Microhomology-Mediated End Joining and mRNA Reframing as Therapeutic CRISPR/Cas9 Editing Strategies for c.1278insTATC Mutation of Tay-Sachs Disease
Bibliographic record
Abstract
Tay-Sachs disease is a neurodegenerative disorder commonly caused by HEXA c.1278insTATC, a 4-base pair duplication mutation disrupting the mRNA reading frame in HexA enzyme expression. In an engineered cell model of c.1278insTATC, therapeutic correction using CRISPR/Cas9 was investigated. We posited that DNA cleavage at or near the duplication junction would induce precise correction via microhomology-mediated end joining (MMEJ) repair, thus restoring HexA function. Precise MMEJ-executed correction and concomitant recovery of wildtype HexA activity was achieved at a modest rate by cutting 1-base pair from the duplication junction. Canonical PAM sequence constraints on CRISPR/Cas9 prevented exact cleavage at the junction. Alternatively, non-corrective indels restoring the mRNA reading frame were examined for production of catalytically active HexA variants. Negligible HexA function was detected in such mRNA-reframing events, dismissing therapeutic prospects. These results validate MMEJ as a CRISPR/Cas9 modality for therapeutic c.1278insTATC editing but illustrate the challenge of achieving robust levels of correction.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".