RT Journal Article SR Electronic T1 Physical positioning markedly enhances brain transduction after intrathecal AAV9 infusion JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaau9859 DO 10.1126/sciadv.aau9859 VO 4 IS 11 A1 Castle, Michael J. A1 Cheng, Yuhsiang A1 Asokan, Aravind A1 Tuszynski, Mark H. YR 2018 UL http://advances.sciencemag.org/content/4/11/eaau9859.abstract AB Several neurological disorders may benefit from gene therapy. However, even when using the lead vector candidate for intrathecal administration, adeno-associated virus serotype 9 (AAV9), the strength and distribution of gene transfer to the brain are inconsistent. On the basis of preliminary observations that standard intrathecal AAV9 infusions predominantly drive reporter gene expression in brain regions where gravity might cause cerebrospinal fluid to settle, we tested the hypothesis that counteracting vector “settling” through animal positioning would enhance vector delivery to the brain. When rats are either inverted in the Trendelenburg position or continuously rotated after intrathecal AAV9 infusion, we find (i) a significant 15-fold increase in the number of transduced neurons, (ii) a marked increase in gene delivery to cortical regions, and (iii) superior animal-to-animal consistency of gene expression. Entorhinal, prefrontal, frontal, parietal, hippocampal, limbic, and basal forebrain neurons are extensively transduced: 95% of transduced cells are neurons, and greater than 70% are excitatory. These findings provide a novel and simple method for broad gene delivery to the cortex and are of substantial relevance to translational programs for neurological disorders, including Alzheimer’s disease and related dementias, stroke, and traumatic brain injury.