A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging. To evaluate the dose range of GDNF biological activity, the inducible AAV vector (8.0 × 10(9) viral genomes) was injected in the rat striatum at four delivery sites and increasing doxycycline doses administered orally. ERK/Akt signaling activation as well as tyrosine hydroxylase downregulation, a consequence of long-term GDNF treatment, were induced at plasmatic doxycycline concentrations of 140 and 320 ng/ml respectively, which are known not to increase antibiotic-resistant microorganisms in patients. In these conditions, GDNF covered the majority of the striatum. No behavioral abnormalities or weight loss were observed. Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses.

Detaljer

Författare
  • Abdelwahed Chtarto
  • Marie Humbert-Claude
  • Olivier Bockstael
  • Atze T Das
  • Sébastien Boutry
  • Ludivine S Breger
  • Bep Klaver
  • Catherine Melas
  • Pedro Barroso-Chinea
  • Tomas Gonzalez-Hernandez
  • Robert N Muller
  • Olivier DeWitte
  • Marc Levivier
  • Cecilia Lundberg
  • Ben Berkhout
  • Liliane Tenenbaum
Enheter & grupper
Externa organisationer
  • Center for Microscopy and Molecular Imaging
  • Free University of Brussels
  • Lausanne University Hospital
  • University of Amsterdam
  • University of La Laguna (ULL)
  • University of Mons
  • Hospital Erasme
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Farmakologi och toxikologi

Nyckelord

Originalspråkengelska
Artikelnummer16027
TidskriftMolecular therapy. Methods & clinical development
Volym5
StatusPublished - 2016
PublikationskategoriForskning
Peer review utfördJa