Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome.
Hyeong-Min Lee, Ellen P Clark, M Bram Kuijer and 3 others
PMID 30140420WHAT IT FOUND
Several cancer-drug compounds reactivated the silenced paternal copy of Ube3a in mouse neurons.
Indotecan looked most promising in cells, but the paper gives no human Angelman patient data, safety, or therapy outcomes.
Key findings
01Several indenoisoquinoline compounds increased expression of the normally silenced paternal Ube3a reporter in mouse cortical neurons.
02Indotecan had the strongest unsilencing profile among the tested compounds, with better potency and efficacy than topotecan and similar toxicity in cultured neurons.
03Indimitecan was less likely to be a good candidate because it was toxic at lower concentrations than topotecan.
STILL TO COME
How it was doneWhat they found
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What it does not show
The study was done in mouse cortical neurons, not in people with Angelman syndrome. The study did not test whether the compounds reach the brain or are safe in people with Angelman syndrome. The compounds were designed as cancer drugs, and predicted off-target effects were not tested. Some analogues had narrow effective dose ranges before toxicity. The paper did not measure speech, movement, learning, or daily function in patients.
Declared interests
Funding came from the National Institute of Neurological Disorders and Stroke, the Angelman Syndrome Foundation, the National Institutes of Health, and the National Cancer Institute. No author conflicts of interest are stated in the supplied text.
The easy way to misread this
Do not read this as evidence that indotecan or any compound can treat Angelman syndrome in patients. The experiments were done in mouse neurons, not in people with Angelman syndrome, and the paper did not measure speech, movement, learning, or safety in this condition.