PROTAC mHTT Degrader-1

In wild-type B6CBA mouse models treated with PROTAC mHTT Degrader-1 (PROTAC 2′) (3 mg/kg; subcutaneous injection; single dose; observation for 6 h post-administration), PROTAC 2′ can cross the blood-brain barrier, remains detectable in mouse brain tissue within 6 h post-administration, and maintains an average concentration of approximately 1.96 ppb^[1].
Following long-term administration of PROTAC mHTT Degrader-1 (3 mg/kg/week; subcutaneous injection; once weekly for 5 consecutive weeks) in wild-type B6CBA mouse models, no significant differences are observed in mouse body weight, cerebral cortex thickness, or striatal volume compared with the control group. No abnormalities are detected in serum liver and kidney function indices, and no obvious toxicity is found in the liver, kidney, or brain tissues^[1].
PROTAC mHTT Degrader-1 (3 mg/kg/week; continuous administration via subcutaneously implanted osmotic pump; continuous infusion; 4 weeks of treatment) significantly retards body weight loss, improves motor coordination and spontaneous exploratory behavior, and prolongs survival in B6CBA-R6/2 Huntington's disease mouse models. Meanwhile, it reduces the level of mHTT aggregates and neuroinflammation in the mouse brain, alleviates cortex and striatum atrophy, and partially restores neuronal function^[1].