Heather Band BDFA Scientific Officer - Findacure

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... 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