Retrovirus and Genetic Transfer - INSERM U622  

  HEADProf. HEARD Jean-Michel /
  MEMBERSDr AUSSEIL Jérôme / Dr BOHL Delphine / Dr DESMARIS Nathalie / HOCQUEMILLER Michael
Dr LIU Song / Dr NOSJEAN Anne / Dr VITRY Sandrine

  Annual Report

The unit was created in 1999 and affiliated to INSERM in 2004. It comprises 11 scientists, engineers and students. Our main focus since 2001 is gene therapy for central nervous system disorders.

Mucopolysaccharidoses (MPSs) form a sub-group of lysosomal storage diseases. Neurological alterations are devastating and untreatable in young children with MPSI or MPSIII. Our aims are to treat neurodegeneration and understand pathogenesis. Our successes in treating neurodegeneration in the mouse and dog models of these two diseases showed that gene therapy is safe and efficient. Animal experiments are almost completed and we are preparing clinical trials to be launched in 2008. Treatment consists in four intracerebral injections of AA.2.5 vectors coding for the missing enzyme. Ongoing works concern the validation of clinical vector batches produced using baculovirus vectors, the supervision of toxicology studies and the constitution of a European registry of affected children to describe natural histories of the diseases.

We showed that partially digested heparan sulfate oligosaccharides accumulating in MPSIIIB mouse brain induce the activation of microglia through TLR4 signaling. However, neuropathology is equally severe in MPSIIIB mice that do not express TRL4 or the adaptor protein MyD88, suggesting that neuroinflammation, which is associated to neurodegeneration, is a secondary event rather than the cause of neuropathology.

When isolated in primary cultures, MPSIIIB neurons show abnormal dendritic growth and altered

trafficking of lysosomes in cell prolongations. Our goal is to elucidate mechanisms responsible for altered endocytosis, exocytosis, membrane export and lysosome homeostasis in neurons and find new therapeutic targets.

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 morphogens, leading to motor neuron differentiation in vitro. Motor neurons were produced upon transplantation in the spinal cord or the facial nucleus of adult recipient rats or mice.

We are currently examining conditions that would allow the development of functional connections of transplanted motor neurons to target muscles and afferents projections. Experiments are performed in chick embryos and adult rats. Transplantation in a mouse model of motor neuron disease is aimed at assessing therapeutic potential.


MPSIIIB mouse neuron. Lysosomes are stained with a lysosomal hydrolase fused to GFP. Enlarged, immobile lysosomes are visible in the axon (arrow).


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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