Patent ID: 8309686

Claim:
A modified Clostridial neurotoxin comprising: a) a botulinum neurotoxin A binding domain comprising a first heavy chain portion able to interact with a surface receptor present in a target cell, wherein said first heavy chain portion comprises a mammalian blood protease cleavage site, said mammalian blood protease cleavage site comprising a modification in one or more regions selected from the group consisting of amino acids 930-935 of SEQ ID NO: 1, amino acids 1060-1063 of SEQ ID NO: 1, amino acids 1136-1144 of SEQ ID NO: 1 and amino acids 1165-1171 of SEQ ID NO: 1; b) a Clostridial neurotoxin translocation domain comprising a second heavy chain portion able to mediate the escape of a light chain portion of said neurotoxin from an endosome to the cytoplasm of said target cell, wherein said Clostridial neurotoxin translocation domain is a BoNT/B translocation domain, a BoNT/C 1 translocation domain, a BoNT/D translocation domain, a BoNT/E translocation domain, a BoNT/F translocation domain, a BoNT/G translocation domain, or a TeNT translocation domain; and c) a Clostridial neurotoxin enzymatic domain comprising said light chain portion able to cleave a SNARE-protein present in said target cell, wherein said Clostridial neurotoxin enzymatic domain is a BoNT/B enzymatic domain, a BoNT/C 1 enzymatic domain, a BoNT/D enzymatic domain, a BoNT/E enzymatic domain, a BoNT/F enzymatic domain, a BoNT/G enzymatic domain, or a TeNT enzymatic domain; wherein said modified Clostridial neurotoxin is able to interact with a surface receptor of said target cell, able to mediate endosomal escape into the cytoplasm of said target cell and able to cleave a SNARE protein present in said target cell; and whereupon said modified Clostridial neurotoxin's ability to interact with a surface receptor of said target cell is inactivated upon cleavage of said mammalian blood protease cleavage site.