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High-content screening for new therapies for Epidermolysis Bullosa Simplex associated with Muscular Dystrophy (EBS-MD)

Completed
Project leadProf. Arnoud Sonnenberg
Organisation The Netherlands Cancer Institute (NKI)
Project budgetEUR 125,875.00
Start date / Duration01. Apr 2017 / 24 months
Funder(s) / Co-Funder(s) DEBRA Austria
Research area Molecular therapy, Cellular therapy

Project details

Short lay summary

Epidermolysis Bullosa (EB) is a group of genetic diseases characterized by recurrent blistering from minor mechanical friction or trauma. EBS-MD is a clinical subtype caused by mutations in the gene encoding the cytoskeletal linker protein plectin (PLEC1). Currently, there is no effective therapy or cure for EBS-MD.
The aim of this project is to identify small-molecules that are useful for the treatment of EBS-MD. We will take advantage of the fact that many of the PLEC1 mutations occur in a single exon that is subject to alternative mRNA splicing. We will perform high-content/ high-throughput screenings for small molecules that promote skipping of the mutated exon in the RNA to generate a smaller variant of plectin, which as we have recently shown can functionally fully compensate for the absence of full-length plectin in genetically modified mice.

Strategic relevance

The high-content/high-throughput screening of small molecule libraries proposed in this project will hopefully identify pharmacological compounds that can be tested for its clinical utility in EBS-MD patients.

What did this project achieve?

EBS-MD is a clinical subtype caused by mutations in the gene encoding the cytoskeletal linker protein plectin (PLEC1). A large number of these mutations are nonsense or frameshift mutations in exon 31, preventing the formation of the full-length plectin protein, but leave the low-level production of a rodless plectin splice variant unaffected. We have found that in genetically modified mice the rod-less plectin protein can functionally replace wild-type plectin and support stable cell adhesion, when the protein is expressed at similar levels as in wild-type mice. The aim of this project was to generate mouse EBS-MD cell lines using gene-editing technology and perform high-throughput screenings for small molecules that promote skipping of the mutated exon in the mRNA to generate rod-less plectin at levels comparable levels to those in healthy individuals. We have successfully generated mouse keratinocyte and skeletal EBS-MD cell line models, and have used them to screen two small molecule libraries. Unfortunately, we have not identified compounds that increased the expression of the rodless variant of plectin, either by skipping of the mutated exon or through epigenetic regulation of the plectin promotor.


Keywords

EBS-DM
small molecules
PLEC1
Sonnenberg
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