Therapeutic vaccines for amyotrophic lateral sclerosis directed against disease specific epitopes of superoxide dismutase 1
Bibliographic record
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 hSOD1 G37R 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".