Retrovirus and Genetic Transfer  

  HEADDr. Heard Jean Michel /
  MEMBERSDr. Ausseil Jérôme / Bigou Stéphanie / Blanchard Stéphane / Dr. Bohl Delphine / Bruyère Julie / Lemonnnier Thomas / Dr. Liu Song / Roy Elise / Toli Ntiana / Dr. Vitry Sandrine

  Annual Report

Paediatric neurodegenerative diseases represent a frequent cause of mental retardation. They are devastating and untreatable. Our objectives are the understanding and the prevention of the alteration of cognitive functions in mucopolysaccharidosis (MPS) type III, a monogenic disease due to a defective lysosomal enzyme. We measured the incidence and described the natural history of the disease in France, UK and Greece. Using dog models for two MPSs, we demonstrated that gene therapy of the brain is suitable for clinical application. A phase I clinical trial sponsored by the Institut Pasteur will be initiated in children with MPSIII.

The consequence of the enzyme defect in MPSIII is the accumulation of abnormal heparan sulfate oligosaccharides. In the mouse model of the disease, neurons accumulate vesicles in soma and neurites that affect axono-dendritic transport. We showed that these vesicles belong to the early secretory compartment, and not to the autophagic or endocytic pathways, as previously suggested. They are misrouted after exiting the endoplasmic reticulum and do not reach the Golgi complex. They form a dead end compartment that progressively amplifies, accounting for progressive storage of undegraded intracellular components. Alterations of Golgi structure and dynamics presumably account for aberrant neuritogenesis and modifications of synaptic vesicle content.

On behave of Dr. D. Bohl, who set up methods to produce induced pluripotent stem (iPS) cells from human skin fibroblasts and induce their differentiation to neurons, we have now access to cultured human neurons. When applied to skin fibroblast from MPSIII patients, the methods revealed cellular abnormalities in human neurons that are reminiscent of the observations made in affected mouse neurons. This material is now used to refine the identification of the molecular targets of the pathogenic effects of heparan sulfate oligosaccharides.

Dr. S Liu is interested in developing applications of gene therapy in combination with microsurgery to repairing lesions of the sensory pathway, which do not spontaneously recover, as for example dorsal root lesions. Therapeutic efficacy in rats was demonstrated using a clinically relevant approach based on the local production of neurotrophin-3 by a genetically engineered nerve graft used to bypass post-traumatic inhibition of axon re-growth.

Keywords: neurodegeneration,lysosome, gene therapy, iPSs, dorsal root injury


Cultured human neurons derived from the iPS cells of a patient with MPSIII (ßIII-tubulin, in green, is a neuronal marker, LAMP1 in pink, shows lysosomal storage)


Hocquemiller M, Vitry S, Bigou S, Bruyère J, Ausseil J, Heard JM. GAP43 overexpression and enhanced neurite outgrowth in mucopolysaccharidosis type IIIB cortical neuron cultures. J. Neurosci. Res. 2010 ; 88(1) :202-13

Liu S, Bohl D, Blanchard S, Bacci J, Saïd G, Heard JM. Combination of Microsurgery and Gene Therapy for Spinal Dorsal Root Injury Repair. Mol Ther. 2009Jun;17(6):992-1002.

Vitry S, Ausseil J, Hocquemiller M, Bigou S, Dos Santos Coura R, Heard JM. Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB. Mol Cell Neurosci. 2009 May;41(1):8-18.

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.

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

Activity Reports 2009 - Institut Pasteur
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