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Our group aims to improve care for the individually rare but collectively large group of paediatric metabolic diseases. We particularly focus on the development of innovative treatments based on understanding the molecular basis and the genetic cause of disease.

Innovative therapies for metabolic disorders

Despite being clinically very diverse, all metabolic diseases are caused by DNA mutations, resulting in abnormal mRNA and a deficient or defective resultant protein. Our strategy to develop novel therapies for this diverse group of disorders is to target their genetic molecular cause. We currently have a particular focus on gene correction, mRNA-therapies and (gene modified) stem cell transplantations, but we have also developed molecularly informed dietary interventions for an increasingly recognized group of patients with diseases in protein translation.

Repairing the genetic cause of metabolic disorders

We use advanced CRISPR/Cas systems—prime and base editors—and TALE-based mitochondrial base editors to precisely repair DNA mutations underlying metabolic disorders. In theory, resulting gene correction therapies hold the promise to permanently cure patients, as they do not target the clinical symptoms, but directly correct the root cause of these diseases. However, correction of the DNA in our cells is not straightforward, as DNA is well protected against such incursions, and every disease-causing variant requires a different approach. Our group aims to deepen our understanding of gene editing processes to develop personalized therapies. We frequently use patient-derived cell models (fibroblasts, IPSCs, adult stem cell derived organoids, tissue slices) to bridge our experimental models to clinical reality. Based at the Hubrecht Institute and closely connected to the Wilhelmina Children’s Hospital (WKZ), and being led by a clinician-scientist, we operate at the interface of basic research and translational medicine.

mRNA therapies

Sabine Fuchs is the principal investigator (Fuchs group) coordinating clinical trials using mRNA-based enzyme-replacement therapies for metabolic diseases. In addition to presenting a novel treatment option for eligible patients, this provides the proof of concept for gene-correction therapies delivered as mRNA. 

Improving tissue-specific delivery

A major challenge for the clinical translation of gene correction or mRNA therapies, is robust delivery of these therapeutic molecules to their site of action. Currently, most research and trials focus on delivery of gene-editors as mRNA and/or proteins, which are fragile molecules that cannot enter cells. Our group explores various strategies to safely and efficiently deliver these molecules to the right cells and organs in the body. Our toolbox spans clinically established delivery systems such as lipid nanoparticles (e.g. similar to the COVID-19 vaccines) and novel, more exploratory nanoparticles such as virus-like particles and extracellular vesicles. But we are also exploring viral delivery for difficult-to-target organs. We test these delivery vectors in various ‘hotspot organs’ for metabolic diseases, including the liver, bone marrow, the eye and the brain, using advanced human (patient-derived) in vitro models and reporter and genetically engineered animal models.

Improving therapies based on clinical and molecular phenotyping 

As the national NFU-acknowledged expertise center for various metabolic diseases including long chain fatty acid oxidation disorders (lcFAOD), aminoacyl-t-RNA-synthetase deficiencies (ARS), and hematopoietic stem cell transplantations for mucopolysacharidosis type I, our group performs standardized national follow-up in our multidisciplinary 1-day diagnostic/follow-up facility (Sylvia Toth Center). During these days, we also collect patient material and tissue that we can use for molecular testing.

In our metabolic biobank for biological material (including organoids, fibroblasts, body fluids), we currently have samples from >400 patients, suspected of genetic/metabolic disease (Metabolic Biobank 19-489). Studies with material from this biobank have already led to an improved liver organoid technology (spun-out as HeLLO R&D for drug toxicity testing), a new amino-acid-based therapy for patients with ARS1 and ARS2 deficiencies (with >20 patients on treatment in our center and many others in international centers following our advice) and innovative exercise tests to provide individualized exercise protocols for all Dutch patients with lcFAOD >6 years.

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