Background Huntington's disease (HD) pathogenesis results from a dominant effect of polyQ-hHtt and a loss of function of Htt. Indeed, addition of wild-type Htt improves polyQ-hHtt-induced defects.
Aims Screening on polyQ-hHtt aggregation in HeLa cells, we identified an inhibitory 23aa peptide (Pep42) lying within human Htt. Interestingly Pep42 acts specifically on HD model through a direct interaction with N17 domain, suggesting a role of Pep42 on nucleation and aggregation processes. The protective properties of Pep42 were confirmed on different polyQ-hHtt-induced phenotypes in HD Drosophila model. Therefore Pep42 presents a clear therapeutical potential that we further tested in R6(2) mice.
Methods/techniques In order to attempt to cross the brain-blood barrier, Pep42 was fused to TAT-HIV. Then, we compared its protective effect after intraventricular injections, intravenous injections, vs buccal and rectal mucosa administrations in a water-in-oil microemulsion-based delivery vector (called Aonys, MedesisPharma).
Results/outcome Pharmacokinetics analysed on brain sections at 6hrs and 24hrs after Pep42 treatment showed a nice spread of the peptide in the brain, still visible at 24 h. Finally, administration of Pep42/Aonys or empty vector was performed daily in 2 wks–11 wks old R6(2) mice for pre-symptomatic treatment and in 9–11 wks old R6(2) mice for post-symptomatic treatment. Several polyQ-hHtt behavioural associated defects were analysed (rotarod, foot-clasping or body weights), and several markers were followed on brain sections. These data globally show the protective effect of Pep42-TAT when delivered through Aonys vector, in both pre- and post-symptomatic treatments.
Conclusions Altogether these data highlight a new therapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology.
- Inhibitory peptide