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AssigneesInstitut Pasteur, Centre Nationale de la Recherche Scientifique
InventorsSylvie Roux, Philippe Brulet, Cecile Saint Cloment, Julien Barbier, Jordi Molgo
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A hybrid protein (GFP-TTC) comprising the non-toxic proteolytic C fragment of tetanus toxin fused to green fluorescent protein was used to analyze the functional synaptic organization of neural networks. When injected intramuscularly in vivo, the GFP-TTC hybrid protein binds to tetanus neurotoxin receptors and clusters very rapidly to the active neuromuscular junction. Membrane traffic by GFP-TTC at the pre-synaptic level of the neuromuscular junction is strongly and rapidly influenced by exogenously co-injecting neurotrophic factors, such as BDNF, NT-4, and GDNF, but not by NGF, NT-3, and CNTF. The membrane traffic, directly detected using GFP-TTC in vivo, permits methods of analyzing synaptic functioning as well as methods of modulating neuronal transport using neurotrophic factors and agonists or antagonists thereof.
A method for in vivo delivery of a desired composition into human or animal central nervous system (CNS) or spinal cord, wherein the method comprises administering to the human or animal a composition comprising a non-toxic, proteolytic fragment of tetanus toxin (TT) in association with at least a molecule having a biological function and said composition is capable of in vivo retrograde axonal transport and transynaptic transport into the CNS or the spinal cord of the human or animal and of being delivered at different areas of the CNS or the spinal cord.
A hybrid fragment of tetanus toxin comprising a fragment C and a fragment B or a fraction thereof of at least 11 amino acid residues capable of transferring in vivo a protein, a peptide, or a polynucleotide through a neuromuscular junction and at least one synapse.
A hybrid fragment of tetanus toxin comprising a fragment C and a fragment B or a fraction thereof of at least 11 amino acid residues and a fraction of a fragment A devoid of its toxic activity corresponding to the proteolytic domain having a zinc-binding motif located in the central part of the chain between amino acids 225 and 245 capable of transferring in vivo a protein, a peptide or a polynucleotide through a neuromuscular junction and at least one synapse.
A polynucleotide variant fragment capable of hybridization under stringent conditions with the natural tetanus toxin sequence.
A method of modulating the transport in a neuron of a tetanus toxin or a fusion protein comprising a fragment C of the tetanus toxin, wherein the method comprises administering to the neuron a TrkB receptor agonist or a TrkB receptor antagonist in an amount sufficient to modulate the neuronal transport of the tetanus toxin or the fusion protein.
The method according to claim 42, wherein the internalization of the tetanus toxin at the neuromuscular junction is decreased.
A method of modulating the transport in a neuron of a tetanus toxin or a fusion protein comprising a fragment C of the tetanus toxin, wherein the method comprises administering to the neuron a GFRα/cRET receptor agonist or a GFRα/cRET receptor antagonist in an amount sufficient to modulate the neuronal transport of the tetanus toxin or the fusion protein.
A composition, comprising a TrkB receptor agonist and a fusion protein comprising a fragment C of the tetanus toxin fused to a second protein.
A composition, comprising a GFRα/cRET receptor agonist and a fusion protein comprising a fragment C of the tetanus toxin fused to a second protein.
A method of detecting an effect of a compound on neuronal transport, comprising administering to a neuron the compound and a fusion protein comprising a fragment C of the tetanus toxin fused to a second protein, wherein the second protein is encoded by a reporter gene, and detecting the second protein to determine the effect of the compound on neuronal transport.
A method of screening for a compound that reduces or prevents transport of a tetanus toxin in a neuron, comprising administering to the neuron the compound and a fusion protein comprising a fragment C of the tetanus toxin fused to a second protein, wherein the second protein is encoded by a reporter gene, detecting the second protein, and selecting the compound that reduces or prevents the neuronal transport of the fusion protein.
Dependencies are inferred from the claim text.