An international team of researchers has developed a new series of light-activated drugs that could serve as a potential treatment for psoriasis. These drugs would allow the modulation of the vitamin D receptor, activating it safely and avoiding the side effects associated with modulating this receptor, related to the deregulation of calcium levels.
The study, recently published in the scientific journal ACS Central Science, has been led by the Institute of Advanced Chemistry of Catalonia (IQAC) of the CSIC, in collaboration with the Bellvitge Biomedical Research Institute (IDIBELL) and the University of Barcelona (UB). Two American universities have also participated, the University of Johns Hopkins and the University of Purdue, and the pharmaceutical company Eli Lilly and Company.
Modulating the vitamin D receptor without side effects
Activation of vitamin D receptor (VDR) has demonstrated beneficial effects in psoriasis. However, its crucial role in calcium metabolism limits clinical applications due to the risk of potentially life-threatening calcium deregulation (hypercalcemia), which can lead to serious diseases such as bone malformations. Several pharmaceutical companies have developed drug discovery programs targeting this receptor that lack these secondary effects, but to date no medication has ever reached the market.
“The objective of this study was the design and synthesis of a series of photocontrollable vitamin D receptor agonist molecules,” explains Dr. Xavier Rovira, researcher at IQAC-CSIC. “Ultimately, we worked with an optimized molecule, PhotoVDRM, which is inactive in the darkness and can be selectively activated with light using specific wavelengths or colors, including visible blue light, which is not phototoxic, and UVB, which is used in current treatments,” Rovira clarifies.
In vivo tests were carried out on mouse models, reducing skin inflammation without causing the usual side effects when activating the vitamin D receptor. “This targeted activation produced a robust therapeutic effect without systematic hypercalcemia, thus addressing, at a preclinical level, an important historical impediment to treatment with VDR agonists in clinical trials”, says Amadeu Llebaría, from the IQAC-CSIC.
This strategy based on photopharmacology paves the way for safer therapies that act on the vitamin D receptor. Furthermore, “our results reinforce the fact that photopharmacology can be applied to locally activate systemically administered drugs”, explains Dr. Francisco Ciruela, leader of the Neuropharmacology and pain group at IDIBELL. “This opens the door to targeted and less invasive treatments for skin diseases such as psoriasis,” he adds.
Photopharmacology, towards a new generation of safe and targeted therapies
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 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. It is precisely this accessibility of the skin that makes pathologies such as psoriasis the priority objective of these new therapies.
Psoriasis, a prevalent disease with limited options
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 crucial proteins for cell-to-cell communication. Although these new treatments significantly reduce psoriasis-associated inflammation and have fewer side effects, they remain very costly. In addition, the use of these biological therapies is not indicated for localized psoriasis, which is classified as mild, and some patients suffer from lesions in particularly sensitive areas.
In this scenario, PhotoVDRM, the drug optimised by the IQAC-CSIC team, in collaboration with IDIBELL and the University of Barcelona, opens the doors to an effective, safe, and localized alternative to treat psoriasis, without the risks of current treatments. In addition, in the future, it could be applied to other diseases mediated by the vitamin D receptor, offering a general approach to develop more precise and safer treatments.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center created in 2004 specialized in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, generate more than 1,400 scientific articles a year. IDIBELL is participating in the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, he is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL is an Accredited Center of the AECC Scientific Foundation (FCAECC).