Retrovirus and Genetic Transfer - INSERM U622  

  HEADDr. Heard Jean Michel /
  MEMBERSDr. Ausseil Jérôme / Blanchard Stéphane / Dr. Bohl Delphine/ Dr. Desmaris Nathalie / Hocquemiller Michaël / Dr. Liu Song / Dr. Nosjean Anne / Dr. Vitry Sandrine

  Annual Report

Our main focus is gene therapy for paediatric neurodegenerative diseases, a frequent cause of mental retardation. Early onset neurological alterations are devastating and untreatable Mucopolysaccharidoses (MPSs). Our objectives are the understanding of the loss of brain plasticity and the restoration of cognitive functions. Our successes in treating neurodegeneration in the mouse and dog models of two MPSs showed that gene therapy is suitable for clinical application. We will launch trials in children with MPSIII (Sanfilippo syndrome) when the clinical vector batch is ready and the European epidemiological survey is completed.

Heparan sulfate oligosaccharides accumulating in MPSIIIB mouse brain are a consequence of the enzyme defect in MPSIII. We show that they activated microglia through TLR4/MyD88 signalling. However, neuropathology was equally severe in MPSIIIB mice when TRL4/MyD88 were not expressed, suggesting that inflammation is not the primary cause of neurodegeneration.

Anatomical lesions in MPSIII neurons are ectopic and dystrophic neurites. We reproduced these phenotypes in primary neuronal cultures and showed reversion by gene therapy. Evidence was obtained for altered trafficking in the secretory pathway with consequences on autophagy and neurite outgrowth. We are now exploring possible links with oligosaccharides accumulation with the hope to find therapeutic targets to help restoring brain plasticity.

D. Bohl supervises works on the use of stem cells for motor neurons replacement. Motor neuron degeneration induces lethal, untreatable paralysis. Cell therapy using foetal stem cells is a credible therapeutic approach. We programmed neural stem cells to motor neuron differentiation. Forced expression of 3 transcription factors known to participate to the generation of motor neurons during embryonic development was obtained with lentivirus vectors. They confer cell responsiveness to the morphogens sonic hedgehog and retinoic acid, leading to motor neuron differentiation. Upon transplantation in the spinal cord ventral horn or the facial nucleus of adult recipient animals, these cells generated motor neurons projecting cholinergic axons to the periphery. Current studies are aimed at examining the development of functional efferents and afferents connections. Experiments are performed in chick embryos, adult rats and a mouse model of motor neuron disease with the aim to assess therapeutic potential.

Keywords: neurodegeneration, neuroinflammation, lysosome, gene therapy, motor neuron, neural stem cells


Cortical neuron with dystrophic axon in the brain cortex of a MPSIIIB mouse
Cholinergic projections from transplanted motor neurons in the mouse facial nucleus


Ciron, C., Desmaris, N., Colle, M.-A. , Raoul, S., Vérot, L., Ausseil, J., Froissard, R., Roux, F., Chérel, Y., Ferry, N., Lajat, Y., Schwartz, B., Vanier, M.T., Maire, I., Tardieu, M., Moullier, P. & Heard, J.M. (2006) Gene therapy of the brain in the dog model of Hurler syndrome. Ann.Neurol. 60, 204-213 (PMID: 16718701).

Bréjot, T., Blanchard, S., Hocquemiller, M, Liu, S., Nosjean, A., Heard, J.-M. & Bohl, D (2006). Forced expression of the motor neuron determinant HB9 in neural stem cells alters neuronal differentiation. Exp. Neurol., 198,167-182 (PMID: 16434037).

Cressant, A., Desmaris, N., Verot, L., Bréjot, T., Froissart, R., Vanier, M.-T., Maire, I. & Heard, J.-M. (2004) Improved behaviour and neuropathology in the mouse model of Sanfilippo type IIIB disease after AAV-mediated gene transfer in the striatum. J.Neurosc., 24,10229-10239 (PMID: 15537895).

Activity Reports 2007 - Institut Pasteur
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