Cis-regulatory elements driving motor neuron-selective viral payload expression within the mammalian spinal cord
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.
Authors
- Shih‐Ching Lo (ORCID: https://orcid.org/0000-0002-5187-0730)
- Stanley Gill (ORCID: https://orcid.org/0000-0001-5430-4550)
- Junghae Suh (ORCID: https://orcid.org/0000-0001-9280-9031)
- Kristina Wang (ORCID: https://orcid.org/0000-0002-5442-3071)
- Robin J. Kleiman (ORCID: https://orcid.org/0000-0002-9415-7433)
- Christopher Henderson (ORCID: https://orcid.org/0000-0002-5291-5742)
- Michael E. Greenberg (ORCID: https://orcid.org/0000-0003-1380-2160)
- Siniša Hrvatin (ORCID: https://orcid.org/0000-0001-7303-4218)
- Spencer Price
- Lorna Jayne
- Erika Ren (ORCID: https://orcid.org/0009-0009-7861-1139)
- Bin Liu (ORCID: https://orcid.org/0000-0003-2184-4723)
- Eric C. Griffith (ORCID: https://orcid.org/0000-0003-0428-3215)
- Xiaodong Lü (ORCID: https://orcid.org/0000-0003-0144-2639)
- M. Aurel Nagy (ORCID: https://orcid.org/0000-0003-4608-1152)
- Victoria Pajak
- Sarah Deighan
- Aïssatou Bailo Diallo (ORCID: https://orcid.org/0000-0002-9011-9069)
Institutions
- Biogen (United States) (US)
- Harvard University (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Harvard Stem Cell Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1073/pnas.2418024121
- Citations
- 5
- Primary Topic
- Neurogenetic and Muscular Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 2.19
Funders
- Foundation for the National Institutes of Health
- Biogen
- National Institutes of Health