A study demonstrates the potential of light-activated molecules to treat psoriasis without side effects

Researchers from the Institute for Advanced Chemistry of Catalonia (IQAC) of the Spanish National Research Council (CSIC) have developed a series of light-activatable drug candidates that could serve as a potential treatment for psoriasis. The results of this study reinforce the concept that photopharmacology can be applied to locally activate systemically administered drugs. This advance opens the door to targeted and less invasive treatments for skin diseases such as psoriasis.

This work, published in the journal ACS Central Science, was carried out in collaboration with the Bellvitge Biomedical Research Institute (IDIBELL) and the Institute of Neurosciences (UBneuro) of the University of Barcelona, together with two U.S. universities—the Johns Hopkins University and Purdue University—and the pharmaceutical company Eli Lilly and Company.

New advances in photopharmacology

Photosensitive molecules do not exert an effect when administered, but they change their structure when illuminated under specific light conditions, allowing their action on target receptors to be induced under light control. This approach enables external control of the therapeutic effect of this new generation of drugs with greater precision, reducing side effects and opening new avenues toward highly specific therapies for pain, cancer or Parkinson’s disease, among others.

The implementation of photopharmacological approaches for therapeutic development is sometimes hindered by several challenges, one of the most significant being the limited penetration of light. In this regard, the most accessible tissue in humans for light-based therapies is the skin, for which several diseases still require adequate and economically accessible treatments.

Diseases with unmet clinical needs

Among skin diseases, psoriasis is one of the most prevalent and debilitating, affecting around 3% of the human population, with about 30% of patients still lacking adequate and affordable treatments.

In recent years, new drugs have been approved for moderate to severe psoriasis, many of them based on biologics targeting cytokines—small proteins that are crucial for cell-to-cell communication, especially in the immune system, regulating inflammation and responses to infection. Although these new treatments significantly reduce psoriasis-associated inflammation and have fewer side effects, they remain very costly. In addition, the use of these biologic therapies is not indicated for localized psoriasis, which is classified as mild, and some patients suffer from lesions in particularly sensitive areas.

Activation of the vitamin D receptor (VDR) has been shown to have beneficial effects in psoriasis. However, its crucial role in calcium metabolism limits its clinical applications due to the risk of potentially life-threatening calcium dysregulation (hypercalcemia), which can cause serious conditions such as bone malformations. Although several pharmaceutical companies have developed programs to identify orally administered drugs targeting the VDR that lack these side effects, no medication has yet reached the market. The most common options remain topical formulations with limited efficacy, which also require medical monitoring due to their narrow therapeutic window.

“The aim of this study was the design and synthesis of a series of photocontrollable VDR agonist molecules,” explains Dr. Xavier Rovira, researcher at IQAC-CSIC. “Ultimately, we worked with an optimized molecule, PhotoVDRM, which is inactive in the dark and can be selectively activated with light using specific wavelengths or colors, including visible blue light, which is non-phototoxic, and UVB light, both of which are used in current treatments,” Rovira clarifies.

In vivo tests were carried out in mouse models, achieving a reduction in skin inflammation without triggering the usual side effects associated with activation of the vitamin D receptor. “This targeted activation produced a robust therapeutic effect without systemic hypercalcemia, thus addressing, at a preclinical level, a major historical obstacle for VDR agonist treatments in clinical trials,” states Amadeu Llebaría from IQAC-CSIC.

This photopharmacology-based strategy paves the way for safer therapies targeting the vitamin D receptor. In the future, it could be applied to other VDR-mediated diseases, offering a general approach to the development of more precise and safer treatments.

IQAC / CSIC Comunication

comunicacion@csic.es