Investigating the therapeutic potential of repurposed drugs that target central nervous system and peripheral pathologies in cellular and animal models of spinal muscular atrophy

Çetin, Özge

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the loss-of-function of the survival motor neuron (SMN) gene resulting in muscle atrophy and weakness. There are currently 3 gene-based therapies (Spinraza®, Zolgensma® and Evrysdi®) approved for the treatment of SMA. Although these treatments lead to significant life-changing and life-saving improvements, they have limitations.
Moreover, going beyond neuronal pathologies in SMA, developmental and metabolic pathologies in many peripheral tissues have been found in both SMA mouse models and patients. Our previous research has demonstrated that prednisolone, a synthetic glucocorticoid (GC), has been found to alleviate the disease SMA genotype phenotype in Smn-/-;SMN2 and Smn2B/- SMA mice. To identify commercially available drugs predicted to ameliorate peripheral pathologies and possess similar effects to prednisolone via RNA sequencing. Combined in silico analysis were used to identify commercially available drugs predicted to restore the levels of differentially expressed genes in SMA muscle and similar activity potential with prednisolone. This comprehensive in silico approach identified strong pharmacological candidates, pioglitazone, melatonin, and insulin.

Through combined in silico analyses, several target genes have been predicted: Thbs1 and Ppar-α, which could be regulated by pioglitazone; Per1, Bcl2, Sirt1, and Ror- α, potentially corrected by melatonin; and Igf1R, Rb1, and InsR, which may be regulated via insulin. First, we validated the abnormal expression of these predicted targeted genes in symptomatic skeletal muscle tissue in both SMA mouse models.
Subsequent research has stated the safety and pharmacological impact of pioglitazone, melatonin and insulin on the C2C12s and LCHN-M2 cell line. Importantly, melatonin has been observed to improve weight, lifespan, and RR (righting reflex); pioglitazone has shown positive contributions to weight and survival; and insulin has demonstrated beneficial effects on weight in Smn2B/- mouse models. Post-treatment of these candidates caused a change in expression of all these genes compared to untreated counterparts both CNS and periphery. Pioglitazone and melatonin show promise in addressing metabolic disorders by potentially enhancing glucose uptake from circulation into skeletal muscle. They may also shift metabolism towards increased ATP production by supporting mitochondrial biogenesis and function.

The perspective results highlights the complexity of SMA and the potential multifaceted approach required for effective treatment, underscoring the importance of targeting not just the primary symptoms but also the broader metabolic disturbances associated with the disease aiming to improve overall patient outcomes and quality of life.

Citation

Çetin, Ö. (2024). Investigating the therapeutic potential of repurposed drugs that target central nervous system and peripheral pathologies in cellular and animal models of spinal muscular atrophy. (Thesis). Keele University. Retrieved from https://keele-repository.worktribe.com/output/853197

• Thesis Type: Thesis
• Deposit Date: Jun 21, 2024
• Publicly Available Date: Jun 21, 2024
• Public URL: https://keele-repository.worktribe.com/output/853197
• Award Date: 2024-06