Pharmaceutical inhibition of the Chk2 kinase mitigates cone photoreceptor degeneration in an iPSC model of Bardet-Biedl syndrome
Bibliographic record
Abstract
Bardet-Biedl syndrome (BBS) is a syndromic ciliopathy leading to progressive blindness starting in childhood, but the mechanism of photoreceptor degeneration remains unclear. The basal body of the photoreceptor primary cilium originates from the centrosome's mother centriole, and BBS-related proteins form a complex at basal body. Centrosomes also organize microtubules of the mitotic spindle. We show here that photoreceptors from Bbs10 −/− mouse pups present a DNA damage response (DDR) that becomes persistent and localizes to the basal body. In patient-derived induced pluripotent stem cells (iPSCs) carrying BBS10 mutations, BBS retinal progenitor cells (RPCs) present a DDR that correlates with activation of the mitotic spindle checkpoint. Pharmaceutical inhibition of the Chk2 kinase in BBS RPCs mitigates cell death and genomic instability and restores the phospho-proteome. Drug treatment of BBS retinal organoids improves tissue organization, cone survival, and outer segment maturation, thus opening a possible therapeutic avenue to delay photoreceptor degeneration in BBS.
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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".