Protein Trafficking Diseases

It is estimated that over 100 inherited human diseases are due to protein trafficking defects caused by mutations in secreted proteins which prevent proper folding of the protein. In most cases, the mutations are not in the trafficking machinery, but, rather, reside in the secreted proteins. These mutant cargo proteins fold inefficiently and, thus, fail to exit the endoplasmic reticulum (ER). This produces a “loss of function” phenotype. The misfolded proteins are detected by a quality control system in the ER and are degraded by the ubiquitin proteasome system. Many mutant cargo proteins retain catalytic activity; thus, there is considerable interest in restoring of trafficking as a possible therapeutic strategy. Recent studies suggest that the folding and secretory capacity of the ER is regulated. It is our hypothesis that stimulation of ER function is a promising therapeutic strategy for treating a variety of inherited diseases, such as cystic fibrosis, lysosomal storage diseases, and long QT syndrome, caused by trafficking defects of misfolded secreted proteins.

A well-studied example of a “cargo mutant” is a variant of the protein cystic fibrosis conductance transmembrane regulator (CFTR), a chloride channel that controls salt balance in the lungs and pancreas. One mutation in CFTR, ΔF508, occurs in the majority of cystic fibrosis patients and has been extensively studied. ΔF508-CFTR lacks a phenylalanine in the first nucleotide binding domain. As a consequence, there is a defect in folding which inhibits forward transport to the Golgi. Instead, the misfolded mutant protein is targeted to the ER assisted degradation (ERAD) pathway. When the folding of ΔF508-CFTR is facilitated by incubation of cells at low temperature or by treatment of cells at physiological temperatures with pharmacological chaperones, some of the mutant protein is delivered to the plasma membrane where it displays partial chloride channel activity. It is our hypothesis that the export of protein cargo from the (ER) is regulated and amenable to modulation by small molecules. Using a rapid, proprietary ER to Golgi trafficking assay, FoldRx has identified compounds that stimulate this pathway and has shown that a subset also correct trafficking ΔF508-CFTR. The FoldRx pathway platform is applicable to additional mutant cargo proteins.