When genes are mutated several different outcomes are possible. The gene can be trunctated, meaning that the full length protein is not made. The mutated protein can have an active-site mutation, meaning the resulting protein can’t perform it’s usual catalytic reaction. Or the mutation can effect the stability and localization of the protein. These are the trafficking mutations.
What makes trafficking mutations especially promising from a therapeutic persecptive is that the full-length protein is being made, and the resulting protein does have a functional active site. All that remains for an effective therapy is to restore the proper folding and localization of the protein.
The cell has a complex and highly regulated logistics network that takes specific proteins to specific compartments within the cell where they carry out their function. When this logistics network gets disrupted, chemical reactions that should be occurring do not take place and the chemical balance in the cell is thrown off (that’s what happens in Gaucher’s disease, for example). Additionally, trafficking defects often involve misfolding of the mutated protein and this can lead to aggregation of proteins within the cell, which is something that stresses cells. Protein aggregates play a large role in neurodegenerative diseases such as ALS, Parkinson’s and Alzheimer’s and having mutated proteins aggregating in neurons is thought to accelerate and even cause these neurodegenerative diseases. Similarly, protein aggregates in other tissues can result in liver disease, heart disease, and even blindness, when the aggregates occur in the eye.
Small molecules can restore protein trafficking, allowing the protein to be delivered to its intended location, and to function normally. Perhaps the best know of these are the Cystic Fibrosis drugs developed by Vertex and the Cystic Fibrosis Foundation. These compounds restore the proper trafficking of the defective protein in CF (a protein called CFTR) and restore activity, with benefits for patients much like those achieved by protein replacement therapies. Such compounds are called chemical chaperones, and many other defective proteins have been corrected using other chaperones developed in the scientific literature, making this a general platform for correcting trafficking defects.