Second‐Generation Antisense Nucleotide Targeting Huntingtin Expression Found to Be Safe in Patients With Huntington's Disease
Bibliographic record
Abstract
Huntington's disease (HD) is a neurodegenerative autosomaldominant disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene (HTT).HD is characterized by progressive neuropsychiatric, cognitive, and motor symptoms and is the most common cause of inherited chorea.Even though the HTT gene was identified more than one-quarter of a century ago, there are no disease-modifying therapies that prevent disease onset or slow its progression.1 Recent research efforts have focused on directly targeting the genetic abnormality.Recently, Tabrizi and colleagues have studied the effects of intrathecal administration of a secondgeneration antisense nucleotide, to inhibit messenger RNA, and therefore reduce huntingtin concentration levels. 2 Earlier research demonstrated that decreasing the levels of HTT in transgenic animal models and nonhuman primates with HTTlowering agents was feasible and safe.3 Forty-six eligible patients between 25 and 65 years of age with early HD, further defined as having ≥36 CAG repeats and a clinical stage 1, were randomized (3:1) into five different dose groups (10, 30, 60, 90, or 120 mg) in an ascending dose design to receive four intrathecal boluses at 4-week intervals of IONIS-HTTRx versus placebo.The primary endpoint was to evaluate safety of the drug.Secondary endpoints included cerebrospinal fluid (CSF) pharmacokinetics as well as plasma pharmacodynamics in addition to identifying its effect on concentration levels of HTT, neurofilament light protein in the CSF, ventricular volume, and the composite cognitive score on the Huntington's Disease Cognitive Assessment Battery.IONIS-HTTRx was found to be safe.Adverse events in both treatment and placebo groups were frequent (reported in 98% of patients), but were mild or moderate and deemed unrelated to direct effects of the drug.The most frequent adverse events were related to the intrathecal administration, including discomfort associated with the lumbar puncture as well as, postdural puncture headache.Serious adverse events were not reported, and no discontinuations or deaths occurred.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".