Abstract
Background:In Huntington’s disease (HD), the ratio between normal and mutant Huntingtin (polyQ-hHtt) iscrucial in the onset and progression of the disease. As a result, addition of normal Htt was shown to improvepolyQ-hHtt-induced defects. Therefore, we recently identified, within human Htt, a 23aa peptide (P42) thatprevents aggregation and polyQ-hHtt-induced phenotypes in HDDrosophilamodel. In this report, we evaluatedthe therapeutic potential of P42 in a mammalian model of the disease, R6/2 mice.Results:To this end, we developed an original strategy for P42 delivery, combining the properties of the cellpenetrating peptide TAT from HIV with a nanostructure-based drug delivery system (Aonys®technology), to form awater-in-oil microemulsion (referred to as NP42T) allowing non-invasiveper mucosalbuccal/rectal administration ofP42. Using MALDI Imaging Mass Spectrometry, we verified the correct targeting of NP42T into the brain, afterpermucosaladministration. We then evaluated the effects of NP42T in R6/2 mice. We found that P42 (and/or derivatives)are delivered into the brain and target most of the cells, including the neurons of the striatum. Buccal/rectal dailyadministrations of NP42T microemulsion allowed a clear improvement of behavioural HD-associated defects(foot-clasping, rotarod and body weights), and of several histological markers (aggregation, astrogliosis or ventricularareas) recorded on brain sections.Conclusions:These data demonstrate that NP42T presents an unprecedented protective effect, and highlight a newtherapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology