Therapeutic vaccines for amyotrophic lateral sclerosis directed against disease specific epitopes of superoxide dismutase 1

• DOI: 10.1016/j.vaccine.2019.07.044
• Publication Date: 2019-07-17T00:15:21Z
• Authors: Beibei Zhao; Kristen Marciniuk; Ebrima Gibbs; Masoud Yousefi; Scott Napper; Neil R. Cashman
• Keywords: Male; 0301 basic medicine; Protein Folding; Vaccines; Amyotrophic Lateral Sclerosis; Mice, Transgenic; Antibodies; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Epitopes; Mice; 03 medical and health sciences; Superoxide Dismutase-1; Th2 Cells; Disease Progression; Animals; Female

Emerging evidence suggests seeding and prion-like propagation of mutant Superoxide Dismutase 1 (SOD1) misfolding to be a potential mechanism for ALS pathogenesis progression. Immuno-targeting misfolded SOD1 has shown positive clinical outcomes in transgenic mice. However, major challenge developing active immunotherapies proteinopathies such as is the design immunogens enabling exclusive recognition pathogenic species self-protein. Ideally, one would achieve robust antibody response against disease-misfolded protein while sparing natively folded conformer avoid inducing deleterious autoimmune complications, or inhibiting its normal function. Using motor neuron disease mouse model expressing human SOD1-G37R, we herein report immunogenicity therapeutic efficacy two vaccines, tgG-DSE2lim tgG-DSE5b, based on notion that native undergo early unfolding present "disease specific epitopes" (DSE). Both vaccines elicited rapid, robust, well-sustained epitope-specific responses with desirable Th2-biased immune response. significantly extended life expectancy hSOD1G37R mice, displaying greater protection than tgG-DSE5b at earlier pre-symptomatic stage. but not tgG-DSE2lim, delayed onset appreciably slowed This implies conformationally distinct may derive from same mutation, thereby modifying phenotypes different fashion. Our results validate rationale conformation-based immuno-targeting promising strategy slow even halt progression familial associated mutations, well prophylactic intervention carriers mutations. study only provides important proof-of-principle data development safe effective therapeutic/prophylactic vaccine SOD1, also predicts great extend our DSE-based vaccination approach other types ALS, those TDP-43 proteinopathies.