Rare Disease Research Platform: The renal ciliopathies national network (RCNN)
Lead Research Organisation:
Newcastle University
Department Name: Translational and Clinical Res Institute
Abstract
A group of rare inherited kidney diseases known as renal ciliopathies represent around 10% of all patients with kidney failure, who need specialist treatments including dialysis and kidney transplantation.
Modern genetics and cell biology has now allowed us some important insights into this group of diseases. The most commonly seen form is called autosomal dominant polycystic kidney disease and recently the first drugs have come to the clinic to slow down this disease. Treatments that prevent or switch off the disease are still lacking. This group of patients with rare disease is relatively large with several thousand patients affected and are significant unmet challenge for our health care system. They also present a significant opportunity for innovation and investment within the UK such as we become world leaders.
We believe that by aligning these patient cohorts to exploit our expertise in molecular diagnostics, deep clinical phenotyping and disease modelling we can accelerate development of novel treatments. Here, we will create an accessible multi-institutional, multi-disciplinary collaborative network for both clinicians and scientists interested in the renal ciliopathies. We will foster the collective engagement of clinical and research teams from across the country, and ensure efficient data sharing between partners. By bringing together different renal ciliopathy disease patients within one network, we can harness the most understanding from our human disease genetics as to how variants and genes control kidney function and disease progression. We will develop powerful patient-derived cell-based functional assays to understand disease mechanisms and to fast-track discovery of much needed therapeutics in the renal ciliopathies.
The renal ciliopathies national network (RCNN) aims to: harmonise clinical, imaging and molecular genetic work-up as standard for all renal ciliopathy patients in the UK; improve genomic interpretation of underlying genetic variants and develop well characterised groups of patients who are trial ready for new personalised medicine treatments. In doing so, we will create a national system of support for ciliopathy patients and their families through partnerships with patient groups and charities, better interfaced with clinical care teams and researchers regardless of postal code. We believe that involving patients in these early steps of shaping the translational landscape for renal ciliopathies as we move forward will lead to better designed trials and identifying endpoints that would be meaningful for our patients.
We believe that MRC/NIHR Rare Disease investment to create the RCNN would help build strong clinical links to care teams nationally, foster successful relationships between industry and our patient advocacy groups to establish meaningful collaborations, and create the opportunity to advocate for significant industry investment to accelerate development of new treatments for the renal ciliopathies. In summary, the RCNN aims to improve renal ciliopathy patient care nationwide, to develop infrastructure for stratified patient cohorts that are 'trial-ready' and build partnerships with academics and industry to accelerate development of much-needed new treatments.
Modern genetics and cell biology has now allowed us some important insights into this group of diseases. The most commonly seen form is called autosomal dominant polycystic kidney disease and recently the first drugs have come to the clinic to slow down this disease. Treatments that prevent or switch off the disease are still lacking. This group of patients with rare disease is relatively large with several thousand patients affected and are significant unmet challenge for our health care system. They also present a significant opportunity for innovation and investment within the UK such as we become world leaders.
We believe that by aligning these patient cohorts to exploit our expertise in molecular diagnostics, deep clinical phenotyping and disease modelling we can accelerate development of novel treatments. Here, we will create an accessible multi-institutional, multi-disciplinary collaborative network for both clinicians and scientists interested in the renal ciliopathies. We will foster the collective engagement of clinical and research teams from across the country, and ensure efficient data sharing between partners. By bringing together different renal ciliopathy disease patients within one network, we can harness the most understanding from our human disease genetics as to how variants and genes control kidney function and disease progression. We will develop powerful patient-derived cell-based functional assays to understand disease mechanisms and to fast-track discovery of much needed therapeutics in the renal ciliopathies.
The renal ciliopathies national network (RCNN) aims to: harmonise clinical, imaging and molecular genetic work-up as standard for all renal ciliopathy patients in the UK; improve genomic interpretation of underlying genetic variants and develop well characterised groups of patients who are trial ready for new personalised medicine treatments. In doing so, we will create a national system of support for ciliopathy patients and their families through partnerships with patient groups and charities, better interfaced with clinical care teams and researchers regardless of postal code. We believe that involving patients in these early steps of shaping the translational landscape for renal ciliopathies as we move forward will lead to better designed trials and identifying endpoints that would be meaningful for our patients.
We believe that MRC/NIHR Rare Disease investment to create the RCNN would help build strong clinical links to care teams nationally, foster successful relationships between industry and our patient advocacy groups to establish meaningful collaborations, and create the opportunity to advocate for significant industry investment to accelerate development of new treatments for the renal ciliopathies. In summary, the RCNN aims to improve renal ciliopathy patient care nationwide, to develop infrastructure for stratified patient cohorts that are 'trial-ready' and build partnerships with academics and industry to accelerate development of much-needed new treatments.
Technical Summary
Renal ciliopathies are a group of inherited cystic kidney diseases that represent around 10% of all patients with kidney failure. The most prevalent form worldwide is called autosomal dominant polycystic kidney disease (ADPKD) secondary to mutations in the cystogenes PKD1 and PKD2. Cystogenesis secondary to these mutations is driven by upregulated cAMP which can be modified in animal and human studies by arginine vasopressin antagonists such as tolvaptan. Pharmacological treatments and genetic interventions that prevent or switch off the disease are still lacking. Therapies for the related autosomal recessive (AR) disorders ARPKD and nephronophthisis is completely lacking despite shared disease mechanisms. Collectively these disorders are termed renal ciliopathies.
The objectives of the renal ciliopathies national network (RCNN) are to: harmonise clinical, imaging and molecular genetic work-up as standard for all renal ciliopathy patients in the UK; improve genomic interpretation of underlying genetic variants and develop well characterised groups of patients who are trial ready for new personalised medicine treatments. In doing so, we aim to create a national system of support for ciliopathy patients and their families through partnerships with patient groups and charities. This will allow better interfaces with clinical care teams and researchers. We believe that involving using the ADPKD translational pathway we can shape the translational landscape for all renal ciliopathies, leading to better mechanistic understandings, well designed preclinical and clinical trials and identifying therapies that would be used in these patient groups.
The objectives of the renal ciliopathies national network (RCNN) are to: harmonise clinical, imaging and molecular genetic work-up as standard for all renal ciliopathy patients in the UK; improve genomic interpretation of underlying genetic variants and develop well characterised groups of patients who are trial ready for new personalised medicine treatments. In doing so, we aim to create a national system of support for ciliopathy patients and their families through partnerships with patient groups and charities. This will allow better interfaces with clinical care teams and researchers. We believe that involving using the ADPKD translational pathway we can shape the translational landscape for all renal ciliopathies, leading to better mechanistic understandings, well designed preclinical and clinical trials and identifying therapies that would be used in these patient groups.
Publications
Schiano G
(2023)
Allelic effects on uromodulin aggregates drive autosomal dominant tubulointerstitial kidney disease.
in EMBO molecular medicine
Claus L
(2023)
Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease
in Kidney International
Esson G
(2024)
Diverse retinal-kidney phenotypes associated with NPHP1 homozygous whole-gene deletions in patients with kidney failure
in Journal of Rare Diseases
Al Riyami MS
(2023)
Genetic analysis and outcomes of Omani children with steroid-resistant nephrotic syndrome.
in Molecular genetics & genomic medicine
Orr S
(2023)
Many lessons still to learn about autosomal dominant polycystic kidney disease.
in Journal of rare diseases (Berlin, Germany)
Schönauer R
(2023)
Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
in American journal of human genetics
Devlin L
(2023)
Renal ciliopathies: promising drug targets and prospects for clinical trials.
in Expert opinion on therapeutic targets
Mariniello M
(2024)
Uromodulin processing in DNAJB11-kidney disease.
in Kidney international
Description | Collaboration with Friedhelm Hildbrandt |
Organisation | Boston Children's Hospital |
Country | United States |
Sector | Hospitals |
PI Contribution | Sharing of Whole Exome Sequencing Data |
Collaborator Contribution | Friedhelm Hildebrandt has shared hole exome data so we can investigate modifier alleles in Joubert syndrome |
Impact | Genome sequencing |
Start Year | 2017 |
Description | CILIAREN Scientific launch at the UK Cilia Network Meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | We had our scientific launch of CILIAREN at the first in-person meeting since before the pandemic of the UK Cilia Network, where we welcomed 75 members and affiliates from around the UK as well as Denmark, Germany and Spain to share the latest in cilia science. The one-day meeting organised by Prof. Pleasantine Mill (University of Edinburgh) and Dr. Girish Mali (University of Oxford) at the Institute for Genetics and Cancer at the University of Edinburgh aimed to showcase the breadth of cilia research currently underway, as well as highlight the interdisciplinary nature of cilia research. Found on the surface of almost everything mammalian cell type, primary cilia function as tiny cellular antennae detecting and amplifying extracellular signalling cues. Defects in the strWeure or function of cilia result in a growing group of rare genetic disorders, known as the ciliopathies. We learned from Daniel Baird (Larssen lab, University of Copenhagen) and Katerina Apolínová (ZeClinics, Barcelona), about the role of primary cilia in congenital heart disease (CHD) and cardiac repair, using zebrafish as a model to identify potential therapeutic targets for ciliopathies. We heard about technologies from Viviana Macarelli (Merckle lab, University of Cambridge) to monitor the dynamic content of primary cilium of human iPSC-derived hypothalamic neurons, which play important roles in controlling food intake and weight, to be able to interrogate cell-type specific ciliary signaling cascades involved in obesity. We had a keynote presentation from Prof. Dagmar Wachten (University of Bonn, DE), who engineers fantastic biosensors which can specifically detect specific signalling in primary cilia, demonstrating how the dysregulation of ciliary signalling triggers kidney cyst formation as well as metabolic and inflammatory remodelling of the adipocyte niche in Bardet-Biedl Syndrome (BBS). Understanding how variants lead to syndromic disease like the ciliopathies requires better models than cells line on plastic. We heard from Dr. Kasia Szymanska (Johnson lab, University of Leeds) about diverse banks of patient-derived 3D mini kidney models to screen therapies for polycystic kidney disease (PKD). We also heard about the importance of microfluidics and kidney organ chips to be able to mimic flow to model PKD progression and therapeutic reversal from Beth Cutting (Knight lab, Queen Mary University of London). It was also the launch of CILIAREN by Prof. John Sayer (University of Newcastle), a joint MRC-NIHR funded UK Rare Disease Research Platform of clinical teams, research centres and patient groups around the UK aiming to improve the care and diagnosis of people with renal ciliopathies. We were swept away by motile cilia too. We heard from Dr. Anu Sironen (Mitchison lab, UCL) about how profiling different motile cilia within the male reproductive system using spatial transcriptomics and structural differences within these cilia types. Dr. Francesco Boselli (Durham University) explained how mathematical models can help us understand this synchronized cilia beat can emerge over developmental time. We were wowed by two outstanding artificial intelligence (AI) talks which promise to revolutionise biomedical research. The first used in clinical diagnostics for primary ciliary dyskinesia, Dr. Mathieu Bottier (Hogg lab, Royal Brompton Hospital) revealed how the platform can screen a patient sample in under 30 seconds, down from hours manually and be more definitive in subtle ultrastructure defect calls than the human experts. Next Analle Abuammar (Mennella lab, University of Cambridge) presented an automated segmentation strategy for generating a 3D model of multiciliated cells, with outstanding structural detail. We had over 25 posters on exciting science from molecules to mechanism to medicines- the future of UK cilia science is bright! We also had a talk from Dr Roly Megaw representing the Ciliopathy Alliance and highlighting ways basic scientists can get involved with rare disease patient groups and involve ciliopathy patients in all aspects of their research. Then it was off to the pub for some much needed informal networking! |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.ciliaren.org/ciliaren-scientific-launch-at-the-uk-cilia-network-fall-meeting-06102023 |
Description | Genetics Matters 2024 Newcastle |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Genetics Matters" is an annual event organised by Newcastle University to mark the International Rare Disease Day. Currently in its 8th edition, the event consists of a combination of lay-language lectures and hands-on research tables. It is a great opportunity to chat to Newcastle University scientists, and find out about the recent developments in genetic research at Newcastle. The event is held in the beautiful Great Hall of the Discovery Museum, and refreshments (tea/coffee/cake) will be provided. We will have 2-3 short researcher and patient talks, with the majority of the afternoon dedicated to the hands-on and face-to-face research tables. We will cover the cutting-edge topics of genomics, epigenetics, single cell research, stem cells and tissue regeneration, personalised medicine, drug repurposing, mitochondrial donation and cancer research, amongst others. |
Year(s) Of Engagement Activity | 2024 |
URL | https://voice-global.org/opportunities/genetics-matters-2024 |
Description | PKD Patient Information Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | oin us for an insightful event hosted by PKD expert, Professor John Sayer. Engage in informative talks, interactive Q&A sessions, and chat with others living with PKD (ADPKD). Attendance is free, including lunch and refreshments throughout the day. You are welcome to bring along a family member or friend who may find this event equally beneficial. It's open to patients, family members, caregivers, and healthcare professionals. You can choose to attend for the full day or selected sessions only - View Programme! |
Year(s) Of Engagement Activity | 2024 |
URL | https://pkdcharity.org.uk/news-events/events/166-adpkd-information-support-day-newcastle-upon-tyne/2... |
Description | Rare Diseases Event Newcastle - Renal Disease Workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | We had a hugely successful in person meeting in Newcastle as part of our MRC NIHR UK Rare Disease Research Network platform nodes focusing on renal ciliopathies (CILIAREN) and urinary tract disorders (REOLUT) . we explorered synergies and opportunities for data sharing and networking, with an emphasis on early career researchers presenting data. We had Prof Ronald Roepman (Radboud University Medical Centre, NL) as our distinguished keynote speaker and there were hugely valuable opportunities for lightning talks and elevator pitches. |
Year(s) Of Engagement Activity | 2024 |
URL | https://www.ciliaren.org/new-page |