Retrovirus and Genetic Transfer - INSERM U622  

  HEADDr. Heard Jean Michel /
  MEMBERSDr. Ausseil Jérôme / Bigou Stéphanie / Blanchard Stéphane / Dr. Bohl Delphine / Hocquemiller Michael / Dr. Liu Song / Dr. Vitry Sandrine / Thouron Françoise

  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 mouse and dog models of two MPSs demonstrated that gene therapy of the brain is suitable for clinical application. We will launch trials in children with MPSIII (Sanfilippo syndrome) whitin the next months. An epidemiological survey of patients in several European countries has been performed.

The consequence of the enzyme defect in MPSIII is the accumulation of abnormal heparan sulfate oligosaccharides. We identified the pathogenic oligosaccharide molecular species and investigated mechanisms affecting the biology of various cell types in the nervous system. In microglial cells, they activate TLR4/MyD88 signalling. In neurons, we showed that oligosaccharides have pleiotropic effects relevant to neuronal plasticity. The activation of the proteosomal degradation of synaptophysin modifies synaptic vesicle components. The disorganisation of the early secretory pathway induces vesicular distension that subsequently alters axono-dendritic transport. The alteration of membrane trafficking results in inefficient neurite retraction and aberrant neuritogenesis.

Dr. D. Bohl supervises works on the programming of stem cells for motor neurons differentiation. She forced expression of 3 transcription factors known to participate to the generation of motor neurons during embryonic development in mouse neural stem cells using lentivirus vectors. Engineered cells preferentially formed motor neurons upon in vitro differentiation and replaced loss motor neurons after local injury in the spinal cord. Methods for the production of inducible pluripotent stem cells from human fibroblasts have been set up in the laboratory and are now used to generate neurons and motor neurons from various human pathologies

Dr. S Liu is interested in developing application of gene therapy in combination with microsurgery for the repair of peripheral nervous system lesions with severe disability, like dorsal spinal root injury.

Keywords: neurodegeneration, heparan sulfate, lysosome, gene therapy, motor neuron, neural stem cells, root injury


Vesicular distension in a myelinated axon of MPSIII neuron


Bohl D, Liu S, Blanchard S, Hocquemiller M, Haase G, Heard JM. Directed evolution of motor neurons from genetically engineered neural precursors. Stem Cells. 2008 Oct;26(10):2564-75. PMID: 18635866

Ausseil J, Desmaris N, Bigou S, Attali R, Corbineau S, Vitry S, Parent M, Cheillan D, Fuller M, Maire I, Vanier MT, Heard JM. Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice. PLoS ONE. 2008 May 28;3(5):e2296. PMID: 18509511

Cheillan D, Malleval C, Ausseil J, Vitry S, Heard JM, Maire I, Honnorat J, Belin MF, Touret M. Abnormal expression of truncated CRMP-1 protein in the brain cortex of MPSIIIB mice.Mol Genet Metab. 2008 May;94(1):135-8. PMID: 18325808

Ciron C, Desmaris N, Colle MA, Raoul S, Joussemet B, Vérot L, Ausseil J, Froissart R, Roux F, Chérel Y, Ferry N, Lajat Y, Schwartz B, Vanier MT, Maire I, Tardieu M, Moullier P, Heard JM. Gene therapy of the brain in the dog model of Hurler's syndrome. Ann Neurol. 2006 Aug;60(2):204-13. PMID: 16718701

Bréjot T, Blanchard S, Hocquemiller M, Haase G, Liu S, Nosjean A, Heard JM, Bohl D. Forced expression of the motor neuron determinant HB9 in neural stem cells affects neurogenesis. Exp Neurol. 2006 Mar;198(1):167-82. PMID: 16434037

Activity Reports 2009 - Institut Pasteur
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