Affiliations: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Note: [] These authors contributed equally.
Note: [] These authors contributed equally.
Note: [] Correspondence to: X. William Yang, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Tel.: +1 310 267 2761; Fax: +1 310 825 6426; E-mail: xwyang@mednet.ucla.edu
Abstract: Background: C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective: In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods: R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results: We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions: Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice.
