Stratégies de transfert du gène codant le GDNF en vue d'une thérapie génique de la maladie de Parkinson

Le transfert du gène codant le facteur neurotrophique dérivé des cellules gliales (GDNF) permet de protéger voire de restaurer les neurones dopaminergiques nigrostriés qui dégénèrent dans la maladie de Parkinson (MP). Afin d'améliorer les systèmes de transfert de gènes, nous avons voulu développer des vecteurs adénoviraux "gutless". Les résultats limités de production nous ont toutefois conduit à recourir aux vecteurs lentiviraux. Nous avons alors montré que des vecteurs lentiviraux pseudotypés avec deux enveloppes virales différentes permettent un transfert de gène efficace et durable dans le cerveau murin et peuvent être injectés plusieurs fois , même en présence de taux élevés d'anticorps neutralisants dirigés contre la protéine d'enveloppe. Enfin, nous avons montré que, dans un modèle expérimental de phase précoce de la MP, l'administrationPARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study

Introduction: Crotoxin has a broad antitumor activity but has shown frequent neurotoxic toxicity. To induce tolerance and limit this toxicity, we propose a new design with intra-patient dose escalation. Methods: A new Dose Limiting Toxicity definition was used. The concept of Target Ceiling Dose was introduced. Results: Dose Limiting Toxicity was the inability to dose escalate twice. Target Ceiling Dose was the highest planned dose to be administered to a patient and could change for patients along time. Recommended Dose was defined similarly as in a (3 + 3) conventional design. Conclusion: This innovant design was used and the clinical trial is now closed for inclusions. Results will be presented later. Keywords: Clinical trial, Phase 1, Intra-patient dose escalation, Cance

Functional reinnervation from remaining DA terminals induced by GDNF lentivirus in a rat model of early Parkinson's disease.

Glial cell-line derived neurotrophic factor (GDNF) is a good candidate agent for restoring functional reinnervation and/or neuroprotection of dopamine (DA) nigrostriatal system and thus for the treatment of Parkinson's disease (PD). Viral delivery is currently the most likely in vivo strategy for delivery of the therapeutic protein into the brain for treatment of neurological diseases. However, one of the important unresolved issues for this strategy is the threshold number of DA nigral neurons and/or of striatal DA terminals necessary for optimal benefit from GDNF therapy. In this study, we examined the intrastriatal neurotrophic effects of long-term GDNF delivery using a lentiviral vector in a new rat model of early PD. Lenti-GDNF was injected into the striatum 4 weeks after partial substantia nigra pars compacta 6-hydroxydopamine-induced lesion. Striatal denervation was evaluated by assessing tyrosine hydroxylase-positive DA fiber density and corroborated by testing motor deficit by means of a staircase test. GDNF treatment restored complete striatal DA innervation in the previously denervated area and this was associated with significant behavioral improvements