Therapies for rare diseases: therapeutic modalities, progress and challenges ahead

• Published in: Nature reviews. Drug discovery Vol. 19; no. 2; pp. 93 - 111
• Main Authors: Tambuyzer, Erik, Vandendriessche, Benjamin, Austin, Christopher P., Brooks, Philip J., Larsson, Kristina, Miller Needleman, Katherine I., Valentine, James, Davies, Kay, Groft, Stephen C., Preti, Robert, Oprea, Tudor I., Prunotto, Marco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 631/154/436; 631/154/556; 692/308/153; 692/699; Analysis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Candidates; CRISPR; Cystic fibrosis; Disease; Drug Approval; Drug Development; Drug Repositioning - statistics & numerical data; Drugs; Economic incentives; Genomes; Health aspects; Humans; Medical research; Medicinal Chemistry; Molecular Medicine; Monoclonal antibodies; Mutation; Orphan Drug Production - statistics & numerical data; Orphan drugs; Patients; Pharmacology/Toxicology; Proteins; Rare diseases; Rare Diseases - drug therapy; Review Article; Success
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/s41573-019-0049-9

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools. Most rare diseases still lack approved treatments. This article analyses the main therapeutic modalities available to researchers interested in translating advances in the scientific understanding of rare diseases into therapies, highlights progress so far and discusses overarching issues in drug development for rare diseases.