Therapeutics: Downstream regulatory element antagonistic modulator (DREAM); ATP-dependent potassium channel (KATP)
In vitro, patient sample and mouse studies suggest inhibiting DREAM with NovoNorm repaglinide could help treat HD. Striatal levels of DREAM were lower in postmortem brain tissue samples from patients and a transgenic mouse model of HD than in samples from normal subjects and mice. Also in the transgenic HD model, heterozygous knockout of DREAM increased survival compared with unmodified DREAM expression. In cell-based DREAM activity assays, the KATP inhibitor NovoNorm inhibited DREAM activation of A-type potassium currents with an IC50 of 15 nM. In the HD mouse model, NovoNorm delayed symptom onset, decreased striatal atrophy and increased motor coordination compared with a non-DREAM-binding KATP inhibitor or vehicle. Next steps include conducting a clinical trial of NovoNorm to treat HD and screening for selective DREAM inhibitors...