I006 Lowering htt1a with sirnas has more impact on early molecular and histological phenotypes than lowering full-length htt
Year: 2024
Type: conference-abstract
Abstract: Background In the context of an expanded CAG repeat, alternative processing of the huntingtin pre-mRNA generates the HTT1a transcript that is translated to produce the highly pathogenic HTTexon1 protein. Huntingtin lowering molecules that are currently being tested in clinical trials target full-length HTT or both full-length HTT and HTT1a, however, the relative benefit of lowering HTT1a or full-length HTT is unknown. Aim Compare the effects of lowering Htt1a and full-length Htt in zQ175 mice. Methods The activity of two Htt1a-targeting siRNAs, HTT486 and HTT634 was confirmed in zQ175-derived MEFs. HTT486/HTT634 or HTT10150 (targeting full-length Htt), were ICV administered in zQ175 and wildtype animals at 2 months of age; at 2 and again at 6 months; at 6 months, and all animals were sacrificed 4 months later. Htt transcript levels were monitored by QuantiGene, HTT proteins by HTRF, while HTT aggregation was assessed by immunohistochemistry. RNA-seq was used as a phenotypic readout. Results The combination of HTT486/HTT634 decreased Htt1a by approximately 50% in vitro. In vivo, the strongest lowering of both huntingtin transcripts was in the hippocampus, with HTT10150 being more potent than HTT486/HTT643. Despite the greater reduction in full-length Htt than in Htt1a, treatment with HTT486/HTT643 from 2 months of age resulted in a near absence of nuclear HTT aggregation in the hippocampal pyramidal cells, whereas any effects of HTT10150 were much more subtle. Preliminary data suggest that these changes in HTT aggregation are reflected in RNA-seq data. Conclusions HTT1a should be considered as a therapeutic target for HD. This work is supported by the CHDI Foundation.
Authors: Aikaterini S Papadopoulou, Christian Landles, Edward J Smith, Dan O’Reilly, Julia F Alderman, Jemima Phillips, Maria Canibano-Pico, Iulia M Nita, Sarah G Aldous, Marie K Bondulich, Casandra Gomez-Paredes, Konstantin Bobkov, Jonathan R Greene, Neil Aronin, Anastasia Khvorova, Gillian P Bates
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374348