1. Targeting STMN2 for neuroprotection and neuromuscular recovery in Spinal Muscular Atrophy: evidence from in vitro and in vivo SMA models.
- Author
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Pagliari E, Taiana M, Manzini P, Sali L, Quetti L, Bertolasi L, Oldoni S, Melzi V, Comi G, Corti S, Nizzardo M, and Rizzo F
- Subjects
- Animals, Humans, Mice, Neuromuscular Junction metabolism, Neuromuscular Junction pathology, Neuroprotection, Dependovirus genetics, Genetic Therapy methods, Stathmin metabolism, Stathmin genetics, Muscular Atrophy, Spinal therapy, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal pathology, Muscular Atrophy, Spinal metabolism, Disease Models, Animal, Motor Neurons metabolism, Motor Neurons pathology, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology
- Abstract
The development of ground-breaking Survival Motor Neuron (SMN) replacement strategies has revolutionized the field of Spinal Muscular Atrophy (SMA) research. However, the limitations of these therapies have now become evident, highlighting the need for the development of complementary targets beyond SMN replacement. To address these challenges, here we explored, in in vitro and in vivo disease models, Stathmin-2 (STMN2), a neuronal microtubule regulator implicated in neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), as a novel SMN-independent target for SMA therapy. Our findings revealed that STMN2 overexpression effectively restored axonal growth and outgrowth defects in induced pluripotent stem cell-(iPSC)-derived motor neurons (MNs) from SMA patients. Intracerebroventricular administration of adeno-associated virus serotype 9 (AAV9) carrying Stmn2 cDNA significantly ameliorated survival rates, motor functions, muscular and neuromuscular junction pathological features in SMA mice, mirrored by in vitro outcomes. Overall, this pioneering study not only provides insight into the therapeutic potential of STMN2 in SMA, but also suggests its broader applications for MN diseases, marking a substantial step forward in addressing the multifaceted challenges of neurological diseases treatment., Competing Interests: Declarations. Ethical approval: All animal experiments strictly follow the guidelines of the Italian Ministry of Health in compliance with U.S. National Institutes of Health Guide for the Care and Use of Laboratory Animals (718/2022). Consent for publication: All the authors have approved and agreed to publish this manuscript. Conflict of interest: The authors declare that they have no conflicts of interest., (© 2024. The Author(s).)
- Published
- 2024
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