Dr. Jochen Kinter and Dr. Christian Klingler

Abstract (Lay summary see below)

Facio-scapulo-humeral muscular dystrophy (FSHD) is the third most common muscular dystrophy. Currently, patients affected by the disease receive only symptomatic treatment. Hallmark of the disease is the ectopic expression of the transcription factor Double Homeobox Protein 4 (DUX4) mainly in skeletal muscle, where it is normally repressed by epigenetic mechanisms. The aberrant expression of the protein leads to progressive dystrophy in a selective skeletal muscle pattern. To a lesser extent, also non-muscle tissue (retinal teleangiectasia and sensorineural hearing loss) can be affected. 

In this grant application we are proposing to use high affinity aptamers against DUX4 for the development of PROTACs as therapeutic strategies to counteract FSHD and potentially other DUX4-related diseases. 

In a previous study, we identified selective high affinity aptamers with a motif, which resemble the canonical DUX4 DNA binding site. The aptamers contain bulge loops at distinct positions that substantially contribute to the affinity for DUX4 and increase the specificity in comparison to other transcription factors with similar binding motifs. In this project, we plan to use theses aptamers as building blocks for proteolysis targeted chimeras (PROTACs). In order to optimize the generation and evaluation of the newly designed molecules we established different methods including target binding assays, stability assays, and cellular delivery experiments. We will investigate these molecules for their ability to mediate targeted degradation of the DUX4 protein in patient derived cells. 

As DUX4 is not only the pathological factor of FSHD but also of other diseases including various cancer types, the research of an entire disease family of DUX4 related diseases will benefit from the findings in this project. 

Lay summary

Fazioskapulohumerale Muskeldystrophie (FSHD) ist eine der häufigsten Formen der Muskeldystrophie. Derzeit ist für diese Erkrankung keine kausale Therapie verfügbar. Eine abnormale Expression des Transkriptionsfaktor DUX4 (ein DNA-Bindungsprotein, welches die Ablesung der Erbinformation reguliert) wurde kürzlich als Auslöser dieser Krankheit entdeckt. 

Wir haben kurze Oligonukleinsäuren (sogenannte Aptamere) entwickelt, die durch ihre Sequenz und ihre räumliche Struktur ein hohes Bindungsvermögen zu DUX4 aufweisen. Wir möchten diese Aptamere dahingehend modifizieren, dass diese den zelleigenen Proteinabbau spezifisch gegen DUX4 richten. Da DUX4 auch bei gewissen Krebserkrankungen dereguliert ist, könnte eine solche Methode ein Fortschritt nicht nur für FSHD sondern auch für die Krebsforschung darstellen.