I09 In vivo mtHTT protein reduction in the CNS and periphery by passive immunization with the monoclonal antibody C6–17
Bibliographic record
Abstract
Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by changes in personality, cognition and motor control. The cardinal neuropathological hallmark of this disease is the massive atrophy of the striatum resulting from neuronal dysfunction and loss, but which extends to other areas of the brain as well as peripheral organs. The genetic mutation underlying HD originates in Exon1 of the huntingtin gene gives rise to a toxic/mutated form of the huntingtin protein (mtHTT). The mtHTT protein is ubiquitously expressed but also exhibits the ability to propagate from cell-to-cell to disseminate pathology, a property which may serve as a new therapeutic focus. We have developed a monoclonal antibody C6-17 targeting a particularly exposed region close to the aa586 Caspase 6 cleavage site of the huntingtin protein and, as recently published, mAB C6-17 is able to block cell-to-cell propagation of mutated HTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether the freely accessible and extracellular mtHTT can be targeted by an antibody. In POC experiments, using the transgenic animal model YAC128, we found that after 3 months mAB C6-17 treatment the circulating mtHTT in the peripheral as well as in the CNS tissues was reduced. Further, we could demonstrate the presence of active mAB C6-17 in PBS/heparin perfused peripheral and CNS tissues. The mAB C6-17 treated YAC128 animals showed benefits in body wight and motor behaviors and we could observe a delay in the HD disease progression. The obtained in vivo results provide the first POC data for the feasibility and efficacy of an antibody-based anti-mtHTT approach and suggest this therapeutic strategy as a potential new HD treatment possibility.
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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) | 0.000 | 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) | 0.001 | 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".