THERAPEUTIC POTENTIAL OF INTRATHECAL APPLICATION OF miR-124-BASED SECRETOME IN THE SOD1 G93A MOUSE MODEL OF AMYOTROPHIC LATERAL SCLEROSIS
Year: 2022
Type: dissertation
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no effective cure and a short life expectancy, characterized by the degeneration of motor neurons (MNs) and glial cell dysfunction. Inflammatory(inflamma)-associated microRNAs (miRNAs/miRs) were found dysreg- ulated in SOD1 G93A (mSOD1) mouse models, as well as in mSOD1 MNs and microglia, and their secre- tome. Prior studies from our lab detected upregulated levels of miR-124 in mSOD1 NSC-34-MN-like cells and demonstrated its association with their degeneration, including mitochondrial dysfunction and axonal/synaptic dysregulation, together with glial activation. Interestingly, the treatment with anti-miR- 124 in mSOD1 MNs prevented their impairment. Furthermore, our group showed that the secretome derived from these modulated mSOD1 MNs (preconditioned secretome) counteracted pathological fea- tures and neuro-immune homeostatic imbalance in spinal cord organotypic cultures from early sympto- matic mSOD1 mice. This issue was never explored in the in vivo model of ALS, though recent evidence sustains that cell secretomes may have therapeutic effects. To decipher the potential therapeutic benefits of such preconditioned secretome, our group performed its intrathecal injection in the mSOD1 mice at the early symptomatic stage of the disease (12-week-old). Notably, this preconditioned secretome pre- vented the glial reactivity/dysfunction, neurodegeneration, and the altered inflammatory-dynamic bal- ance of the 15-week-old symptomatic mSOD1 mice. At the molecular level, the injection of this engi- neered secretome enhanced NeuN mRNA/protein expression levels and the Dlg4/Mbp/Plp/Trem2/Arg1/Inos/Il-10 genes, thus precluding the neuronal/glial cell dysregulation that characterizes the ALS mice. The upregulated GFAP/Cx43/S100B/Iba-1 and the inflamma-associated miRNAs (miR-146a/miR-155/miR-21) displayed by the symptomatic mSOD1 mice were also pre- vented. Overall, this study highlights the intrathecal administration of the anti-miR-124-treated mSOD1 MN preconditioned secretome as a promising cell-free based therapeutic strategy to halt/delay disease progression in the ALS mouse model, supporting its translation potential into the ALS patient as a per- sonalized and autologous treatment.
Author: Santos, Marta Alexandra Marques dos
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6987589318