Preclinical assessment of splicing modulation therapy for ABCA4 variant c.768G>T in Stargardt disease
Bibliographic record
Abstract
BACKGROUND: Stargardt disease type 1 (STGD1) is a progressive retinal disorder caused by bi-allelic variants in the ABCA4 gene. A recurrent variant at the exon-intron junction of exon 6, c.768G>T, causes a 35-nt elongation of exon 6 that leads to premature termination of protein synthesis. METHODS: To correct this aberrant splicing, twenty-five 2'-O-methoxyethyl antisense oligonucleotides (AONs) were designed, spanning the entire exon elongation. RESULTS: Testing of these AONs in patient-derived photoreceptor precursor cells and retinal organoids allow the selection of a lead candidate AON (A7 21-mer) that rescues on average 52% and 50% expression of wild-type ABCA4 transcript and protein, respectively. In situ hybridization and probe-based ELISA demonstrate its distribution and stability in vitro and in vivo. No major safety concerns regarding off-targets, immunostimulation and toxicity are observed in transcriptomics analysis, cytokine stimulation assays in human primary immune cells, and cytotoxicity assays. CONCLUSIONS: Additional optimization and in vivo studies will be performed to further investigate the lead candidate. Considering the high prevalence of this variant, a substantial number of patients are likely to benefit from a successful further development and implementation of this therapy.
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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 | 0.001 | 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".