USE OF A HOLOTOXIN TO REDUCE ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION OF MISFOLDED PROTEINS

摘要

Provided is a use of a holotoxin to reduce endoplasmic reticulum-associated degradation (ERAD) of misfolded or abnormally folded proteins The holotoxin can thus be used in a method to treat diseases related to ERAD Examples of misfolded proteins that are degraded in the ER include the cystic fibrosis transmembrane conductance regulator (CFTR) delta F508 mutant protein, a misfolded mutant (G268V) of multi-drug resistance 1 (MDR1), and the glucocerebrosidase (GCC) enzyme in Gaucher' s dis¬ease cells Examples of suitable holotoxins include ricin, shiga toxin, exotoxin A, plasmid-encoded toxin, cholera toxin, and verotoxin 1 (VT1) VT1 is also known as vero-toxin A, shiga-like toxin 1, shiga-like toxin 1, or shiga tox¬in type 1 A non-toxic inactive VT1 can also be used wherein crucial residues of the A subumt active site are mutated, for example, the mutations Y77S and E167Q