NICO-Webinar: "Targeting pathogenic β6/β7-loop epitope of misfolded SOD1 - a potential therapeutic strategy for ALS" 10/11/22 h. @ 2:00 pm
Stas Engel, Ben-Gurion University of the Negev, Israel
Targeting pathogenic β6/β7-loop epitope of misfolded SOD1 - a potential therapeutic strategy for ALS
The current strategy to mitigate the toxicity of misfolded SOD1 in familial ALS is by blocking SOD1 expression in the CNS. Being indiscriminative toward misfolded and intact SOD1 proteins, such treatment, however, entails a risk of depriving the CNS cells of their essential antioxidant potential. We developed scFv-SE21 intrabody to block the β6/β7 loop epitope exposed exclusively in misfolded SOD1, as an alternative approach to neutralize misfolded SOD1 species and spare unaffected SOD1 proteins. ScFv-SE21 expression in the CNS of hSOD1G37R mice rescued spinal motoneurons, reduced the accumulation of misfolded SOD1, decreased gliosis, and thus delayed disease onset and extended survival by 90 days. Our results provide evidence that the exposure of the β6/β7 loop epitope is part of the pathogenic mechanism of misfolded SOD1, and raise the possibility that its blocking may constitute a novel therapeutic approach for ALS, with a reduced risk of collateral oxidative damage to the CNS.
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