... David Palmer & Nadia Mitchell, Lincoln, NZ. CLN5 sheep at Lincoln University, NZ. Page 17. Drug repurposing in B
Heather Band BDFA Scientific Officer
What is Batten Disease? Batten disease, the Neuronal Ceroid Lipofuscinoses (NCLs) are several different genetic life-limiting neurodegenerative diseases that share similar features.
Batten disease are ‘Simple’ Genetic Diseases
Recessive Inheritance
Types of Batten disease ‘CLN’ genes
CLN1
CLN1/PPT1 (Infantile) CLN2/TPP-I (Late Infantile) CLN3 (Juvenile) CLN5-CLN8 (Variant) CLN10/CTSD (Congenital)
CLN7
CLN8
CLN6 (Adult recessive) CLN4/DNAJC5 (Adult dominant) Identified in 2011
CLN3 CLN6 CLN5
CLN11/GRN, CLN12/ATP13A2 CLN13/CTSF, CLN14/KCTD7 Identified in 2012
CLN10
CLN2
Lysosomes
Breakdown & recycling of waste fails
Neuron
X
c v c v
The BDFA was founded in 1998 by a group of parents with affected children and with the help of Contact a Family and Seeability. The aim then, as now, was to ensure that no family face the devastating diagnosis of Batten disease alone.
The BDFA has three main aims
To support families and the professionals who work with them
To raise awareness and advocate for better services and treatments
To directly fund research into potential therapies and ultimately a cure
BDFA Research Strategy • • • • • •
The BDFA funds research into all forms of the NCLs Funding excellence in research Partner with universities, foundations & charities Proactive in our relationships with key stakeholders Innovative approach Support families funding research
Development of screen using Patient derived CLN5 cells
Cell based system for CLN3
Basic research
Identify Targets
Uncovering fundamental differences in cell biology in CLN5
Support and Advocacy for families on BMN190 clinical trial in the UK and worldwide
Gene therapy to treat visual failure in CLN6/3 Include other NCLs
Drug discovery
Therapy development
DanioVision Locomotion detection system Zebrafish studies Freeman Family
Pre clinical testing
Clinical Trials
Treatments
Assessing the efficacy of gene therapy upon neuropathology in CLN5 sheep NCL International Registry
NCL Patient Registry
= participating countries
Norway Ingrid Helland, MD Oslo University Hospital
USA Ron Crystal, MD PhD Weill Cornell Medical College
Germany Angela Schulz, MD , Co-ordinator University of Hamburg
Denmark Jon R. Ostergaard, MD Aarhus University Hospital
Argentina Ines Noher de Halac, MD Universidad Nacional de Cordoba
Italy Alessandro Simonati MD University of Verona UK Ruth Williams, MD GSTT, London Finland Laura Aberg Folkhälsan, Helsinki
France Catherine Caillaud MD PhD INSERM, Paris Turkey Meral Topcu, MD PhD University Children’s Hospital, Ankara
Brazil Charles Lourenco, MD PhD University of São Paulo
India Pratibha Singhi, MD PGIMER, Chandigarh
PhD Studentships
£15,000 - £20,000
£5,000+
£5,000 -£8,000
STIPEND
FEES/TRAVEL/ TRAINING
CONSUMABLES
15
£ 000
10
5
0 CK/Jon Cooper
TK/Jon Cooper
MV/Sara Mole
DM/Sara Mole
KW/ Claire Russell
LP/ Brenda Williams
OC/Jeffrey Gerst
Matched Funding-PhD studentships
Uncovering fundamental differences in cell biology in CLN5 Dr. Emyr Lloyd-Evans & Katie Shipley 3-year project Cardiff University Stipend - £40,000 BDFA, on behalf of Battle Batten consumables - £25,000
Testing Gene Therapy in CLN5 Sheep
CLN5 sheep at Lincoln University, NZ Ana Assis, Prof. Jon Cooper, PSDL; David Palmer & Nadia Mitchell, Lincoln, NZ
Drug repurposing in Batten disease Fishing for a Cure
Why use zebrafish?
Wild-Type Sibling Normal Appearance
CLN2
Mahmood et al., 2003
CLN2 Severe phenotype
Wild-Type
CLN2
CLN2 zebrafish screen of FDA-approved library
560 compounds 19 re-tested 1 remained positive (RVC1)
Effect of RVC1 on CLN2 zebrafish
[Please note: this slide has been removed as it contained unpublished research results]
Gene therapy at the eye The aim of this 3 year PhD project was to investigate whether a gene therapy is feasible to improve vision in Batten Disease. Introduce healthy copies of the faulty gene
Institute of Ophthalmology Prof. Robin Ali, Dr. Sander Smith
MRC Laboratory of Molecular Cell Biology Dr. Sara Mole
Retinal gene therapy AAV2/5
Inner retinal gene therapy AAV.7m8, intravitreal injection at postnatal day 6 – CMV promoter Merge projection image Merge single image magnification
50 μm
Sophia kleine Holthaus
25 μm
Retinal CLN6 gene therapy
[Please note: this slide has been removed as it contained unpublished research results]
Developing new therapies for Batten Disease CLN3, CLN6 & CLN7 Co-ordinator Professor Sara Mole PIs from 13 organisations in 8 different countries, including BDFA
Pre-discovery
Disease Models
WP01 + WP04
Iden fica on of Surrogate Markers
WP02 + WP03
Discovery
Lead Iden fica on & Op miza on
WP05 + WP06
Pre-clinical
Drug & Gene Therapeu c Strategies
WP07 + WP08
Prepare for Clinical Trials
WP09
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 666918
BATCure Administrator
BATCure Administrator Appointed on 30th April 2016
Laura Codd
[email protected] Wednesdays 9:30am-5:30pm
£210,000
• 2012-2016 • PhD Studentship CLN3, CLN6 (3-Year) • Post Doctoral studies CLN3, CLN6 (1-Year)
£437,000
• 2016-2019 • Post Doctoral studies CLN3, CLN6 & CLN7 (3-Years) • Post Doctoral studies CLN2 (3-Years)
Conclusion • Excellence in science peer review & setting priorities for research • Partnerships are key Universities, Foundations • Proactive seeking matched funding, ensuring continuity of funding • Innovative approach utilise a range of resources • Provide a mechanism for individual families to fund research
BDFA Research Partners Dr. Claire Russell Gini Brickell MSc Dr. Fahad Mahmood Karen and Martin Freeman Professor Jon Cooper Dr. Benda Williams Dr. Tytus Murphy Ana Assis Prof. Sara Mole Prof. Robin Ali Dr. Sander Smith Dr. Sophia Holthaus Prof. Paul Gissen Dr. Dan Little Dr. Emyr Lloyd-Evans Dr. Luke Haslett Katie Shipley Battle Batten Campaign