A single drug could be a near-universal therapy for a rare disease

An international study involving the Centre for Genomic Regulation (CRG) in Barcelona, ​​published in Nature Structural & Molecular Biology , offers the first evidence that a single drug can stabilize almost all mutated versions of a human protein , regardless of where the mutation occurs.

The work focuses on the vasopressin V2 receptor (V2R), a protein essential for normal kidney function. Mutations in the gene that encodes it prevent kidney cells from responding to the hormone vasopressin , causing nephrogenic diabetes insipidus (NDI), a rare disease that affects approximately 1 in 25,000 people. Those who suffer from it experience excessive thirst and the production of large volumes of dilute urine.

Rare diseases affect fewer than 1 in 2,000 people, but collectively they affect around 300 million patients worldwide. The development of therapies is often slow and unattractive to the pharmaceutical industry, so findings like this represent a promising step toward broader and more effective treatments.

The scientific team generated more than 7,000 mutated V2R variants in the laboratory. They then evaluated the effect of the drug tolvaptan, an oral medication already approved for other kidney diseases. The results show that this compound was able to restore normal protein levels in 87% of the mutations studied, suggesting that it acts as a "nearly universal" pharmacological chaperone.

"Tolvaptan stabilizes the receptor long enough for it to pass cellular quality controls and reach the cell surface," explains Taylor Mighell, first author of the study and a postdoctoral researcher at the CRG.

The discovery opens the door to a new therapeutic strategy for rare diseases: moving from the traditional " one drug per mutation" approach to a one drug per protein model .

According to the authors, this approach could greatly accelerate the development of treatments. More than 40% of rare diseases are due to mutations that destabilize proteins, suggesting that this mechanism could be extended to other pathologies.

The V2R belongs to the large family of G protein-coupled receptors (GPCRs), which are targeted by approximately one-third of approved drugs. Many misfolded GPCRs are implicated not only in rare diseases but also in common pathologies.

"If this behavior is replicated in other members of the receptor family, we could move toward developing general pharmacological chaperones that would benefit many more patients," says ICREA Professor Ben Lehner, group leader at the Wellcome Sanger Institute (UK) and the CRG.

For Francesc Palau, a researcher at the CSIC and the Sant Joan de Déu Hospital , the study "provides results that could have great therapeutic relevance." Speaking to SCM, Palau emphasizes that the repositioning of already approved drugs "accelerates the leap to clinical practice" and that, in this case, "the almost universal nature of the effect is the most innovative aspect."

However, he cautions that the approach is primarily limited to missense mutations (changing one amino acid for another), so not all genetic diseases would be treatable with this strategy.