Abstract 17292: Long QT Syndrome Variant 3 Patient Derived Induced Pluripotent Stem Cells: Novel and Critical Platform for Drug Screening
Bibliographic record
Abstract
Congenital LQTS is a heritable family of arrhythmias caused by mutations in 12 genes coding for ion channels or ion channel associated proteins. Variant 3 (LQT-3) is caused by mutations in SCN5A, the gene coding for the α subunit of the primary cardiac Na+ channel. Based primarily on studies in heterologous expression systems, a mutation-specific pharmacology has proven useful in which drugs such as Mexiletine that preferentially inhibit mutation-induced late Na+ channel current (INaL), have been shown to be effective as therapeutic agents in the treatment of LQT-3. Here we isolated cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) produced by lentiviral reprograming of skin fibroblasts from three individuals in a LQT-3 family: a proband carrying a de novo SCN5A mutation (INa_F1473C) and the proband's parents who carried wild type (WT) Na+ channels. Whole-cell patch clamp recordings were used to characterize INa properties in the three subjects: INa_F1473C channels failed to completely inactivate during 100ms-depolarizing pulses (INaL) in the action potential plateau voltage range, and were characterized by steady state inactivation that was significantly shifted in the depolarizing direction compared with WT channels. These properties agree well with those determined previously of the same mutation in HEK293 cells and are consistent with mutation-induced QT interval prolongation in the proband. Based on HEK cell experiments, we previously reported that mutation-induced Na+ channel dysfunction was corrected by 50 µM Mexiletine, a result confirmed for the mutant channels expressed in hiPSC-CMs. However, we find that the same Mexiletine concentration significantly inhibits two off target channel currents ICaL and IKr, results that could not be obtained from heterologous expression studies. These results, establish the critical importance of hiPSC-CMs not only as mechanistic models of channelopathies such as LQTS, but as important and unique platforms for screening drugs, for both effectiveness in correcting mutation-induced dysfunction and also for target specificity.
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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) | 0.003 | 0.002 |
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".