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About usMedical SciencesResearchDepartment of GeneticsStaff
University Medical Center Groningen

Peter van den Akker, MD, PhD

Clinical geneticist & research fellow with a special interest in genetic skin disorders
Peter van den Akker
Peter van den Akker

MSc & MD: Medicine, 2004, University of Groningen, the Netherlands

Clinical Geneticist 2012, University Medical Centre Groningen (UMCG), the Netherlands

PhD Awarded Cum laude, 2013, University of Groningen. Thesis entitled Dystrophic epidermolysis bullosa. Novel insights into the genotype-phenotype correlation and somatic mosaicism. Supervisors: Prof. Marcel Jonkman (Dermatology, UMCG) and Prof. Robert Hofstra (Genetics, UMCG)

Research focus exon skipping and gene silencing using antisense oligonucleotides as therapeutic approaches for epidermolysis bullosa

Keywords Exon skipping, gene silencing/knockdown, antisense oligonucleotides, epidermolysis bullosa, genodermatoses

Publications Pubmed; GoogleScholar

Research Interests

My research work focuses on therapy development for epidermolysis bullosa using antisense oligonucleotides (AONs). Epidermolysis bullosa (EB, incidence ˜1:10,000) is a group of rare, genetic skin disorders featuring blistering of the skin and mucous membranes after the slightest friction. Currently, there are more than 40 different subtypes of EB recognized that are caused by mutations in genes involved in epidermal keratinocyte adhesion and epidermal-dermal anchorage. 19 genes are known to underlie the different subtypes of EB.

The severity of EB ranges from the mildest phenotype, in which only the nails of the big toes are affected, to the most devastating subtype called ‘generalized severe recessive dystrophic EB’ (RDEB). RDEB is characterized by continuous severe blistering and scarring over the whole body that greatly affects quality of life. Patients die before the age of 40 due to highly aggressive squamous cell carcinomas. RDEB patients’ skin completely lacks the epidermal-dermal anchoring protein type VII collagen, due to biallelic null-mutations in the collagen gene, COL7A1. In a socio-economic sense, patients need six hours of care a day plus life-long home care, and the annual cost of dressings and medication is approximately €200,000 per patient. For more information about RDEB see the award-winning documentary “The Boy Whose Skin Fell Off” on YouTube

There is no cure for EB and new therapeutic strategies are urgently needed. As long as permanent cure by in vivo genome editing with permanent mutation correction is not clinically applicable, I think that RNA-based therapeutic approaches are attractive alternatives, as they target the RNA rather than the DNA, which makes them relatively safe. As the COL7A1 gene is the perfect candidate gene for exon skipping, I initiated the research into exon skipping as a therapeutic approach for EB during my PhD work.

Exon skipping is mediated by AONs, chemically modified RNA-oligos, that interfere with normal splicing. By complementary binding to their target sequence they hide the exon from the splicing machinery causing it to be spliced out together with its surrounding introns. Targeting exons that harbor pathogenic null-mutations thus bypasses the mutation allowing translation to continue and a protein to be produced. Although this protein is slightly shorter and may not be fully functional, this will undoubtedly be better than no protein at all, at least for RDEB. The anticipated effect of exon skipping therefore is not a complete cure, but even the slightest improvement will significantly benefit EB patients.

Together with close collaborators of the department of Dermatology, UMCG, we first obtained an E-RARE 2012 Young Investigator grant to support the exon skipping work. In 2015 I obtained a ZonMW Clinical Fellowship grant for this work. This helped us to kick start the exon skipping research and enabled us to demonstrate in vitro and in vivo proof-of-concept for AON-mediated exon skipping as systemic therapeutic approach for RDEB (Bremer, Mol Ther Nucl Acids 2016). Upon systemic administration of AONs to nude mice, we induced COL7A1 exon 105 skipping and type VII collagen re-expression in vivo, in skin grafted on nude mice. The functionality of recombinant type VII collagen lacking exon 105 was unaltered (Bornet, Mol Ther 2016). These very encouraging results emphasize that exon skipping is a very promising approach to treat EB.

For a part of my Clinical Fellowship research I moved to the School of Life Sciences, University of Dundee, in 2015 and 2016, where I worked in the lab of Prof. Irwin McLean and Dr. Robyn Hickerson. There, I also became involved in their exciting research programme on AON-mediated gene silencing as a therapeutic approach for EB. Given the large overlap in approaches, with identical challenges and opportunities, the expertise I gained there is extremely helpful in my exon skipping work in Groningen. My visit was financially supported by DEBRA UK. I still hold a part-time position in Dundee until the end of 2017; this is also funded by DEBRA UK.

I am convinced that these RNA-based approaches will find their way to the clinic in some form in the future and am determined to make this a true success story.

Funding awarded

Selected papers

Last modified:10 July 2018 1.00 p.m.