Researchers from Oregon Health and Science University (OHSU), led by P. Michael Conn, have demonstrated in mice a novel technique used to cure disease caused by misfolded protein molecules. The same technique could be used to cure human diseases with similar etiology.
Human diseases caused by misfolded proteins are diverse and numerous. Among them are many neurodegenerative diseases – Alzheimer’s, Parkinson’s, Huntington’s – as well as certain types of diabetes, lysosomal storage diseases, cystic fibrosis, inherited cataracts and many others.
Misfolded proteins are not intrinsically non-functional, but rather they fail to function because they never reach their physiologic site of action. Upon recognizing a misfolded protein as such, a cell’s quality control system either retains the protein in the endoplasmic reticulum or misroutes it to another site. Retention results in loss of function at the normal site of biological activity, with pathological consequences.
Pharmacoperones are target-specific small molecules that diffuse into cells and serve as folding templates that enable mutant proteins to pass the criteria of the quality control system and route to their physiologic site of action, thus retaining functionality.
The OHSU study, published in the December 2013 issue of PNAS, used pharmacoperones to cure mice of hypogonadotropic hypogonadism, a disease which also occurs in humans. Caused by a mutation in the gonadotropin-releasing hormone receptor gene (GnRHR) which produces a misfolded GnRHR protein, hypogonadotropic hypogonadism is characterized by failed puberty associated with low or apulsatile luteinizing hormone. By treating mice with a pharmacoperone of the gonadotropin releasing hormone receptor, researchers successfully restored spermatogenesis and returned androgen and other proteins associated with steroid transport and steroidgenesis to their normal levels, successfully curing the mice.
The results from Conn and his team are the culmination of nearly 13 years of work, that he believes may have broad impact; “The ability of these drugs to rescue misfolded proteins and return them to normalcy could someday be an underlying cure to a number of diseases. Drugs that act by regulating the trafficking of molecules within cells are a whole new way of thinking about treating disease.”
The next step, Says Conn, will be clinical trials to see if the same technique can work in humans.
Pharmacoperones have also shown promise as an alternative to enzyme replacement therapy for treating lysosomal storage diseases such as Gaucher disease. The novel approach for protein rescue may be translatable to diverse human diseases with pathologies resulting from misrouting of misfolded proteins.