A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease

Dagorn, Pascale Gluais; Buchholz, Bjoern; Kraus, Andre; Batchuluun, Battsetseg; Bange, Hester; Blockken, Laura; Steinberg, Gregory R.; Hallakou‐Bozec, Sophie

doi:10.1016/j.kint.2023.01.026

Cited by 7 publications

(4 citation statements)

References 59 publications

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“…A full list of these prioritised predictions can be seen in Supplementary Table S1 . In order to evaluate these drug predictions, we made use of a patient-derived in vitro model system which recapitulates three dimensional (3D) cyst growth in the correct genetic context, and has previously been used to interrogate novel therapeutic strategies ( Dagorn et al, 2023 ). We evaluated drug predictions alongside tolvaptan in the presence and absence of the cyst swelling stimulus desmopressin (ddAVP), and determined that three predicted drugs—demeclocycline, cloperastine and mebendazole—demonstrated dose-dependent inhibition of cyst growth in both ddAVP-stimulated and unstimulated conditions, while tolvaptan only exhibited dose-dependent effects on cyst growth in the presence of ddAVP, as expected based on its mechanism of action ( Reif et al, 2011 ) ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…In order to assess the efficacy of mebendazole against ADPKD-relevant phenotypes in vivo , we utilised the P18 iKsp- Pkd1 del mouse model, which employs a tamoxifen-inducible cadherin promoter to selectively disrupt Pkd1 expression in the kidney epithelium at postnatal day (PND) 18, and has previously been employed to evaluate new therapeutic strategies ( Dagorn et al, 2023 ; Song et al, 2023 ). While perinatal inactivation of Pkd1 in this genetic background produces a rapid and severe model of kidney cystogenesis and functional decline over a compressed timeline, inactivation of Pkd1 at PND18 induces an adult-onset, slowly progressing model of cystic kidney disease which leads to renal failure over the course of several months, and offers the opportunity to evaluate treatment strategies over a chronic time window ( Leeuwen et al, 2007 ; Leonhard et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

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Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

Brownjohn,

Zoufir,

O’Donovan

et al. 2024

Front. Pharmacol.

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Autosomal dominant polycystic kidney disease (ADPKD) is a rare genetic disorder characterised by numerous renal cysts, the progressive expansion of which can impact kidney function and lead eventually to renal failure. Tolvaptan is the only disease-modifying drug approved for the treatment of ADPKD, however its poor side effect and safety profile necessitates the need for the development of new therapeutics in this area. Using a combination of transcriptomic and machine learning computational drug discovery tools, we predicted that a number of existing drugs could have utility in the treatment of ADPKD, and subsequently validated several of these drug predictions in established models of disease. We determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity. These findings demonstrate the utility of combining computational approaches to identify and understand potential new treatments for traditionally underserved rare diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

Brownjohn,

Zoufir,

O’Donovan

et al. 2024

Front. Pharmacol.

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“…Treatment with PXL770 inhibited cyst growth in both mouse- and patient-derived cells. Notably, it mirrored the effects of metformin, such as the attenuation of macrophage infiltration and fibrosis via AMPK activation and the enhancement of mitochondrial biogenesis ( Dagorn et al ., 2023 ). These findings underscore PXL770’s potential as a novel target with anti-fibrotic effects.…”

Section: Renal Fibrosis-related Potential Therapeutic Targets For Adpkdmentioning

confidence: 88%

Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis

Ahn,

Park

2024

Biomol Ther (Seoul)

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Autosomal dominant polycystic kidney disease (ADPKD), a congenital genetic disorder, is a notable contributor to the prevalence of chronic kidney disease worldwide. Despite the absence of a complete cure, ongoing research aims for early diagnosis and treatment. Although agents such as tolvaptan and mTOR inhibitors have been utilized, their effectiveness in managing the disease during its initial phase has certain limitations. This review aimed to explore new targets for the early diagnosis and treatment of ADPKD, considering ongoing developments. We particularly focus on cell polarity, which is a key factor that influences the process and pace of cyst formation. In addition, we aimed to identify agents or treatments that can prevent or impede the progression of renal fibrosis, ultimately slowing its trajectory toward end-stage renal disease. Recent advances in slowing ADPKD progression have been examined, and potential therapeutic approaches targeting multiple pathways have been introduced. This comprehensive review discusses innovative strategies to address the challenges of ADPKD and provides valuable insights into potential avenues for its prevention and treatment.

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“…In a preclinical investigation focusing on Autosomal dominant polycystic kidney disease (ADPKD), PXL770 treatment activates AMPK and restored mitochondrial DNA copy number and PGC-1α mRNA expression in mice with ADPKD. 355 Another compound, Metformin, widely known for its role in diabetes management, also bolsters mitochondrial biogenesis by activating AMPK, leading to an upsurge in PGC-1α expression and activation. 356 Furthermore, sirtuin-activating compounds (STACs), such as Resveratrol, enhance activity of the SIRT1-PGC-1α axis, thereby promoting muscle remodeling in Duchenne muscular dystrophy (DMD) mice.…”

Section: Therapeutics For Mitochondrial Dysfunctionmentioning

confidence: 99%

Mitochondrial dysfunction: mechanisms and advances in therapy

Zong,

Li,

Liao

et al. 2024

Sig Transduct Target Ther

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Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

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A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease

Cited by 7 publications

References 59 publications

Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis

Mitochondrial dysfunction: mechanisms and advances in therapy

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