Abstract
Individually, rare genetic diseases affect a small number of individuals. However, collectively they represent an important public health burden by impacting 8% of the EU population. Many rare genetic diseases have a large impact on the quality of life of people affected often resulting in disability or early death. Usually,
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these diseases are caused by a single genetic defect. The study of rare genetic diseases teaches us how a gene functions in health and disease, thereby providing insights for processes in common diseases.
Rare genetic disorders form a unique category of disorders and therefore face incomparable challenges when it comes to diagnosis and therapy options. Despite scientific advances in modern genetics and genomics, the diagnosis of rare diseases is often delayed or incorrect, and most rare conditions still lack effective treatment options.
This is also the case for Cantú syndrome (CS), a rare autosomal dominant condition caused by gain-of-function (GoF) mutations in genes encoding subunits of ATP-sensitive potassium (KATP) channels (ABCC9, KCNJ8). CS patients present with coarse facial features, excessive body hair, and extensive cardiovascular anomalies. To generate a critical mass of CS patients to find further clinical characteristics of the disease as well as to ensure a rapid progression towards future interventional studies we developed an international standardized registry. Clinical data is obtained during annual CS research clinics.
Clinical management of CS currently involves symptomatic treatments to address second-order complications such as heart failure. The off-patent KATP inhibitor glibenclamide which is already widely applied in clinic to block GoF KATP channels involved in Type 2 diabetes holds promise as a potential treatment for CS.
To perform therapeutic drug screening, we have developed novel CS zebrafish models in which disease-causing mutations were knocked-in to the endogenous abcc9 and kcnj8 loci using CRISPR/Cas9 genome engineering. Resulting models recapitulate key cardiovascular features of CS including hypercontractility and abnormally high cardiac output which significantly reverse after glibenclamide administration in zebrafish larvae.
These results provide key pre-clinical evidence for the in vivo efficacy of glibenclamide for the treatment of CS. Hence, a clinical trial to test glibenclamide in CS patients has been designed.
In conclusion, applying Cantú syndrome as an example, this thesis highlights a path from gene discovery to investigating treatment options for a rare genetic disorder by successfully applying multiple tools and technologies available nowadays: (i) accurate and in-depth phenotyping to establish a detailed natural history and improve diagnosis, (ii) functional modeling of patient-specific variants in zebrafish to validate diagnosis and elucidate underlying pathophysiology as well as (iii) repurposing an existing drug to establish treatment.
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