Combination Therapy with Doxycycline, Chlorpromazine or Quinacrine Inhibits Prion Protein Replication in a N2A Model (P5.204)
Bibliographic record
Abstract
Objective: Using combination therapy to synergistically inhibit aggregation of prion protein and prevent the development of drug resistant prions. Background: Transmissible spongiform encephalopathies are a group of fatal neurodegenerative diseases affecting humans and animals1. The disease results from conformational conversion of the cellular prion protein (PrPC) into infectious isoforms (PrPSc). A current therapeutic strategy is to block conversion of PrPC into PrPSc. Some drugs are known to bind PrPC at different ‘initiator motifs’ and thereby stabilize the protein in its natural isoform. Unfortunately use of single compounds can allow PrPSc to adopt drug resistant isoforms. By combining therapies that target different motifs we theorize we can prevent PrPSc adaptation. Methods: Mouse neuroblastoma cell lines (N2a) infected with a rodent-adapted RML scrapie strain were treated with prion conversion inhibitors and PrPsc seeding reducers and were tested for ongoing infection by immunoblot assay of protease resistant prion protein (PrPres) in cell lysates. Cell cultures were treated with individual and combinations of therapeutic compounds including chlorpromazine, doxycycline, quinacrine and Tauroursodeoxycholic acid (TUDCA) with fresh drug present in the media with each passage and cell collection every 2-3 days. Samples were taken though multiple passages to allow clearance of infection and monitoring for any adaptation resulting in re-emergence of a drug-resistant or drug-dependent strain of PrPres. Results: RESULTS: Anti-prion effects of doxycycline were not seen, however, chlorpromazine, quinacrine at 3mmol and 0.5mmol concentrations by themselves and at 1mmol and 0.1mmol in combination respectively inhibited PrPres. TUDCAs effects and emergence of drug resistance are currently being investigated. Conclusions: We investigate a therapeutic approach to prion disease treatment by strategically combining anti-prion compounds to prevent PrPC conversion to PrPSc. Our results have yielded successful combinations of therapeutics that may lower disease drug-resistance and drug toxicities. These results will direct further testing in vivo in future studies.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".