Document Type
Article
Publication Date
6-5-2024
Journal / Book Title
Molecular Therapy
Abstract
Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression. AAV-associated dendritic loss is accompanied by a decrease in the frequency and amplitude of miniature excitatory postsynaptic currents and an increase in the proportion of GluA2-lacking, calcium-permeable AMPA receptors. The AAV genome is rich in unmethylated CpG DNA, which is recognized by the innate immunoreceptor Toll-like receptor 9 (TLR9), and acutely blocking TLR9 preserves dendritic complexity and AMPA receptor subunit composition in AAV-injected mice. These results reveal unexpected impacts of an immune response to the AAV genome on neuronal structure and function and identify approaches to improve the safety and efficacy of AAV-mediated gene delivery in the nervous system.
DOI
10.1016/j.ymthe.2024.03.036
Montclair State University Digital Commons Citation
Suriano, Christos M.; Kumar, Neerav; Verpeut, Jessica L.; Ma, Jie; Jung, Caroline; Dunn, Connor E.; Carvajal, Brigett V.; Nguyen, Ai Vy; and Boulanger, Lisa M., "An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission" (2024). Department of Biology Faculty Scholarship and Creative Works. 538.
https://digitalcommons.montclair.edu/biology-facpubs/538
Rights
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Published Citation
Suriano, C. M., Kumar, N., Verpeut, J. L., Ma, J., Jung, C., Dunn, C. E., Carvajal, B. V., Nguyen, A. V., & Boulanger, L. M. (2024). An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission. Molecular therapy : the journal of the American Society of Gene Therapy, 32(6), 1721–1738.