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2014 BDSRA Palmer CLN 5 and CLN 6

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2014 BDSRA Palmer CLN 5 and CLN 6

  1. 1. Batten Animal Research NNeettwwoorrkk ((BBAARRNN)):: VVaarriiaanntt IInnffaannttiillee BBaatttteenn DDiisseeaassee  BARN is an international collaboration set up to coordinate studies of animal models of Batten disease.  We share resources, experiments and grants, exchange students, visit each other and plan together. WHAT THIS MEANS FOR THERAPY Increasing understanding of the normal function of NCL proteins will increase the likelihood of successful drug development. Gene therapy using AAV vectors for CLN5 and CLN6 sheep are in progress. Sheep were treated at 2-3 months of age (Nov/Dec 2013). Analysis of disease progression using the biomarker tests we have developed is ongoing. BARN has shown the benefits of collaboration with increased research outputs, sharing of resources and funding, increased student opportunities and two-way information sharing with parent groups. People: Professor David Palmer, PhD students, Nadia Mitchell Janet Xu, Jarol Chen, Katharina Russell and our invaluable animal technicians. Focus: Disease mechanisms and developing therapies, gene injections, biomarkers, neuroinflammation, providing neural cell cultures Resources: CLN5 affected Borderdales and CLN6 affected South Hampshire sheep. david.palmer@lincoln.ac.nz People: Dr. Stephanie Hughes, PhD students Nicole Neverman and Hannah Best, Hollie Wicky, Dr. Lucia Schoderböck and Kristina McIntyre Focus: Gene therapy vectors for sheep gene therapy trials. Modelling pathology of Batten disease in neuronal cultures and the effectiveness of drug and gene therapies. Understanding how the disease-causing mutations affect the biology of neurons. Resources: Vector development and neural culture expertise stephanie.hughes@otago.ac.nz People: Associate Professor Imke Tammen, PhD student, Izmira Mohd Ismail, technical support, and Sydney U veterinary staff Focus: Molecular characterisation of animal models for NCLs, disease progression and behaviour studies of the affected Merino flock Resources: CLN6 affected Merino sheep and genetics laboratory imke.tammen@sydney.edu.au> Collaborators: Professor Sir John Walker, Mitochondrial Biology Unit, MRC, Cambridge, Professor Jenny Morton, Cambridge University and Professor Jon Cooper, Kings College, London; and their colleagues KEY RECENT RESEARCH Neuronal cultures from both CLN5 and CLN6 sheep models are showing us the very early stages of disease, and suggesting potential drug targets to halt these. These cells are being used to understand the normal function of CLN5 and CLN6 proteins and to rapidly screen drug and gene therapies. Measures of disease progression (biomarkers) such as behavioral and sight testing, CT and MRI scanning and inflammatory markers have been developed. These biomarkers are being used in our gene and drug therapy trials to access their effectiveness. The mutations in the two sheep CLN6 forms and the CLN5 form have been identified, and the effects of these mutations on protein function studied in neuronal culture and sheep tissues. Analysis of the neuroinflammatory cascade during disease development aim to identify new drug targets. GENE THERAPY TRIALS IN CLN5 AND CLN6 DISEASE Previous lentiviral gene therapy trials showed limited effect due to the small spread of the viral vector. Adeno-associated virus (AAV) tests in sheep show significant spread of gene products throughout the brain (brown staining in figure). BARN TEAMS

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