Transcript No Slide Title

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]
CURRENT KEY PROJECTS
INTRODUCTION
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
1
Neuroinflammation
and Drug Therapy
Neuroinflammation:
 First discovered to be
associated with NCLs in the
CLN6 sheep
 Begins prenatally and
spreads
Pre-symptomatic microglial activation
12 days after birth
2
Vectors and Gene
Injections
Research findings:
 A zone of extended
neurogenesis was found
and identified as a key
target site for gene
injections
Newly
generated
neurons
3
Biomarkers of
Disease Progress
 Developing biomarkers for
assessing the efficacy of
therapies
CT scanning
 non-invasive measurement
of brain volume changes
during disease progression
Normal
Control
Subventricular zone in 2 year affected, PSA-NCAM
 Was not suppressed by
treatment with the antiinflammatory drug,
minocycline
 Chimeric studies showed
that correcting only some
cells is all that is required
Affected
Brain volume changes in chimeric sheep
compared to affected and normal
 The inflammation
cascade is complex!
Clearance of storage bodies
 Have developed lentiviral
vectors and successful
injection protocols
Social networking
 GPS monitoring to analyse
changes in animal
behaviour and social
interaction
Led by Prof AJ Morton, University of Cambridge
Collaboration: Dr SM Hughes, University of Otago
 The sheep are economic
and easy to maintain in our
environment
 Samples are available from
birth through to end stage
disease
 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
WHAT THIS MEANS
FOR THERAPY
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
1 cm
It is likely a combination of
therapies will prove best
Gene expression in the sheep brain
one year after injection
Ready for definitive gene
lentiviral therapy trials and to
test AAV derived vectors
Vision and maze testing
 Assessment of vision and
neurological function
Led by Prof AJ Morton, University of Cambridge
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).