BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

Department of Molecular Animal Physiology Donders Institute for Brain Cognition and Behaviour Centre for Neuroscience Faculty of Science Radboud University Nijmegen The Netherlands

Department of Neurosurgery St Anne's University Hospital Brno Czech Republic

Department of Research and Development uniQure Biopharma B 5 Amsterdam The Netherlands

Department of Stereotactic Radioneurosurgery Na Homolce Hospital Prague Czech Republic

Institute of Animal Physiology and Genetics Libechov Czech Republic

Interventional Cardiac Electrophysiology St ' Anne's University Hospital Brno Czech Republic

Renishaw Neuro Solutions ltd Renishaw plc Gloucestershire UK

Small Animal Clinic Veterinary and Pharmaceutical University Brno Czech Republic

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$a Pietersz, K L $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, The Netherlands; Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Faculty of Science, Radboud University, Nijmegen, The Netherlands

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$a Transduction profiles in minipig following MRI guided delivery of AAV-5 into thalamic and corona radiata areas / $c KL. Pietersz, S. Pouw, J. Klima, Z. Ellederova, B. Bohuslavova, J. Chrastina, R. Liscak, D. Urgosik, Z. Starek, M. Crha, O. Lewis, M. Wooley, D. Johnson, CC. Brouwers, M. Evers, J. Motlik, GJM. Martens, PS. Konstantinova, B. Blits

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$a BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

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