AAV viral vector delivery to the brain by shape-conforming MR-guided infusions Krystof S. Bankiewicz ⁎, Vivek Sudhakar, Lluis Samaranch, Waldy San Sebastian, John Bringas, John Forsayeth Interventional Neuro Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94110, USA abstract article info Article history: Received 23 September 2015 Received in revised form 17 February 2016 Accepted 22 February 2016 Available online xxxx Gene transfer technology offers great promise as a potential therapeutic approach to the brain but has to be viewed as a very complex technology. Success of ongoing clinical gene therapy trials depends on many factors such as selection of the correct genetic and anatomical target in the brain. In addition, selection of the viral vector capable of transfer of therapeutic gene into target cells, along with long-term expression that avoids immunotoxicity has to be established. As with any drug development strategy, delivery of gene therapy has to be consistent and predictable in each study subject. Failed drug and vector delivery will lead to failed clinical tri- als. In this article, we describe our experience with AAV viral vector delivery system, that allows us to optimize and monitor in real time viral vector administration into affected regions of the brain. In addition to discussing MRI-guided technology for administration of AAV vectors we have developed and now employ in current clinical trials, we also describe ways in which infusion cannula design and stereotactic trajectory may be used to maxi- mize the anatomical coverage by using fluid backflow. This innovative approach enables more precise coverage by fitting the shape of the infusion to the shape of the anatomical target. © 2016 Elsevier B.V. All rights reserved. Keywords: Brain delivery Adeno-associated virus Axonal transport Gene therapy Clinical trial Pre-clinical research MRI Shape fitting 1. Introduction Central nervous system (CNS) drug discovery along with drug devel- opment are seen as one of the most challenging areas of pharmaceutical development. Pharmaceuticals for neurological diseases are frequently plagued by poor efficacy and serious side effects. Accordingly, the intro- duction of first-in-class neurological medications has become infrequent. More than any other factor, the conflicting roles of a given drug target in one brain region versus another make finding a balance between efficacy and safety extremely difficult. Thinking of the brain as a single functional entity, therefore, may not be the best way to affect optimal therapeutic outcomes. We have focused for many years on ad- vancing the technology of local delivery of genes and drugs to affected regions of the brain (and brain tumors) to treat disease. Particularly in the past 5 years, we have brought into the clinic an infusion technology in which intra-operative MRI is used to guide cannula placement and to monitor infusate distribution. The potential flexibility and power of this approach permit to achieve specificity through anatomical localization while minimizing off target effects. Gene therapy is potentially an excellent way to deliver therapeutic agents directly to the human brain using the adeno-associated virus (AAV). However, there are various aspects of AAV-based gene therapy that present significant challenges as identified below. AAV vectors are classified into serotypes based on their capsid sequence. Our studies have focused on AAV2 for clinical development because it is neuron-specific, offers essentially permanent expression [1], and has been used in more patients than any other vector [2,3]. AAV2 is subject to anterograde axonal transport in the brain. When infused into the thalamus, for example, neurons in brain regions that re- ceive thalamic projections, like cortex, are abundantly transduced [4]. In contrast, AAV6 is transported in an entirely retrograde direction [5,6] and AAV9 appears to be bidirectional (in press). While it is clear that Journal of Controlled Release xxx (2016) xxx–xxx Abbreviations: 16-G, 16-gauge; 3D, three-dimensional; 6-OHDA, 6- hydroxydopamine; AAV, adeno-associated virus; AD, Alzheimer's disease; CED, convection enhanced delivery; cGMP, current Good Manufacturing Practice; CN, caudate nucleus; CNS, central nervous system; CsCl, caesium chloride; DA, dopamine; FDA, Food and Drug Administration; FDG PET, fluorodeoxyglucose positron emission tomography; GABA, gamma-amino butyric acid; GAD, glutamic acid decarboxylase; GCH-I, cyclohydrolase I; GDNF, glial cell-derived neurotrophic factor; GFP, green fluorescent pro- tein; hAADC, human aromatic L-amino acid decarboxylase; HD, Huntington's disease; min, minute; mm, millimeter; MP-RAGE, magnetization prepared rapid acquisition gradient recalled echo; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MR, magnetic reso- nance; MRI, magnetic resonance imaging; MSA, multiple system atrophy; NE, norepineph- rine; NHP, non-human primate; NIH, National Institutes of Health; NTN, neurturin; OD, outer diameter; PD, Parkinson's disease; PDQ-39, 39-item Parkinson's disease question- naire; PUT, putamen; SNpc, substantia nigra pars compacta; STN, sub thalamic nucleus; TH, tyrosine hydroxylase; UCSF, University of California San Francisco; UPDRS, Unified Parkinson's Disease Rating Scale; VTA, ventral tegmental area. ⁎ Corresponding author at: Department of Neurosurgery, University of California San Francisco, 1855 Folsom Street, MCB, Room 226, San Francisco, CA 94103, USA. E-mail address: Krystof.Bankiewicz@ucsf.edu (K.S. Bankiewicz). COREL-08147; No of Pages 9 http://dx.doi.org/10.1016/j.jconrel.2016.02.034 0168-3659/© 2016 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel Please cite this article as: K.S. Bankiewicz, et al., AAV viral vector delivery to the brain by shape-conforming MR-guided infusions, J. Control. Re- lease (2016), http://dx.doi.org/10.1016/j.jconrel.2016.02.034