I003 Tolerability of HTT-lowering; learnings from nonhuman primates

<h3>Background</h3> 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. <h3>Aims</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> Treatment of NHPs with a C16-conjugated siRNA achieved robust reduction in HTT protein expression (&gt; 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. <h3>Conclusions</h3> 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.