RNA Therapeutics for Pompe Disease and other metabolic disorders

This project aims to advance RNA therapeutics for metabolic diseases, and in particularPompe disease, a lysosomal storage disorder caused by pathogenic variants in theGAA gene leading to glycogen accumulation in muscles. We focus on antisense oligonucleotides (ASOs) to correct defective RNA splicing or upregulate gene expression, addressing the root molecular causes. Current efforts emphasize optimizing ASO delivery to challenging tissues like skeletal muscle, where poor penetration limits efficacy. By leveraging lipid nanoparticles as the delivery vehicle, we enhance stability, targeting, and cellular uptake while minimizing required dose and off-target effects. In parallel, we explore peptide-mediated delivery. This translational approach involves preclinical testing in skeletal muscle disease models to evaluate safety, biodistribution, and therapeutic outcomes, with the goal of improving patient mobility, respiratory function, and ultimately quality of life. Collaborations with experts in nanotechnology and rare diseases support our progress toward therapeutic implementation.

We prioritize lipid nanoparticle (LNP) formulations for ASO delivery, engineering them with muscle-specific ligands to improve tissue and intracellular delivery. Key innovations include optimization of LNP composition and functionalization of LNPs. Preclinical studies assess pharmacokinetics, glycogen reduction, and enzyme activity restoration in Pompe models. Secondarily, we test cell-penetrating peptide (CPPs) conjugates, evaluating their efficiency against toxicity risks such as immune activation or membrane disruption. This dual strategy aims to identifyoptimal, safe delivery systems for broader applications in metabolic disorders.

Internal Collaboration 
Department of Pediatrics
Department of Neurology
Department of Internal Medicine
Department of Pathology
Center for Lysosomal and Metabolic Disorders

External Collaboration
UMC Utrecht
LUMC
Radboud UMC