Skipping to improve scar management: modulation of TGF-B in hypertrophic scars via exon skipping

Author(s):
Raktoe, R.S.
Published
2024
Publication type
Doctoral Thesis

Abstract

Wound healing following severe burn injuries is accompanied by the development of recurrent hypertrophic scars (HTS) in the vast majority of cases. These scars lead to substantial functional impairment as well as aesthetic disfigurement, substantially affecting the quality of life of these patients.

Here, TGF-B signaling plays a central role in HTS development. Exon skipping of exon 2 of the TGF-B receptor I (a.k.a. ALK5) could be potential therapeutic approach to treat and/or prevent HTS development.

In this thesis, we have used different in vitro models to inevestigate the effects of ALK5 exon skipping on HTS development. Moreover, we introduced a improved three-layered skin equivalent that could be used for drug testing.

Exon skipping of ALK5 features effects that could reduce the fibrotic process through, for example, reduced SMAD2 signaling and lowered alpha-smooth muscle actin expression (hallmark of myofibroblasts). Next steps should be assessment of the anti-fibrotic effects in in vivo models that ultimately could lead up to deploy the antisense therapy in clinical trials. Altogether, ALK5 exon skipping is a promising tool that could open up an avenue for effective scar treatment.

Hypertrophic scarsTransforming growth factor bèta type IActivin-like kinase 5MyofibroblastsFibroblastsAlpha-smooth muscle actinAntisense oligonucleotidesExon skippingCollagenSkin fibrosis
Defense date
2024-11-05
Language
English
Supervisor(s)
Vermeer, M.H.
Advisor(s)
Ghlbzouri, A. el
Committee member(s)
Doorn, R. van; Dijke, P. ten; Genders, R.E.; Rissman, R. Laethem, A. van
Qualification
Ph.D.
Degree granting institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University, Leiden
hdl
1887/4107638
ISBN(s)
9789465065441

Funding

Sponsorship
Nederlandse Brandwonden Stichting (NO.14.105)