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In vitro evaluation of the effect of extracellular vesicles derived from Mesenchymal Stem Cells (MSCs) genetically modified to overexpress IGF-1 on neurite growth after oxidative stress

Grant number: 23/13879-2
Support Opportunities:Scholarships in Brazil - Program to Stimulate Scientific Vocations
Effective date (Start): January 12, 2024
Effective date (End): March 02, 2024
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Milena Botelho Pereira Soares
Grantee:Ytalo Pau-Ferro Duarte
Host Institution: Centro de Pesquisas Gonçalo Moniz. Fundação Oswaldo Cruz (Fiocruz). Ministério da Saúde (Brasil). Salvador , SP, Brazil

Abstract

Spinal cord injury (SCI) refers to damage to the spinal cord and has devastating consequences for the physical, financial, and psychosocial well-being of patients. Clinical complications include loss of mobility, urinary, sexual and reproductive dysfunction, spasticity, loss of sensation, and paradoxically, neuropathic pain. Pain significantly impacts the health status and quality of life of these patients, considering not only its severity and duration but also its refractory profile to pharmacological treatment. Treatment for SCI includes surgery, palliative pharmacological therapies, and rehabilitation, which only induce modest clinical improvements. In this context, our research group has demonstrated over the past decade, both in experimental and clinical conditions, the therapeutic potential of mesenchymal stem cells (MSCs) in spinal cord injury and neuropathic pain. In one of our previously published studies, using an experimental SCI model, it was observed that genetically modified MSCs to overexpress insulin-like growth factor-1 (IGF-1) - a cytokine involved in neural development and lesion repair - promoted an increase in the expression of antioxidant genes and protected against myelin loss. Advances in the field of cell therapy indicate that extracellular vesicles (EVs) derived from MSCs (MSC-EVs) preserve the therapeutic properties of these cells. The therapeutic use of EVs circumvents the risks and limitations associated with live cell therapies and has an intrinsic profile for the development of therapeutic products. However, the development of products based on MSC-EVs requires overcoming obstacles such as low yield and production under xeno-free and GMP (Good Manufacturing Practices) conditions. Based on the above, the present proposal was outlined to develop an off-the-shelf therapeutic product based on human MSC-EVs, produced on an optimized scale and under xeno-free and GMP conditions, investigate its stability profile, and validate its preclinical therapeutic properties in spinal cord injury and neuropathic pain. Simultaneously, experimental studies (in vitro and in vivo) will be conducted to assess the therapeutic potential of EVs derived from genetically modified MSCs to overexpress cytokines. Data from this project could be applied to the generation of an allogeneic advanced cell therapy product, providing an innovative therapeutic approach for the treatment of patients with refractory spinal cord injury and neuropathic pain. (AU)

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