title: Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease.
abstract: BACKGROUND
  In Huntington's disease (HD), the ratio between normal and mutant Huntingtin (polyQ-hHtt) is crucial in the onset and progression of the disease. As a result, addition of normal Htt was shown to improve polyQ-hHtt-induced defects. Therefore, we recently identified, within human Htt, a 23aa peptide (P42) that prevents aggregation and polyQ-hHtt-induced phenotypes in HD Drosophila model. In this report, we evaluated the 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 cell penetrating peptide TAT from HIV with a nanostructure-based drug delivery system (Aonys® technology), to form a water-in-oil microemulsion (referred to as NP42T) allowing non-invasive per mucosal buccal/rectal administration of P42. Using MALDI Imaging Mass Spectrometry, we verified the correct targeting of NP42T into the brain, after per mucosal administration. 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 daily administrations 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 ventricular areas) recorded on brain sections.
  
  
  CONCLUSIONS
  These data demonstrate that NP42T presents an unprecedented protective effect, and highlight a new therapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Arribat
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Talmat-Amar
authors.forename: Alexia
authors.initials: A
authors.lastname: Paucard
authors.forename: Pierre
authors.initials: P
authors.lastname: Lesport
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonneaud
authors.forename: Caroline
authors.initials: C
authors.lastname: Bauer
authors.forename: Nicole
authors.initials: N
authors.lastname: Bec
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Parmentier
authors.forename: Lorraine
authors.initials: L
authors.lastname: Benigno
authors.forename: Christian
authors.initials: C
authors.lastname: Larroque
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.forename: Florence
authors.initials: F
authors.lastname: Maschat
mesh_terms: D000278:Administration, Buccal; D000285:Administration, Rectal; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D045442:Rotarod Performance Test
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; C000598099:P42 peptide; D010446:Peptide Fragments
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