Investigational agents for autosomal dominant polycystic kidney disease: preclinical and early phase study insights

ABSTRACT

Introduction

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney condition caused by a single-gene mutation. It leads patients to kidney failure in more than 50% of cases by the age of 60, and, given the dominant inheritance, this disease is present in the family history in more than 90% of cases.

Areas covered

This review aims to analyze the set of preclinical and early-phase studies to provide a general view of the current progress on ADPKD therapeutic options. Articles from PubMed and the current status of the trials listed in clinicaltrials.gov were examined for the review.

Expert opinion

Many potential therapeutic targets are currently under study for the treatment of ADPKD. A few drugs have reached the clinical phase, while many are currently still in the preclinical phase. Organoids could be a novel approach to the study of drugs in this phase. Other than pharmacological options, very important developing approaches are represented by gene therapy and the use of MiRNA inhibitors.

KEYWORDS:

• ADPKD
• cystogenesis
• drugs
• preclinical
• polycystic
• therapies

Article highlights

• Many molecular mechanisms are involved in ADPKD starting from alteration of PC1 and PC2. Cyclic-AMP (cAMP) was the first mechanism studied, but its pathway has intersection with several others: intracellular calcium availability, AMP-activated protein kinase (AMPK) that inhibits PKA and mTOR, EGF-receptor and B-Raf/MEK/ERK factors, as well as the metabolism of lipids and sphingolipids.

• Various new drugs have been investigated in pre-clinical and clinical trial, targeting all the altered pathways present in polycystic disease.

• Tolvaptan is the first worldwide approved drugs that targets cAMP and has good results in reducing TKV growth and eGFR decline.

• Currently, Metformin has garnered significant attention. Two phase three RCT are currently underway to assess its efficacy in ADPKD patients. Among pre-clinical drugs, 2-DG targets cellular metabolic reprogramming and will shortly pass to a clinical phase.

• Promising non-pharmacological approaches are related to dietary manipulation through ketogenic diet and caloric restriction.

• Attention has been directed toward gene therapy and Anti-MiRNAs. Anti-MiRNAs can increase normal PC1 and PC2 production by reducing phenotypical expression of mutated genes. The discovery of a correlation between a short segment of PC1 and the cystic phenotype demonstrated a new potential target for gene therapy.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.