Emerging evidence suggests seeding and prion-like propagation of mutant Superoxide Dismutase 1 (SOD1) misfolding to be a potential mechanism for ALS pathogenesis and progression. Immuno-targeting of misfolded SOD1 has shown positive clinical outcomes in mutant SOD1 transgenic mice. However， a major challenge in developing active immunotherapies for proteinopathies such as ALS is the design of immunogens enabling exclusive recognition of pathogenic species of a self-protein. Ideally， one would achieve a robust antibody response against the disease-misfolded protein while sparing the natively folded conformer to avoid inducing deleterious autoimmune complications， or inhibiting its normal function. Using a ... More
Emerging evidence suggests seeding and prion-like propagation of mutant Superoxide Dismutase 1 (SOD1) misfolding to be a potential mechanism for ALS pathogenesis and progression. Immuno-targeting of misfolded SOD1 has shown positive clinical outcomes in mutant SOD1 transgenic mice. However， a major challenge in developing active immunotherapies for proteinopathies such as ALS is the design of immunogens enabling exclusive recognition of pathogenic species of a self-protein. Ideally， one would achieve a robust antibody response against the disease-misfolded protein while sparing the natively folded conformer to avoid inducing deleterious autoimmune complications， or inhibiting its normal function. Using a motor neuron disease mouse model expressing human SOD1-G37R， we herein report the immunogenicity and therapeutic efficacy of two ALS vaccines， tgG-DSE2lim and tgG-DSE5b， based on the notion that native SOD1 would undergo early unfolding in disease to present "disease specific epitopes" (DSE). Both vaccines elicited rapid， robust， and well-sustained epitope-specific antibody responses with a desirable Th2-biased immune response. Both vaccines significantly extended the life expectancy of hSOD1 mice， with tgG-DSE2lim displaying greater protection than tgG-DSE5b at earlier pre-symptomatic stage. tgG-DSE5b， but not tgG-DSE2lim， significantly delayed disease onset and appreciably slowed disease progression. This implies that conformationally distinct species of misfolded SOD1 may derive from the same mutation， thereby modifying disease phenotypes in a different fashion. Our results validate the rationale for conformation-based immuno-targeting of misfolded SOD1 as a promising therapeutic strategy to slow or even halt disease progression in familial ALS associated with SOD1 mutations， as well as a prophylactic intervention for carriers of SOD1 mutations. Our study not only provides important proof-of-principle data for the development of a safe and effective human therapeutic/prophylactic ALS vaccine against misfolded SOD1， but also predicts a great potential to extend our DSE-based vaccination approach to other types of ALS， such as those associated with TDP-43 proteinopathies.
