Evidence of a universal lockpick against rare diseases

A single drug capable of stabilizing nearly all mutated versions of the same protein , regardless of the type and location of the disease-causing mutation: this is the first clue to a universal lockpick , which could help address the complex challenge of rare diseases, where research is severely hampered by the fact that the same disorder can be caused by so many different mutations . The result, published in the journal Nature Structural & Molecular Biology, is the work of a team of researchers led by the Center for Genomic Regulation (CRG) in Barcelona.

Researchers Taylor Mighell and Ben Lehner engineered 7,000 different versions of the V2R protein in the laboratory , the receptor for the hormone vasopressin , which is essential for normal kidney function . Mutations in this protein cause a disease that affects approximately 1 in 25,000 people . By examining the most commonly observed mutations in patients, they discovered that the drug tolvaptan, already clinically approved for other kidney diseases , can restore the function of the V2R receptor in 87% of the variants, or approximately 9 out of 10 cases.

According to the study's authors, tolvaptan works regardless of the location of the mutation because it helps the protein fold into its correct shape , stabilizing it. Previous research has shown that between 40% and 60% of mutations underlying rare diseases affect the stability of a protein , so the study opens new avenues for the development of universal or near-universal drugs : instead of searching for a molecule that targets a single mutation, one can generically stabilize the entire protein. "Drug developers could avoid spending years searching for tailored therapeutic molecules," Lehner comments, "significantly accelerating the development of drugs for many genetic diseases."