The Ciliopathy

Alliance

5th Anniversary Meeting

ICH

19 October 2015

Rare disease day 2011

Hannah Mitchison

UCL Institute of Child Health

h.mitchison@ucl.ac.uk

Ciliopathies: UK research update

Cilia in the body: motile & sensory/primary

PL. Beales. NewScientist | 2 November 2013

1674 Antonj van Leeuwenhoek

1990s: central role

development & tissue maintenance

1960s. Primary cilia not vestigial:

signalling and disease

Denys Wheatley,

Barbara Barnes

Dysfunctional cilia have devastating impact

Lee and Gleeson

Genome Medicine 2011 3:59

Cardenas-Rodriguez, Am J Med Genet C 2009

What is a ciliopathy? ‘tick box’

PCD

General population: Child obesity 20-30%, kidney cysts 1 in 500, retinal

degeneration 1 in 3000, polydactyly 1 in 500.

The Ciliopathy

Alliance

Alström Syndrome

Bardet-Biedl Syndrome

Jeune Syndrome

Joubert Syndrome

Nephronophthisis

Polycystic Kidney Disease (PKD)

Primary Ciliary Dyskinesia (PCD)

Retinitis Pigmentosa

Usher Syndrome

Clinical research at UK MDT clinics

Diagnostics

Management

Registries

Trials

PCD Alstrom

BBS

BBS

PCD

PCD

PCD

Other

UK cilia

lab

research:

snapshot

(incomplete!)

Leeds

Colin A. Johnson

Sheffield

Jarema Malicki

Albert Ong

Andrew Streets

London QMUL

Martin Knight

Newcastle

John Sayer

Birmingham

Tim Barrett

Edinburgh

Pleasantine Mill

Andrew Jarman

Toby Hurd

Harwell

Dominic Norris

Exeter

Helen Dawe

Bristol

David Stephens

Kingston

Evi Goggolidou

Dublin

Oliver Blacque

London UCL

CDL (Beales, Mitchison)

Stephen Hart

Chris O’Callaghan

Andrew Webster

Maria Bitner-Glindzicz

Jane Sowden

Alison Hardcastle/

Mike Cheetham

Dan Jagger London RBH

Amelia Shoemark,

Claire Hogg

Oxford

Angus Wann

Keith Gull

Cambridge

Maurizio

Chioccioli

Pietro Cicuta

Lancaster

Paul McKean

Michael Ginger

Southampton

Jane Lucas

Leicester

Rob Hirst

Chris O’Callaghan

Kerry Leeson-Beevers Alstrom research update

Big Lottery funding update

Elizabeth Forsythe, Phil Beales Phenotype prognosis in BBS

Genetic predictors of cardiovascular morbidity

in Bardet-Biedl syndrome. Clin Genet. 2015 87:343-9

Phil Beales group BBS clinical research

• Human urine derived renal epithelial cell model for drug

screening

• Trialling retinal gene replacement therapy in BBS mice

• Modelling and drug-modifying of intraflagellar transport

Colin A. Johnson, Hannah Mitchison Ciliogenesis screen reveals Jeune syndrome cause

SPATA7

NEK1

C21orf2

Miriam

Schmidts

C21orf2 mutations

Wheway et al. Nat Cell Biol. 2015 17:1074-87

• Using human urine derived renal epithelial cells for mechanistic and drug treatment studies, in Joubert patients (and some with OFD1)

• Patients and families interested can contact John directly. Need a fresh urine sample from patient

• Already know the ciliary defects are druggable, so are finding out which drugs work best next

• Presenting their work at the Joubert Syndrome UK patient day on 31st Oct in South Shields (see JoubertSyndromeUK Facebook page for details)

John Sayer, Shalabh Srivastava Drug screening in Joubert syndrome, Nephronophthisis

John Sayer

Univ Newcastle

• PKD1 loss alters ciliogenesis in different cell models - trying to identify how/why this is altered in ADPKD

• Test prostaglandin receptor inhibitors as a novel therapy in ADPKD mice (3D cell assays growing kidney cysts in culture to test novel therapeutic agents)

• Seeking new biomarkers of progression in ADPKD - changes in expression of small RNA molecules (microRNAs) in patient urine

• Trialling novel imaging techniques to accurately measure changes in kidney volume of patients over time

• ADPKD patients will be added to RaDaR (rare renal registry)

• Aiming to deeply characterise ~5000 within 2 years

Prof Albert Ong,

Dr Andrew Streets, Univ.

Sheffield Medical School

Andrew Streets (Albert Ong group) Biomarkers and therapies for

autosomal dominant PKD

• PKD Charity is funding a study into the influence of ATMIN on development and progression/severity of ARPKD

• Looking at its roles in DNA damage repair and ciliogenesis

• ATMIN KO mice have kidney defects and abnormal cilia signalling - have identified changes in gene expression in components of Wnt signalling in ARPKD kidneys compared to controls

Paraskevi Goggolidou

Kingston University

Evi Goggolidou Mouse models of autosomal recessive PKD

European Respiratory Society Taskforce – Diagnostic guidelines for PCD - best practise for diagnosis of PCD

– Literature review to determine evidence-based (rather than consensus based) guidelines for

multiple diagnostic outcome measures - Report by end of 2017

H2020 funded COST Action BEAT-CILIA – lead, Jane Lucas for PCD Network • Aim to develop research for treatments for PCD – networking of clinicians, basic scientists, patient

organisations

• Inaugural conference

Randomised Controlled Trial (RCT) of azithromycin maintenance therapy in

Primary Ciliary Dyskinesia – Multicentre participation

UCL-ICH: Readthrough therapy trials for selected PCD patients. Chris

O’Callaghan, Stephen Hart, Hannah Mitchison

UK PCD clinical research

UK PCD Network leads

Andrew Bush, Jane Lucas,

Claire Hogg, Amelia Shoemark

• Usher Syndrome Coalition joining Ciliopathy Alliance

• UCL Institute of Child Health • Maria Bitner-Glindzicz, Jane Sowden: making iPS cells from patients with Usher.

iPS->RPE, photoreceptors.

• GOSH offer genetic panel testing for Usher here as an NHS service

• UCL Institute of Ophthalmology • Andrew Webster, next generation sequencing gene discovery in retinal ciliopathies

• Alison Hardcastle, Mike Cheetham genetic cell biology of x-linked RP ciliopathies - exploring translational readthrough therapy for RP2 in iPS derived RPE

• Prof Pete Coffey: First UK stem cell treatment to cure AMD related loss of vision

UCL research into RP and Usher syndrome Patient iPS cells, genetic testing, stem cell therapy

GOSHome Ciliopathies gene panel service

Research conferences and meetings

Keystone

Cilia, Development

and Human Disease

2017/2018

Gordon Research Conference

Cilia, Mucus & Mucociliary

Interactions

2017

FASEB

The Biology of Cilia

and Flagella

2017

Special sessions:

ASCB

ARVO

ASN

ATS

ERS

Cilia2016

From Fundamental Biology to Human

Disease

4-7 October 2016

5th International caesar Conference

The Omnipresent Cilium - Structure,

Signalling, and Motion

30 Sept-2 Oct 2015

Biochemical Society

Cilia, Cytoskeleton

& Cancer

25-26 April 2016

Radboud New Frontiers

in Cilia Medicine

30 Nov 2015