenotypic screening can also be used for repositioning clinical drugs to treat ciliopathies ( Benmerah et al, 2023 ). For example, eupatilin, a drug used to treat gastritis and peptic ulcers, was identified as a positive hit that could induce ciliogenesis in a drug screening using CEP290-null cells ( Kim et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

Saito,

Otsu,

Miyadera

et al. 2023

Front. Mol. Biosci.

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The primary cilium is a single immotile microtubule-based organelle that protrudes into the extracellular space. Malformations and dysfunctions of the cilia have been associated with various forms of syndromic and non-syndromic diseases, termed ciliopathies. The primary cilium is therefore gaining attention due to its potential as a therapeutic target. In this review, we examine ciliary receptors, ciliogenesis, and ciliary trafficking as possible therapeutic targets. We first discuss the mechanisms of selective distribution, signal transduction, and physiological roles of ciliary receptors. Next, pathways that regulate ciliogenesis, specifically the Aurora A kinase, mammalian target of rapamycin, and ubiquitin-proteasome pathways are examined as therapeutic targets to regulate ciliogenesis. Then, in the photoreceptors, the mechanism of ciliary trafficking which takes place at the transition zone involving the ciliary membrane proteins is reviewed. Finally, some of the current therapeutic advancements highlighting the role of large animal models of photoreceptor ciliopathy are discussed.

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Section: Discussionmentioning

confidence: 99%

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

Saito,

Otsu,

Miyadera

et al. 2023

Front. Mol. Biosci.

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“…In addition to kidney cysts, common pathologies in syndromic forms of PKD, are progressive decline in renal function, tubulointerstitial fibrosis, and tubular atrophy or degeneration without kidney enlargement. NPHP is the most common genetic cause of renal failure in children and young adults 9,10 and together with ADTKD account for 10-20% of children with chronic renal failure and for 1-5% of all patients undergoing dialysis or transplantation 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Patel,

Gerakopoulos,

Petsouki

et al. 2024

Preprint

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Nephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deleting Fbxw7 encoding FBW7, the recognition receptor of the SCFFBW7 E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion of Fbxw7 in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.

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“…While ciliopathies are rare disorders, they often present with shared clinical features. These include cystic kidneys, situs inversus, retinal issues, brain malformation and/or intellectual disability, heterotaxy, hydrocephaly, craniofacial and skeletal abnormalities, liver disease, anosmia, congenital heart diseases and cardiac fibrosis, infertility, improper circulation of cerebral spinal fluid, hypoplasia, obesity, retinal degeneration, blindness, diabetes, tumorigenesis, and polydactyly (Lee and Gleeson, 2011;Wirschell et al, 2011;Christensen et al, 2012;Goto et al, 2017;Villalobos et al, 2019;Arora et al, 2023;Benmerah et al, 2023). From this list it is clear that ciliopathies impact several vital organs including the brain, heart, kidneys, liver, eyes, respiratory tract, and reproductive system as well as digits.…”

Section: Introductionmentioning

confidence: 99%

“…Ciliopathies can be quite organ-specific with examples such as polycystic kidney disease, retinitis pigmentosa, and nephronophthisis. They can also be pleiotropic disorders, like cerebello-oculo-renal syndrome, Primary Ciliary Dyskinesia (PCD), Bardet-Biedl syndrome, Meckel-Gruber syndrome, orofaciodigital syndrome 1, Joubert syndrome, STAR syndrome, and Jeune asphyxiating thoracic dystrophy (Zaghloul and Katsanis, 2009;Hildebrandt et al, 2011;Lee and Gleeson, 2011;Wirschell et al, 2011;Guen et al, 2016;Goto et al, 2017;Smith et al, 2022;Benmerah et al, 2023). More comprehensive reviews of ciliopathies provide additional details on their inheritance, genetics, clinical symptoms, and other features (Hildebrandt et al, 2011;Lee and Gleeson, 2011;Christensen et al, 2012;Abraham et al, 2022;Modarage et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Illumination of understudied ciliary kinases

Flax,

Rosston,

Rocha

et al. 2024

Front. Mol. Biosci.

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Cilia are cellular signaling hubs. Given that human kinases are central regulators of signaling, it is not surprising that kinases are key players in cilia biology. In fact, many kinases modulate ciliogenesis, which is the generation of cilia, and distinct ciliary pathways. Several of these kinases are understudied with few publications dedicated to the interrogation of their function. Recent efforts to develop chemical probes for members of the cyclin-dependent kinase like (CDKL), never in mitosis gene A (NIMA) related kinase (NEK), and tau tubulin kinase (TTBK) families either have delivered or are working toward delivery of high-quality chemical tools to characterize the roles that specific kinases play in ciliary processes. A better understanding of ciliary kinases may shed light on whether modulation of these targets will slow or halt disease onset or progression. For example, both understudied human kinases and some that are more well-studied play important ciliary roles in neurons and have been implicated in neurodevelopmental, neurodegenerative, and other neurological diseases. Similarly, subsets of human ciliary kinases are associated with cancer and oncological pathways. Finally, a group of genetic disorders characterized by defects in cilia called ciliopathies have associated gene mutations that impact kinase activity and function. This review highlights both progress related to the understanding of ciliary kinases as well as in chemical inhibitor development for a subset of these kinases. We emphasize known roles of ciliary kinases in diseases of the brain and malignancies and focus on a subset of poorly characterized kinases that regulate ciliary biology.

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Repurposing small molecules for nephronophthisis and related renal ciliopathies

Cited by 6 publications

References 67 publications

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets

Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD

Illumination of understudied ciliary kinases

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