J03 Partial lowering of total huntingtin levels to treat adults with huntington’s disease (hd): potential benefits and theoretical risks from human studies and animal models
Bibliographic record
Abstract
Background RG6042 (formerly IONIS-HTTRx) is an antisense oligonucleotide (ASO) in development for Huntington’s disease (HD). It is expected to partially lower levels of both disease-causing mutant huntingtin (mHTT) and wild-type huntingtin (wtHTT) regardless of the causative mutation. In a Phase I/IIa study in adults with HD (NCT02519036), RG6042 lowered levels of mHTT in cerebrospinal fluid with no safety signals of concern. Nevertheless, theoretical risks of lowering wtHTT in addition to mHTT remain. Aim To review published clinical and in vivo studies involving reduced wtHTT levels. Method Following a comprehensive PubMed search, relevant articles were evaluated and summarized. Results People with reduced wtHTT levels due to a rare disruption in one HTT copy did not have HD or other abnormalities (1 study). People with two mutant HTT copies (i.e. no wtHTT) developed normally until HD onset at a similar age to heterozygotes, with mostly similar symptoms (4 studies). No detrimental effects of partial wtHTT lowering using ASOs or other modalities were reported in normal adult animals (rodents, 5 studies; non-human primates, 4 studies) or HD rodent models (4 studies). ASO-mediated mHTT lowering ameliorated disease in 3 HD mouse models, with similar benefits for total HTT (wtHTT plus mHTT) lowering (1 study). In HD mouse models, wtHTT knockouts (1 study) and mice with 10% of normal wtHTT levels from conception (1 study) had worse HD-like phenotypes than those with normal levels, but wtHTT overexpression did not alleviate HD-like phenotypes (2 studies). Although HTT is essential for embryogenesis (4 studies) and development (2 studies), near-complete genetic ablation (deletion) of wtHTT expression in adulthood had little or no reported neurological effects in otherwise normal mice (2 studies). Conclusion These studies indicate that the theoretical risks of partially lowering wtHTT in adults are low. The absence of safety signals of concern in the Phase I/IIa study of RG6042 provides clinical support. Unlike gene silencing/editing, which may have irreversible effects, HTT lowering with ASOs is transient and reversible, and the dose is titratable, allowing risk mitigation. As RG6042 is not mutation specific, it has potential to lower HTT levels in all adults with HD. Funded by F. Hoffmann-La Roche
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.003 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.013 | 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".