A Dutch translational knowledge agenda for inherited metabolic diseases

Abstract

The advancement of innovative diagnostics, such as newborn screening and -omics strategies targeting DNA, RNA and metabolites, has led to the identification of a rapidly growing number of patients with an inherited metabolic disorder (IMD) as well as new IMDs, currently encompassing more than 1500 distinct diseases (www.icimd.org). Concurrently, significant therapeutic milestones have been achieved and are being developed for a number of IMDs, including the creation of specific diets, enzyme replacement therapy and DNA/RNA targeting therapies. A recent review of ICIMD identified 287 IMDs amenable to one or more of these treatments (www.iembase.org).

Despite these advancements, or perhaps partly because of them, numerous clinical, scientific and societal challenges continue to impede the delivery of optimal care to the majority of IMD patients. To identify current knowledge gaps and areas for improvement (i.e. research questions), and to set priorities for the IMD field for the next 4–8 years with an emphasis on achieving improved care and outcomes for IMD patients, the “United for Metabolic Diseases” (UMD) consortium (www.umd.nl) in the Netherlands initiated the development of a Translational Knowledge Agenda for Inherited Metabolic Diseases. The process and outcomes, detailed in a publication in JIMD Reports¹ involved equal participation of professionals with diverse expertise as well as patient representatives. A multidisciplinary steering committee, comprising 12 metabolic experts—including laboratory specialists, metabolic researchers, metabolic pediatricians, internists, pediatric neurologists, dieticians, nurse specialists, and patient organizations- collected research questions from the field via an online survey using the snowball sampling method. A total of 158 participants completed the survey, with a balanced composition of 54% patient representatives and 46% healthcare professionals and researchers. The 462 proposed research questions were subsequently discussed, categorized and prioritized during a meeting attended by 22 representatives of the aforementioned stakeholder groups, using as main criteria: patient-centeredness, implications for the development of the entire field, unmet needs, feasibility of research and relevance for other stakeholders. The resulting top 10 research questions cover multiple themes, including prediction of disease progression, development of novel tools, mechanistic insights, improved diagnostics, therapeutic integration of multi-omics techniques, assessment of impact on daily life, expansion of treatment avenues, optimal study designs, effects of lifestyle interventions and data utilization following FAIR principles.

An essential aspect in the development of the knowledge agenda was the consistent incorporation of patients' input and perspectives at each development stage. This active patient engagement ensured the inclusion of lifestyle-related questions and psychosocial burden as critical aspects from the patients' viewpoint. The broad and translational nature of the field made it challenging to prioritize only 10 research questions of overarching significance for all IMDs. Consequently, research questions with particular impact on specific or subsets of diseases were excluded from the prioritization. However, they can be inferred from the set priorities. Of note, several examples of international research agendas have previously been developed for specific groups of IMDs, for example, nephropathic cystinosis, liver glycogen storage disease and mitochondrial disorders.^2-4

This knowledge agenda offers a clear research focus for IMDs over the next 5 years.