bims-meglyc 2025-03-16 papers

J Inherit Metab Dis. 2025 Mar;48(2): e70011

The Therapeutic Future for Congenital Disorders of Glycosylation.

I J J Muffels, T Kozicz, E O Perlstein, E Morava.

The past decade, novel treatment options for congenital disorders of glycosylation (CDG) have advanced rapidly. Innovative therapies, targeting both the root cause, the affected metabolic pathways, and resulting manifestations, have transitioned from the research stage to practical applications. However, with novel therapeutic abilities, novel challenges await, specifically when it concerns the large number of clinical trials that need to be performed in order to treat all 190 genetic defects that cause CDG known to date. The present paper aims to provide an overview of how the CDG field can keep advancing its therapeutic strategies over the coming years with these challenges in mind. We focus on three important pillars that may shape the future of CDG: the use of disease models, clinical trial readiness, and the possibility to make individualized treatments scalable to the entire CDG cohort.

Keywords: CDG; basket trials; clinical trial readiness; congenital disorder of glycosylation; disease models; glycosylation; novel therapies

DOI: https://doi.org/10.1002/jimd.70011

Mol Genet Metab. 2025 Mar 01. pii: S1096-7192(25)00064-2. [Epub ahead of print]144(4): 109073

SIMPATHIC: Accelerating drug repurposing for rare diseases by exploiting SIMilarities in clinical and molecular PATHology.

Clara D M van Karnebeek, Annelieke R Müller, Laura Benkemoun, Ibrahim Boussaad, Martina C Cornel, Joanna IntHout, Martin de Kort, Sofia de Oliveira Martins, Alessandro Prigione, Tessel Rigter, Kit C B Roes, Anna Sanchez, Raymond Schipper, Mark D Wilkinson, Peter A C 't Hoen.

Rare diseases affect over 400 million people worldwide, with approved treatment available for less than 6 % of these diseases. Drug repurposing is a key strategy in the development of therapies for rare disease patients with large unmet medical needs. The process of repurposing drugs compared to novel drug development is a time-saving and cost-efficient method potentially resulting in higher success rates. To accelerate and ensure sustainability in therapy development for rare neurometabolic, neurological, and neuromuscular diseases, an international consortium SIMilarities in clinical and molecular PATHology (SIMPATHIC) has been established where we move away from the one drug one disease concept and move towards one drug targeting a pathomechanism shared between diseases, by applying parallel preclinical and clinical drug development. Here the consortium describes accelerators of drug repurposing pursued by the consortium, including 1) co-creation, 2) patient empowerment, 3) use of standardized induced pluripotent stem cell (iPSC)-derived disease models and cellular and molecular profiling, 4) high-throughput drug screening in neurons, 5) innovative clinical trial design, and 6) selection of appropriate exploitation and patient access models. In this way, a fast and effective drug repurposing pathway for several rare diseases will be established to reduce time from discovery to patient access.

Keywords: Basket trial; Drug repurposing; Drug screening; Induced pluripotent stem cells; Rare diseases; Therapy development

DOI: https://doi.org/10.1016/j.ymgme.2025.109073

Front Public Health. 2025 ;13 1510818

A global survey about undiagnosed rare diseases: perspectives, challenges, and solutions.

Background: Undiagnosed rare diseases (URDs) are a complex and multifaceted challenge, especially in low-and medium-income countries. They affect individuals with unique clinical features and lack a clear diagnostic label. Although the Undiagnosed Diseases Network International (UDNI) definition of URDs is not universally accepted, it is widely recognized.
Methods: We surveyed UDNI members and participants from other countries to explore the challenges posed by URDs and identify possible solutions. Participation in the survey was completely voluntary.
Results: The survey revealed a need for more consensus on a universally accepted definition for URDs. Still, the UDNI definition gained widespread recognition and serves as a valuable framework for understanding and addressing the challenges of URDs. In addition to national or international networks, fostering a more substantial engagement and resource-sharing ethos among member countries is critical. Despite advances in genomics and diagnostic tools, the diagnostic journey for people living with URDs (PLURDs) remains arduous and often inconclusive. The availability of specialized centers and the utilization of whole exome sequencing (WES) and whole genome sequencing (WGS) vary across countries, with disparities due to healthcare systems, economic status, and government policies. Advocacy groups play a crucial role in supporting PLURDs.
Conclusion: A unified commitment to prioritizing URDs on the global health agenda, paired with targeted funding, stipulated national strategies, and aligned international cooperation, is imperative to leveling the playing field for the diagnosis and management of URDs and capitalizing on the potential of Advocacy Groups as allies in this endeavor.

Keywords: advocacy groups; diagnostic journey; genomic diagnosis; healthcare disparities; people living with URDs (PLURDs); undiagnosed rare diseases (URDs)

DOI: https://doi.org/10.3389/fpubh.2025.1510818