Genetic Skin Diseases and Therapies

Novel genetic treatments for genetic conditions emerge every day. Treating patients with genetic conditions using such treatments or developing them in our lab requires that we know the exact genetic cause. In this research, we aim to solve the genetic cause in all patients with genetic skin conditions, applying innovative and experimental genomic diagnostic techniques in a multidisciplinary collaboration involving (clinical) geneticists, dermatologists, pathologist and laboratory specialists, PhD students and trainees.

Antisense oligonucleotides (ASOs) are small stretches of chemically modified RNA bases that can influence mRNA splicing and expression. Splice switching ASOs can be used to hide a mutated exon from the splicing machinery and bypass a disease-causing mutation, thereby restoring protein production and ameliorating the disease. This RNA-therapeutic strategy is called exon skipping. We are pursuing ASO-mediated exon skipping for the rare skin blistering disease epidermolysis bullosa, in collaboration with the Epidermolysis Bullosa and related disorders and Experimental Dermatology research groups in Dermatology.

The main challenge in RNA therapeutics in the coming years will be delivery of sufficient amounts of active ASOs to the right tissues and cells. In order to enhance the delivery of exon skipping ASOs to the basal keratinocytes in the epidermis to treat epidermolysis bullosa, we are studying two different delivery approaches using ASO-conjugation to specific antibodies and polymers. We do this in close collaboration with the Experimental Dermatology research group and international partners.

The goal of the UMCG Personalized ASO Therapy Platform that we launched in 2025 is to develop ultra-individualized (N-of-1) ASO therapies for patients with ultrarare genetic diseases. Most approved and N-of-1 ASOs target the central nervous system (CNS) through intrathecal delivery, which makes the CNS the prime candidate for rapid clinical translation of ASO therapies. Therefore, we are currently focusing on ASO development for genetic neuro-metabolic diseases caused by deep-intronic variants that introduce toxic pseudo-exons. ASO-mediated correction of pseudo-exons will restore the wildtype situation. Within the platform, we collaborate with many committed (research) groups in the departments of Genetics, Pediatrics, Metabolic diseases, and Dermatology, ERIBA - European Research Institute for the Biology of Ageing, Ipsomics, the Hospital Pharmacy, the Technology Transfer office, and the Dutch Center for RNA Therapeutics.

Most rare genetic diseases have no effective treatment, and classic drug development for these diseases is impossible due to the small number of patients with each condition. Yet thousands of approved drugs already exist, and for many their effects on gene expression have been determined. In parallel to these advances, the Functional Genomics group in the Department of Genetics has identified organ-specific gene network interactions. In an ongoing project, we aim to integrate these network-based predictions with drug-response data to systematically prioritize drug repurposing candidates for patients with otherwise non-treatable genetic conditions.

Our research strategy on epidermolysis bullosa (EB) was established in close collaboration with the Dutch patient organization for EB (DEBRA NL), and the Dutch EB fund-raising organization the Butterfly Child Foundation (Stichting Vlinderkind NL), and the Epidermolysis bullosa research group in the Dermatology department. The Dutch Butterfly Child Foundation generously supports many of the EB projects our group is working on. Together with the Epidermolysis bullosa research group, we have regular meetings with the Dutch EB patient organizations to discuss current project progress, plans for new research projects, and new fund-raising opportunities.
For several research projects, we are collaborating with international EB patient organizations as well. For instance, together with the British EB patient organization DEBRA UK, we are studying key hurdles that hinder rapid diagnostics in EB. DEBRA UK have also funded a drug repurposing project.