Year: 2024
Type: conference-abstract
Abstract: Background Huntington’s Disease (HD) is a neurodegenerative disease caused by CAG expansion in the huntingtin (HTT) gene, resulting in expression of mutant HTT protein. HTT-lowering is a potential approach for the treatment of HD actively being explored. A long-standing question is the extent to which HTT-lowering can be tolerated in adults. Aims We sought to explore the tolerability of deep and sustained HTT-lowering in wild-type (wt) non-human primates (NHPs) over 6 months after single and repeated intrathecal administration of a C16-conjugated small interfering RNA (siRNA) targeting HTT. Methods Tolerability of HTT-lowering was assessed in NHPs through in-life clinical observations, neurological exams, detailed histopathology assessments, and multiple CSF parameters. HTT protein levels were assessed in CNS tissues at 3- and 6-months to confirm extent of lowering. Results Treatment of NHPs with a C16-conjugated siRNA achieved robust reduction in HTT protein expression (> 90% lowering in the cortex) and appeared to be well tolerated throughout the study period. There were no treatment-related clinical observations, abnormalities in neurological exams or histopathology assessments, and no changes in any measured CSF parameters, including NfL, total protein, and cell counts. Conclusions Our results suggest that deep, sustained lowering of HTT protein expression in the CNS of adult non-human primates by a C16-siRNA conjugate can be well tolerated for at least 6 months, supporting future clinical evaluation of C16-siRNA conjugates as a novel platform approach to HTT-lowering in the CNS.
Authors: William Cantley, Maja Janas De Angelis, Shelley Patrick, Xuemei Zhang, Diana Cha, Feng Gao, Chris Tran, Olufemi Adeduji, Jia Chen, Soky Koy, Kevin Sloan, Jim Reindel, Joe Dybowski, Kirk Brown
Institution: Alnylam Pharmaceuticals (United States)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373667