Home » Seminars » Cell Therapy for Parkinson’s disease using Carotid Body as a source of GDNF: pros and cons of the coronavirus pandemic

Cell Therapy for Parkinson’s disease using Carotid Body as a source of GDNF: pros and cons of the coronavirus pandemic

Juan José Toledo Aral

Universidad de Sevilla (Spain)

26 May 2023 13:00

Aketxe Room, Sede Building, Leioa

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Intrastriatal carotid body (CB) grafts produce trophic protection and restoration of the dopaminergic nigrostriatal pathway in rodent and primate models of Parkinson’s disease (PD), which is mediated by high levels of glial cell line-derived neurotrophic factor (GDNF) produced by CB implants. Phase I/II open trials showed that CB autotrasplantation improve motor symptoms in PD patients. However, the efficiency of CB cell therapy observed in clinical trials is lower than in experimental models, being patient age one of the factors influencing the clinical outcome. To explore limiting factors that affect the efficacy of human CB transplants, we have studied how aging and chronic hypoxia present in intracerebral grafts can modify CB GDNF expression. Chronic hypoxia induced an up-regulation of CB GDNF expression in young mice, while the same treatment in aged mice decreased CB GDNF expression. This age-related differential regulation of GDNF is also present in the intrastriatal graft and affects the efficacy of mice antiparkinsonian CB cell therapy. Moreover, human CB xenografts from young (≤40 years) donors induced an important protection of the nigrostriatal dopaminergic neurons of parkinsonian mice, while CB implants from aged (≥60 years) donors failed to produce a significant effect. Finally, we performed a study of the methylation status of human and murine GDNF promoter from young and aged CBs, identifying hypoxia-related regions that could explain the differential regulation of GDNF expression. These findings provide a molecular explanation of the outcome of previous clinical trials and offer insights for the design of new antiparkinsonian cell therapy treatments.

As a consequence of the coronavirus pandemic, experiments with human samples had to be stopped. The fact that the CB expressed the ACE2 receptor led us to study the protective efficacy of vaccines against SARS-CoV-2 infection in the brain. In the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important pathological alterations such as neuronal loss, incipient signs of glial activation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection.

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