Emerging treatments and personalised medicine for ciliopathies associated with cystic kidney disease

ABSTRACT

Introduction: Renal ciliopathies are a class of heterogeneous disorders that can manifest with nephronophthisis, cystic kidneys or renal cystic dysplasia. Disease causing genes encode for ciliary proteins, suggesting that defects in the primary cilium underlie a common pathogenesis. Currently, no cure and limited treatment options are available for renal ciliopathies patients.

Areas covered: We will review here the results of preclinical and clinical studies on drugs that modify dysregulated pathways in ciliopathies associated with cystic kidney disease. Substantial progress in the clarification of underpinning molecular mechanisms along with implementation of in vivo models has led to the identification of several compounds with promising therapeutic effects in preclinical studies. Clinical trials are currently evaluating safety and efficacy of several emerging therapies in human, but to date only the V2 receptor antagonist tolvaptan has been utilised in the clinic for the treatment of adult patients with rapidly progressive polycystic kidney.

Expert opinion: The extreme genetic and clinical heterogeneity that characterizes renal ciliopathies patients may in part explain the limited success of clinical trials and highlights the need for precision treatments. Gene based therapies and personalized drug screenings may represent the future standard of care for renal ciliopathies patients with cystic kidney disease.

KEYWORDS:

• Precision medicine
• randomised controlled trial
• murine model
• nephronophthisis
• cystic kidney disease

Article highlights

• Renal ciliopathies are genetically heterogeneous but phenotypically overlapping disorders, characterized by nephronophthisis, cystic kidneys or renal cystic dysplasia. No completely effective treatment is currently available for renal ciliopathies patients

• Overlapping phenotypes and a shared ciliary localization of gene products suggest a common aetiology for these disorders

• Advances in the identification of disease genes and the increasing availability of animal models of renal ciliopathies allow a better understanding of underpinning pathophysiology and the development of several emerging treatments

• Many of the drugs that were shown to be effective in the treatment of renal ciliopathies in animal models have led to disappointing results when tested in human clinical trials

• The high clinical and genetic variability across renal ciliopathies patients is difficult to model in animals and complicates the scalability of clinical trials, warranting a more personalized approach in the development of novel treatments for these disorders

• Personalized drug screenings and gene based therapies may represent the future precision approaches required for the treatment of highly heterogeneous diseases such as renal ciliopathies

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Declaration of interest

J Sayer has received consultancy fees and lecture fees from Otsuka Pharmaceuticals LTD and Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Kids Kidney Research Fund, Newcastle upon Tyne Hospitals NHS Charity, Northern Counties Kidney Research Fund, Kidney Research UK, Medical Research Council.