1 Batten animal research Network :Lincoln NZ Finnish and Variant Late Infantile Batten Disease David...
-
Upload
mariah-carroll -
Category
Documents
-
view
215 -
download
1
Transcript of 1 Batten animal research Network :Lincoln NZ Finnish and Variant Late Infantile Batten Disease David...
No Slide Title
1Batten animal research Network :Lincoln NZ Finnish and Variant Late Infantile Batten DiseaseDavid Palmer, Lucy Barry, Hannah Lee, Nadia Mitchell, Janet Xu, Jarol Chen, Huibing Jiang, Stephanie Hughes, Hollie PeacockFaculty of Agriculture and Life Sciences, Lincoln University; Department of Biochemistry, Otago University, New Zealand. Email: [email protected] 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
FeaturesModels 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 diseaseCLN5CLN6
BDSRA 20122Current Key Projects3What this means For Therapy
Neuroinflammation and Drug Therapy
Vectors and Gene InjectionsBiomarkers of Disease ProgressWe are working, in collaboration, on a number of different therapeutic strategies
Gene TherapiesOur 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 geneSpecific areas of extended neurogenesis are targeted
Anti-inflammatory TherapiesMapping the neuroinflammatory pathways will indicate potential drugs and target sites
Drug TherapiesWe 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 bestAcknowledgements: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 cmNeuroinflammation: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 CLN6Research 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 protocolsCollaboration: Dr SM Hughes, University of Otago
Ready for definitive gene lentiviral therapy trials and to test AAV derived vectorsDeveloping biomarkers for assessing the efficacy of therapies
CT scanningnon-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 testingAssessment of vision and neurological function Led by Prof AJ Morton, University of Cambridge
introduction
Pre-symptomatic microglial activation12 days after birth
Subventricular zone in 2 year affected, PSA-NCAMControlNewly generated neurons
Clearance of storage bodiesGene expression in the sheep brain one year after injection
Brain volume changes in chimeric sheep compared to affected and normalNormalAffected