Cis- regulatory elements driving motor neuron- selective viral payload expression within the mammalian spinal cord

• 成果类型: Article
• 署名作者: Nagy, M. Aurel; Price, Spencer; Wang, Kristina; Gill, Stanley; Ren, Erika; Jayne, Lorna; Pajak, Victoria; Deighan, Sarah; Liu, Bin; Lu, Xiaodong; Diallo, Aissatou; Lo, Shih-Ching; Kleiman, Robin; Henderson, Christopher; Suh, Junghae; Griffith, Eric C.; Greenberg, Michael E.; Hrvatin, Sinisa
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University; Biogen; University of California System; University of California San Francisco; Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9264
• DOI: 10.1073/pnas.2418024121
• 发表日期: 2024-12-03
• 关键词: adenoassociated virus; gene delivery; cortical-neurons; therapy; brain

摘要

Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN- related disorders, there are no viral delivery mechanisms that achieve MN- restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis- regulatory elements (CREs) capable of driving MN- selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN- selective gene expression in the spinal cord as well as reduced off- target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)- binding region that drives MN- selective gene expression. Finally, we demonstrated that selective spinal cord expression driven by this mouse CRE is preserved in non- human primates. These findings suggest that cell- type- selective viral reagents in which cell- type- selective CREs drive restricted gene expression will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans.