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

Abstract

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 hSOD1G37R 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.

• Authors: Beibei Zhao, Kristen Marciniuk, Ebrima Gibbs, Masoud Yousefi, Scott Napper, Neil R Cashman
• Journal: Vaccine (Vaccine) Vol. 37 Issue 35 Pg. 4920-4927 (08 14 2019) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 31324499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Antibodies
• Epitopes
• Vaccines
• Superoxide Dismutase-1

Topics

• Amyotrophic Lateral Sclerosis (immunology, therapy)
• Animals
• Antibodies (blood)
• Disease Models, Animal
• Disease Progression
• Epitopes (chemistry, immunology)
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Protein Folding
• Superoxide Dismutase-1 (immunology)
• Th2 Cells (immunology)
• Vaccines (immunology, therapeutic use)