Neuroprotection and Neuromuscular Preservation in ALS: Therapeutic Potential of Umbilical Cord Blood Plasma-Derived Extracellular Vesicles and the Antioxidant Tempol

• Grant number: 25/07521-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2025
• End date: June 30, 2028
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Alexandre Leite Rodrigues de Oliveira
• Grantee: Ana Laura Midori Rossi Tomiyama
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 23/02615-4 - New frontiers in nerve regeneration: combining surgical, pharmacological and 3D bioprinting approaches, AP.TEM

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by muscle weakness, slurred speech, and dysphagia, leading to atrophy and paralysis. It involves more than 20 gene mutations, with C9orf72, SOD1, and TARDBP being the most prevalent. Late onset hinders early diagnosis, as symptoms only appear after approximately 40% of motor neurons are lost. In addition to neurodegeneration, ALS is described as a distal axonopathy since alterations at the neuromuscular junction (NMJ) precede neuronal degeneration. Current treatments are limited, merely slowing disease progression. In this context, cell therapy is explored for its potential neuroprotective effects but faces challenges such as immune rejection and low cell survival. Alternatively, extracellular vesicles (EVs) derived from stem cells emerge as a promising strategy, offering therapeutic benefits without the risks of cell transplantation. Studies in SOD1G93A models indicate that EVs improve motor function, preserve lumbar motor neurons, and reduce glial activation. This study will investigate the effects of stem cell-derived EVs from umbilical cord blood plasma in the SOD1G93A transgenic model of ALS, combined with the antioxidant Tempol, which mitigates oxidative stress but has limited efficacy alone. SOD1G93A mice (n=5 males and n=5 females per group) will be treated from 90 to 120 days of age. Disease progression will be monitored through motor tests, neurological scores, and neuroelectromyography. After euthanasia, analyses will include neuronal survival, glial reactivity, synaptic modulation, MHC-I expression, myelin preservation (immunofluorescence), NMJ structure (scanning electron microscopy - serial block face), and spinal cord inflammation (flow cytometry). This approach aims to elucidate the neuroprotective and anti-inflammatory mechanisms of EVs combined with Tempol, contributing to novel therapeutic strategies for ALS.