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Harnessing rAAV-retro for gene manipulations in multiple pathways that are interrupted after spinal cord injury.
- Source :
-
Experimental neurology [Exp Neurol] 2022 Apr; Vol. 350, pp. 113965. Date of Electronic Publication: 2021 Dec 30. - Publication Year :
- 2022
-
Abstract
- This paper explores the potential of rAAV2-retro to deliver gene modifying cargoes to the cells of origin of multiple pathways that are interrupted by spinal cord injury (SCI), summarizing data from previous studies and new data from additional experiments. rAAV-retro exhibits uniquely robust and reliable long-distance retrograde transport from pre-terminal axons and synapses back to neuronal bodies. Previous studies have documented that various AAV-based genetic modifications can enable axon regeneration after SCI, but these have targeted the cells of origin of one pathway at a time. In contrast, rAAV-retro can simultaneously transduce large numbers of neurons of origin of multiple spinal pathways with single injections into the spinal cord. Our initial studies use Rosa <superscript>tdTomato</superscript> and double transgenic PTEN <superscript>f/f</superscript> ; Rosa <superscript>tdTomato</superscript> mice in which transfection with rAAV-retro/Cre deletes PTEN and activates tdT expression in the same neurons. Injections of rAAV-retro/Cre into the cervical, thoracic and lumbar spinal cord led to topographically specific retrograde transduction in cortical motoneurons and neurons in subcortical regions that give rise to different spinal pathways. Our results confirm and extend previous studies indicating selective transduction of neurons that terminate at the level of the injection with minimal retrograde transduction of axons in transit to lower levels. We document feasibility of using rAAV-retro expressing shRNA against PTEN along with a GFP reporter (rAAV-retro-shPTEN/GFP) to effectively knock down PTEN in multiple populations of neurons, which can be used in any species. Some limitations and caveats of currently available rAAV-retros are discussed. Together, our results support the potential applications of rAAV-retro for AAV-based gene-modifications for SCI.<br /> (Copyright © 2021. Published by Elsevier Inc.)
- Subjects :
- Animals
Axons
Female
Humans
Male
Mice
Mice, Knockout
Mice, Transgenic
Nerve Regeneration genetics
Neural Pathways injuries
PTEN Phosphohydrolase genetics
RNA, Small Interfering genetics
Rats
Rats, Sprague-Dawley
Genetic Therapy methods
Genetic Vectors genetics
Neural Pathways growth & development
Spinal Cord Injuries therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2430
- Volume :
- 350
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 34973965
- Full Text :
- https://doi.org/10.1016/j.expneurol.2021.113965