Blocking an epitope of misfolded SOD1 ameliorates disease phenotype in a model of amyotrophic lateral sclerosis

Shamchal Bakavayev, Alexandra Stavsky, Shirel Argueti-Ostrovsky, Galit Yehezkel, Yael Fridmann-Sirkis, Zeev Barak, Daniel Gitler, Adrian Israelson, Stanislav Engel

Research output: Contribution to journalArticlepeer-review


The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.

Original languageAmerican English
Pages (from-to)4594-4607
Number of pages14
JournalBrain : a journal of neurology
Issue number11
Early online date3 Jul 2023
StatePublished - 1 Nov 2023


  • AAV vector
  • ALS
  • SOD1
  • ScFv
  • intrabody

All Science Journal Classification (ASJC) codes

  • Clinical Neurology


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