Mechanisms driving Autosomal Dominant Polycystic Kidney Disease: The novel role of the RNA-binding protein ANKHD1.

This FLF proposal seeks to improve understanding of the cause of Autosomal Dominant Polycystic Kidney Disease (ADPKD), in order to discover new medicines to halt disease progression. ADPKD is the most common genetic renal disorder, affecting over 12 million people worldwide. Of those, 50% will lose kidney function by the age of 50, requiring either kidney transplantation or lifelong dialysis to survive. Currently we have a limited source of kidneys for transplantation. To add to this problem, a high proportion of patients with ADPKD develop intracranial aneurysms due to profound vascular defects. Although Tolvaptan is the first drug approved for ADPKD, providing strong evidence that the disease can be modified, it only has a modest therapeutic effect. Moreover, Tolvaptan comes with significant obligate side effects. Hence, there is a major unmet therapeutic need for new targets. Therefore, the urgent need for new therapies together with the exciting advancements in the field, mean that my proposal for innovative research in polycystic kidney disease is highly timely.

To be in a position to offer new therapies, it is necessary to understand the processes by which growth of multiple cysts take place in the kidney. The mechanisms that control relentless growth of cysts and excessive extracellular matrix (ECM) accumulation in ADPKD are unknown. My group has recently made a discovery that has the potential to unlock the mechanisms of ADPKD pathogenesis. I discovered a gene, called Ankhd1, which controls cell proliferation and fibrosis in the polycystic kidney by controlling a novel RNA metabolism mechanism. Remarkably, Ankhd1-deficiency improves renal function, reduces cystic growth and limits fibrosis in cellular and mouse models of ADPKD. Using cutting-edge novel methods, I discovered that ANKHD1 promotes ADPKD by directly interacting with target mRNAs. Intriguingly, mutations or deletions in the RNA binding domain of ANKHD1 render the protein inactive, strongly suggesting that ANKHD1 promotes ADPKD via mRNAs. In this proposal, I will discover the mechanisms regulated by ANKHD1 that lead to altered apoptosis, increased proliferation and fibrosis, thus making cells 'activated'. To study the contribution of the newly identified genes to disease, it is necessary to use human cells and mice, which will model the human disease closely. Moreover, I will describe how altered RNA metabolism contributes to ADPKD-mediated vascular dysfunction. This ambitious multi-disciplinary programme will pave the way for a clinical trial of new nucleic-acid based compounds to halt ADPKD progression.

To maximise project impact and leadership potential, I have integrated a Fellowship Development Plan with the research aims and builds towards the translational goal of the 7-year plan. The Development plan includes field visits to wold leading labs to learn new cutting edge methods, which I plan to bring back to Sheffield (eRIC, RBNS, computational pipelines); official training (leadership, clinical trials, bioinformatics for PIs) and dissemination of work and generation of new opportunities by hosting a British Society of Matrix Biology meeting in Sheffield and ADPKD patient information days.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic disorder causing kidney failure. It has no cure and affects over 12 million people worldwide. It is a multi-organ disease resulting in damage to kidneys and the vasculature, eventually leading to widespread tissue fibrosis, renal failure and significantly increased risk of intracranial aneurysms. It poses a huge socio-economic burden of a global scale. Research to understand its pathobiology is hence of paramount importance. While the initiating events of the disease are well understood, what causes relentless growth of cysts and associated vascular dysfunction are less clear. It is well-accepted that enhanced proliferation, and fibrosis are key contributors to disease progression, yet the molecular events responsible for these actions are not understood. My research aims to use cutting edge technologies to answer the following questions (i) which of the newly identified ANKHD1 RNA targets are pathogenic? (ii) Which of the ANKHD1 targets are differentially activated during ADPKD? (iii) How does ANKHD1 alter RNA metabolism? and (iv) can therapeutic targeting of ANKHD1 target RNAs using nanoparticles be used as a new treatment strategy for ADPKD?

The design of the project is based on the premise that ADPKD can be rationally targeted following functional characterisation of its RNA targets. Indeed, there is precedent for success in applying basic biomedical knowledge towards the design of new therapeutics (e.g. targeting the liver with therapeutic siRNA-based nanoparticles to treat Hereditary Transthyretin Amyloidosis, New Engl J Med 2018; 379: 11-21). This research will contribute to the following long-term impacts: (i) A greater understanding of the pathobiology of ADPKD, with a focus on the mechanism that drive fibrosis and tissue overgrowth and (ii) identify the RNA binding protein 'interactome' of the polycystic kidney and (iii) development of novel therapeutics for ADPKD based on RNA-targeting nanoparticles. The insights gained from my research will benefit other disciplines including fibrosis of multiple organs (liver, lung, skin etc), multiple malignancies which, are also characterised by tissue overgrowth as well as additional renal diseases.

My proposed research is deep-rooted in underpinning science, yet the findings will make a positive impact on human health. Discovery research will contribute to the knowledge required for drug development. Therefore, the mid-term beneficiaries will be in drug development teams in the pharmaceutical industry and government organisations. If drug development is successful, the long-term beneficiaries will people affected with ADPKD worldwide, their families and the health care professional teams that look after them.