Repurposing Tazarotene for Multiple Sulfatase Deficiency: A Path TowardClinical Application

Abstract

Despite increasing research efforts, Multiple Sulfatase Deficiency (MSD, MIM #272200) remains an untreatable disease with a high unmet medical need. Various therapeutic approaches, including gene therapy and hematopoietic stem cell transplantation, have been explored. Among them, small-molecule drug identification has been a key strategy for therapy development. Drug repurposing—repositioning existing medications for new indications—

offers a fast-track route to treatment by leveraging existing knowledge on formulation, toxicity, dosage, safety, and side effects. This significantly reduces the time and cost associated with early pharmacological and clinical development. A high-throughput drug screening on MSD patient-derived cells identified tazarotene, a third-generation retinoic acid derivative, as a potential therapeutic candidate capable of reversing disease pathology in vitro. Currently approved for topical treatment of plaque psoriasis and acne, tazarotene was previously evaluated for oral administration in clinical trials (Phase I–III) with approximately 1,500 participants. While proven efficacious for its intended indications, oral tazarotene was not licensed by the FDA due to post-marketing safety monitoring concerns.As part of the REMEDI4ALL initiative, an EU-funded consortium of 24 partners—including academia,

industry, patient organizations, and regulatory agencies—tazarotene has been selected as a demonstrator project for drug repurposing. REMEDI4ALL has facilitated a target product profile and gap analysis, leading to reformulation, evaluation, and production of oral tazarotene for clinical development in MSD. Collaboration with the pharmaceutical industry ensures

access to existing toxicity, preclinical, and clinical data, aiding regulatory processes. These efforts have culminated in scientific advice meetings with regulators, paving the way for the first clinical trial in MSD patients, scheduled to begin by the end of 2025.