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Our laboratory has established two flocks of sheep with naturally occurring forms of NCL CLN5 in Borderdales CLN6 in South HampshiresThese provide excellent large animal models to study and compare Batten disease mechanisms and to identify and validate potential therapies

Features Models of both

membrane bound and soluble protein forms of Batten disease

Genetic testing allows diagnosis at birth. Clinical disease is obvious 12-14 months later

With a larger more complex brain than mice, the sheep brain is ideally suited for modeling human disease

The sheep are economic and easy to maintain in our environment

Samples are available from birth through to end stage disease

CLN5CLN6BDSRA 2012

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CURRENT KEY PROJECTS

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WHAT THIS MEANS FOR

THERAPYNeuroinflammation and Drug Therapy

Vectors and Gene Injections

Biomarkers of Disease Progress We are working, in

collaboration, on a number of different therapeutic strategiesGene Therapies Our studies show cross-cell

correction may be an option for CLN5 and CLN6

In vivo trials are underway to inject DNA encoding the functional, therapeutic gene in order to replace a mutated gene

Specific areas of extended neurogenesis are targeted

Anti-inflammatory Therapies Mapping the

neuroinflammatory pathways will indicate potential drugs and target sites

Drug Therapies We have developed facilities,

expertise and protocols to test drug therapies in Batten disease sheep.

Functional and behavioural studies have been established to monitor their efficacy

Ready to test drugs as soon as realistic candidates are discovered. Already testing a novel calpain inhibitor

It is likely a combination of therapies will prove best

Acknowledgements:Technical support from MJ Ridgway and NP Jay (JML Research Farm). Financial support from BDSRA, the Neurological Foundation (NZ), Pub Charities (NZ), CDHI and FoRST (NZ).

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Neuroinflammation: First discovered to be

associated with NCLs in the CLN6 sheep

Begins prenatally and spreads

Was not suppressed by treatment with the anti-inflammatory drug, minocycline

The inflammation cascade is complex!

Need to know more about the disease mechanisms to identify potential drug targets and to pick a drug more likely to work

Currently mapping the cascade by gene expression and immmunohistochemistry studies in CLN5 and CLN6

Research findings: A zone of extended

neurogenesis was found and identified as a key target site for gene injections

Chimeric studies showed that correcting only some cells is all that is required

Have developed lentiviral vectors and successful injection protocols

Collaboration: Dr SM Hughes, University of Otago

Ready for definitive gene lentiviral therapy trials and to test AAV derived vectors

Developing biomarkers for assessing the efficacy of therapies

CT scanning non-invasive

measurement of brain volume changes during disease progression

Social networking GPS monitoring to

analyse changes in animal behaviour and social interaction Led by Prof AJ Morton, University of

Cambridge

Vision and maze testing Assessment of vision

and neurological function Led by Prof AJ Morton, University of

Cambridge

INTRODUCTION

Pre-symptomatic microglial activation

12 days after birth

Subventricular zone in 2 year affected, PSA-NCAMControl

Newly generated neurons

Clearance of storage bodies

Gene expression in the sheep brain one year after injection

Brain volume changes in chimeric sheep compared to affected and

normal

Normal

Affected