Therapeutic vaccines for amyotrophic lateral sclerosis directed against disease specific epitopes of superoxide dismutase 1 |
| |
Institution: | 1. Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC V6T 2B5, Canada;2. Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada;3. Vaccine and Infectious Disease Organization International Vaccine Research Center, University of Saskatchewan, Saskatchewan, SK S7N 5E3, Canada |
| |
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. |
| |
Keywords: | DSE"} {"#name":"keyword" "$":{"id":"k0010"} "$$":[{"#name":"text" "_":"disease-specific epitope SOD1"} {"#name":"keyword" "$":{"id":"k0020"} "$$":[{"#name":"text" "_":"superoxide dismutase 1 ALS"} {"#name":"keyword" "$":{"id":"k0030"} "$$":[{"#name":"text" "_":"amyotrophic lateral sclerosis tgG"} {"#name":"keyword" "$":{"id":"k0040"} "$$":[{"#name":"text" "_":"truncated rabies glycoprotein G |
本文献已被 ScienceDirect 等数据库收录! |
|