Wednesday June 21 2006
CEA
The astrocyte: a new therapeutic target for Huntington’s disease?
Journal of Neurosciences (2006).
CEA
Researchers at the Frédéric Joliot Hospital Service (DRM, CEA, CNRS URA 2210 Orsay), jointly with other French and Swiss teams, have successfully characterised the mechanisms of action of ciliary neurotrophic factor (CNTF). This trophic factor is a candidate agent for the treatment of Huntington’s disease.
Huntington’s disease (HD) is a dominant hereditary neurodegenerative disorder characterised by motor dysfunction (chorea) and cognitive deficits. It appears at a young age (30-40 years in general). On average the disease is fatal in 10-15 years. In France, it affects some 5000 to 6000 persons. There is still no effective treatment to slow the progress of the disease.
Our research department has developed different experimental strategies to treat this disease, one of which uses gene therapy. This consists in causing the brain cells themselves to produce a potentially therapeutic protein by making local injections of genetically modified viruses containing genes coding for these proteins. These vectors penetrate neighbouring cells, so that the genes delivered are directly incorporated into the DNA of the host cell. Our research department had already demonstrated the neuroprotector effect of a lentivirus and an adenovirus coding for a specific neurotrophic factor, the ciliary neurotrophic factor (CNTF), in primate, rat, transgenic mice and cell models of HD. Although the results are promising, the mechanisms of action of CNTF were still not well understood and its possible long-term toxicity largely unknown.
One hypothesis was that one target of CNTF might be the astrocyte. These glial cells make up 90% of brain cells, and are involved in a great many functions. They are often activated in pathological situations, but their role in these conditions is not well known. The results obtained show that an expression of CNTF induced by a lentivirus (lenti-CNTF) in the rat striatum strongly modifies the phenotype of the astrocytes and the energy metabolism. Also, the glutamate homeostasis is improved by a new mechanism of redistribution of these astrocytal transporters in the subcellular compartments. In excitotoxic conditions, which partly mimic the neurodegenerative mechanism of Huntington’s disease, glutamate management, energy supply and neurone survival are significantly improved by lenti-CNTF. These results underline the beneficial role of astrocytes activated by CNTF, which display phenotypic and functional modifications that favour neurone survival. This work opens up a new field of potential therapeutic intervention targeting not neurones but astrocytes. The identification of agents and the assessment of their therapeutic efficacy will soon be carried out in different genetic models of Huntington’s disease using the MIRCEN facility at CEA Fontenay-aux-Roses.
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Treatment of astrocyte cell cultures with CNTF modifies the appearance of the astrocytes labelled with an antibody directed against GFAP (green)