Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice
5 affiliations
- 1Laboratory Animal Center, Fudan University, Shanghai 200433, China
- 2Laboratory Animal Resource Center, Fudan University, Shanghai 200433, China
- 3School of Life Sciences, Fudan University, Shanghai 200438, China
- 4Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
- 5Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
Abstract
Amyotrophic lateral sclerosis (ALS) kills within a few years of onset, and the drugs licensed for treatment change that course only marginally. Silencing SOD1 has become a credible treatment route, but two gaps hold this approach back: an efficient vector platform for spinal cord transduction with limited peripheral transduction and evidence on whether adding neurotrophic support to gene silencing has any effect. We built an rAAV2-retro platform for intrathecal delivery. One intrathecal dose of an eGFP-expressing vector transduced all spinal cord segments and several brain regions, with a clear preference for spinal motor neurons and low expression in the liver and heart. Side by side in adult mice, we then used this platform to compare miRNA-mediated silencing of human SOD1, overexpression of IGF1, and the two together in SOD1G93A animals. A single injection of rAAV2-retro carrying an anti-hSOD1 miRNA extended median survival by 25 days, improved motor performance, protected neuromuscular junctions, spared α-motor neurons, and damped gliosis and apoptosis. IGF1 on its own also lengthened survival and limited neuronal loss, but it left motor performance unchanged. The benefit of IGF1 over miRNA alone was observed on most endpoints under the conditions tested; a modest, nominally significant improvement in hindlimb clasping was observed, which should be interpreted as exploratory given the number of comparisons performed. Silencing of hSOD1 therefore accounts for most of the benefit, and no statistically detectable additional benefit was observed for IGF1 on top of hSOD1 silencing under the conditions tested. A single intrathecal dose of rAAV2-retro-miRNA is thus an effective gene silencing approach in the SOD1G93A mouse model, with limited peripheral transduction in the liver and heart observed in C57BL/6J mice. However, these data also show the difficulty of achieving additional benefit by adding IGF1 under the conditions tested.
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BibTeX
@article{gong2026singledose,
title = {{Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice}},
author = {Xueqi Gong and Hao Wei and Lang Shen and Qin Wang and Jiayi Wu and Wenyuan Wang and Tonghui Xu},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15201890},
url = {https://www.mdpi.com/2073-4409/15/20/1890},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice
AU - Xueqi Gong
AU - Hao Wei
AU - Lang Shen
AU - Qin Wang
AU - Jiayi Wu
AU - Wenyuan Wang
AU - Tonghui Xu
PY - 2026
DA - 2026/10/16
JO - Cells
DO - 10.3390/cells15201890
UR - https://www.mdpi.com/2073-4409/15/20/1890
AB - Amyotrophic lateral sclerosis (ALS) kills within a few years of onset, and the drugs licensed for treatment change that course only marginally. Silencing SOD1 has become a credible treatment route, but two gaps hold this approach back: an efficient vector platform for spinal cord transduction with limited peripheral transduction and evidence on whether adding neurotrophic support to gene silencing has any effect. We built an rAAV2-retro platform for intrathecal delivery. One intrathecal dose of an eGFP-expressing vector transduced all spinal cord segments and several brain regions, with a clear preference for spinal motor neurons and low expression in the liver and heart. Side by side in adult mice, we then used this platform to compare miRNA-mediated silencing of human SOD1, overexpression of IGF1, and the two together in SOD1G93A animals. A single injection of rAAV2-retro carrying an anti-hSOD1 miRNA extended median survival by 25 days, improved motor performance, protected neuromuscular junctions, spared α-motor neurons, and damped gliosis and apoptosis. IGF1 on its own also lengthened survival and limited neuronal loss, but it left motor performance unchanged. The benefit of IGF1 over miRNA alone was observed on most endpoints under the conditions tested; a modest, nominally significant improvement in hindlimb clasping was observed, which should be interpreted as exploratory given the number of comparisons performed. Silencing of hSOD1 therefore accounts for most of the benefit, and no statistically detectable additional benefit was observed for IGF1 on top of hSOD1 silencing under the conditions tested. A single intrathecal dose of rAAV2-retro-miRNA is thus an effective gene silencing approach in the SOD1G93A mouse model, with limited peripheral transduction in the liver and heart observed in C57BL/6J mice. However, these data also show the difficulty of achieving additional benefit by adding IGF1 under the conditions tested.
SN - 2073-4409
ER -