Dr Hannah Mitchison, UCL Institute of Child Health, gives an update on UK research into cilia and ciliopathies

1. The Ciliopathy
Alliance
5th Anniversary Meeting
ICH
19 October 2015
Rare disease day 2011

2. Hannah Mitchison
UCL Institute of Child Health
h.mitchison@ucl.ac.uk
Ciliopathies: UK research update

3. 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

4. Dysfunctional cilia have devastating impact
Lee and Gleeson
Genome Medicine 2011 3:59

5. 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.

6. 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

7. Clinical research
at UK MDT clinics
Diagnostics
Management
Registries
Trials
PCD
Alstrom
BBS
BBS
PCD
PCD
PCD

8. 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 JaggerLondon 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

9. Kerry Leeson-Beevers
Alstrom research update
Big Lottery funding update

10. Elizabeth Forsythe, Phil Beales
Phenotype prognosis in BBS
Genetic predictors of cardiovascular morbidity
in Bardet-Biedl syndrome. Clin Genet. 2015 87:343-9

11. 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

12. 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

13. • 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

14. • 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

15. • 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

16.  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

17. • 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

18. GOSHome Ciliopathies gene panel service

19. 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