Feasibility of disease terminology systems for mapping orphan conditions and therapeutic indications of designated orphan medicines in the European Union.

BACKGROUND: In the European Union, rare diseases are defined as diseases that affect maximum 5 in 10,000 citizens. These diseases are typically associated with a high unmet medical need. To stimulate development and authorisation of medicines for rare diseases ('orphan conditions'), the European Commission (EC) can grant orphan designations. In order to enable systematic evaluation and communication of the diseases for which designated orphan medicines have (not) been developed and authorised, we aimed to investigate the feasibility of important disease terminology systems for mapping orphan conditions and therapeutic indications. METHODS: We selected all designated orphan medicines that were authorised by the EC during 2022-2023 from the EC's Union Register of medicinal products. For these medicines, we extracted orphan conditions and associated therapeutic indications at initial marketing authorisation. The orphan conditions and separate elements of therapeutic indications such as target disease or condition, severity criteria and target population were assessed for availability in six major disease terminology systems: ICD-10, ICD-11, MedDRA, MeSH, Orphanet nomenclature of rare diseases, and SNOMED CT. Descriptive statistics were used to describe the ability of each disease terminology system to map orphan conditions and elements of therapeutic indications. RESULTS: During 2022-2023, 37 designated orphan medicines were authorised that were designated for 40 orphan conditions (of which 37 unique) and granted 39 therapeutic indications (of which 37 unique). Overall, SNOMED CT covered most descriptions of orphan conditions (33/37, 89 %) and target diseases or conditions within therapeutic indications (28/37, 76 %). However, when allowing descriptions to be partly included and/or complemented by additional words, SNOMED CT, the Orphanet nomenclature, ICD-11 and MedDRA all had high coverage (92-97 %). Other elements than target diseases or conditions within therapeutic indications were mostly lacking. CONCLUSIONS: Regulatory data concerning orphan conditions and therapeutic indications of designated orphan medicines seem to be best covered by SNOMED CT. However, which disease terminology system best facilitates systematic evaluation and communication about development and authorisation of designated orphan medicines also depends on the specific use case. Given the frequent use of SNOMED CT in healthcare settings, it may also facilitate interoperability between regulatory and healthcare data, while for example ICD-11 may be better suited to generate statistics concerning drug development for rare diseases.

Antisense Oligonucleotide-mediated Exon Skipping as a Systemic Therapeutic Approach for Recessive Dystrophic Epidermolysis Bullosa.

The "generalized severe" form of recessive dystrophic epidermolysis bullosa (RDEB-gen sev) is caused by bi-allelic null mutations in COL7A1, encoding type VII collagen. The absence of type VII collagen leads to blistering of the skin and mucous membranes upon the slightest trauma. Because most patients carry exonic point mutations or small insertions/deletions, most exons of COL7A1 are in-frame, and low levels of type VII collagen already drastically improve the disease phenotype, this gene seems a perfect candidate for antisense oligonucleotide (AON)-mediated exon skipping. In this study, we examined the feasibility of AON-mediated exon skipping in vitro in primary cultured keratinocytes and fibroblasts, and systemically in vivo using a human skin-graft mouse model. We show that treatment with AONs designed against exon 105 leads to in-frame exon 105 skipping at the RNA level and restores type VII collagen protein production in vitro. Moreover, we demonstrate that systemic delivery in vivo induces de novo expression of type VII collagen in skin grafts generated from patient cells. Our data demonstrate strong proof-of-concept for AON-mediated exon skipping as a systemic therapeutic strategy for RDEB.

Analysis of the functional consequences of targeted exon deletion in COL7A1 reveals prospects for dystrophic epidermolysis bullosa therapy.

Genetically evoked deficiency of collagen VII causes dystrophic epidermolysis bullosa (DEB)-a debilitating disease characterized by chronic skin fragility and progressive fibrosis. Removal of exons carrying frame-disrupting mutations can reinstate protein expression in genetic diseases. The therapeutic potential of this approach is critically dependent on gene, protein, and disease intrinsic factors. Naturally occurring exon skipping in COL7A1, translating collagen VII, suggests that skipping of exons containing disease-causing mutations may be feasible for the treatment of DEB. However, despite a primarily in-frame arrangement of exons in the COL7A1 gene, no general conclusion of the aptitude of exon skipping for DEB can be drawn, since regulation of collagen VII functionality is complex involving folding, intra- and intermolecular interactions. To directly address this, we deleted two conceptually important exons located at both ends of COL7A1, exon 13, containing recurrent mutations, and exon 105, predicted to impact folding. The resulting recombinantly expressed proteins showed conserved functionality in biochemical and in vitro assays. Injected into DEB mice, the proteins promoted skin stability. By demonstrating functionality of internally deleted collagen VII variants, our study provides support of targeted exon deletion or skipping as a potential therapy to treat a large number of individuals with DEB.