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AssigneeInstituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A.
InventorsIsabelle Gloaguen, Annalise Di Marco, Anna De Martis, Ralph Laufer, Isabella Saggio
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The subject of the present invention are variants of ciliary neurotrophic factor with enhanced receptor selectivity (CNTFR), useful for the treatment of diseases and disorders including motor neuron diseases and muscle degenerative diseases. Another subject of the invention is to provide a method for identifying the above mentioned CNTF variants. The hCNTF variants with the amino acid substitutions in accordance with the present invention, have a reduced ability, as compared to the human CNTF, to elicit biological effects through soluble CNTFR, without affecting its ability to activate membrane-bound neuronal CNTF receptors, thereby improving its therapeutic properties. FIG. 1 shows the reduced CNTFR binding affinity of a CNTF variant according to the invention (IA-CNTF; SEQ ID NO: 2). It is evident that the binding affinity of this variant to the CNTFR is reduced as compared to the wild-type human CNTF molecule.
A variant of the ciliary neurotrophic factor (CNTF), characterized in that the residues in the positions corresponding to the positions 169 and 174 of the human CNTF wild type (SEQ ID NO:1) are replaced with the residue of isoleucine and the residue of alanine respectively, said variant exibiting an unaltered binding affinity for the CNTF membrane receptor with respect to the CNTF wild type and a reduced binding affinity for the soluble CNTF receptor with respect to the CNTF wild type.
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