Our laboratory has established two flocks of sheep with naturally occurring forms of NCL
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1 Batten animal research Network :Lincoln NZ Finnish and Variant Late Infantile Batten Disease David Palmer, Lucy Barry, Hannah Lee, Nadia Mitchell, Janet Xu, Jarol Chen, Huibing Jiang, Stephanie Hughes, Hollie Peacock Faculty of Agriculture and Life Sciences, Lincoln University; Department of Biochemistry, Otago University, New Zealand. Email: [email protected] Our laboratory has established two flocks of sheep with naturally occurring forms of NCL CLN5 in Borderdales CLN6 in South Hampshires These 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 CLN5 CLN6 BDSRA 2012 2 CURRENT KEY PROJECTS 3 WHAT THIS MEANS FOR THERAPY Neuroinflammatio n and Drug Therapy Vectors and Gene Injections Biomarkers of Disease Progress We are working, in collaboration, on a number of different therapeutic strategies Gene 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 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). 1 cm 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 immmunohistochemistr 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 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 INTRODUCTION Pre-symptomatic microglial activation 12 days after birth Subventricular zone in 2 year affected, PSA-NCAM Contro l Newly generate d 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 Affecte d
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CLN5CLN6 BDSRA 2012. Our laboratory has established two flocks of sheep with naturally occurring forms of NCL CLN5 in Borderdales CLN6 in South Hampshires - PowerPoint PPT Presentation
Transcript of Our laboratory has established two flocks of sheep with naturally occurring forms of NCL
1
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
2
CURRENT KEY PROJECTS
3
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).
1 cm
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
