561. CRISPR-Induced Deletion (CinDel) Method Allows Permanent and Efficient Restoration of the DMD Gene Reading Frame in Duchenne Patient Myoblasts and Preserves Truncated Dystrophin Structure
Bibliographic record
Abstract
The CRISPR/Cas9 system is a great revolution in biology. This technology allows the modification of genes in vitro and in vivo in a wide variety of living organisms. In most Duchenne Muscular Dystrophy (DMD) patients, expression of dystrophin (DYS) protein is disrupted because exon deletions result in a frame shift. Here we present CRISPR-induced deletion (CinDel), a new gene therapy approach to correct the DMD gene in Duchenne patients with one or more exons deletions. By using adequate pair of gRNAs targeting specifically the exons precede and follow the patient deletion in DMD gene, CinDel induces precise DSB in targeted sequences and allows an additional deletion. The remaining parts of the exons were fusioned by NHEJ to form a hybrid exon and restored the DMD reading frame in 62 % of hybrid exons in vitro in patient myoblasts and in vivo in electroporated muscle hDMD/mdx mice. Moreover, adequate pairs of gRNAs also restored the normal spectrin-like repeat of the dystrophin rod domain; such restoration is not obtained by exon skipping or deletion of complete exons. The expression of an internally deleted dystrophin protein was detected following the formation of myotubes by the unselected treated DMD myoblasts. Given that CinDel induces permanent reparation of the DMD gene this treatment would not have to be repeated as it is the case for exon skipping induced by oligonucleotides.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".