Mechanisms of disease: Mendelian disorders of membrane trafficking

It is reasonable to hope that our basic knowledge of membrane trafficking will continue to provide insights into the pathogenesis of mendelian diseases and that studies of these diseases will continue to enhance our understanding of the membrane- trafficking system. In particular, it will be of great interest in this context to learn how to place the genes that are involved in trafficking-related diseases into coherent pathogenetic pathways. Regrettably, the wealth of new insights into the molecular defects in membrane-trafficking disorders has not yet led to a proportionate availability availability of effective therapies. However, in the past few years, the potential of mendelian diseases to drive the process of drug development has been recognized. ^52,53 An example in the field of membrane transport is cystic fibrosis. Effective modulators of the folding, trafficking, and activity of CFTR (the chloride channel that is mutated in cystic fibrosis³⁵) have been found through high-throughput screening that was aimed at identifying pharmacologic treatments for this disease. Some of these modulators (e.g., VX-809) are now being tested in clinical trials.⁵⁴ In addition, interest in the pathways affected in mendelian disorders is being raised further by the recognition that efforts to develop drugs for their treatment might also prove useful in common diseases in which the same pathways might have a pathogenetic role, such as type 2 diabetes and Alzheimer's disease. ^52,53