Rare keratinsation disorders – from gene to therapy: In-vitro disease modelling and patient-specific protein replacement approaches – Dr Katja Eckl
Rare, congenital keratinisation disorders, among those the autosomal recessive congenital ichthyosis (ARCI) have a prevalence of approx. 1 to 100,000 persons in Europe and the US, and therapy is up to date only symptomatic and by no means sufficient. In recent years mutations in nine genes causing ARCI have been identified. Furthermore, the identification of mutation in genes causative for others rare keratinisation disorders shed additional light on epidermal pathways and epidermal barrier integrity.
Today we can postulate, that the replacement of the protein which is lacking in the patients epidermis caused by a homozygous or compound heterozygous mutation will return the epidermis to normal or nearly normal function. Tremendous work has been done by us and co-operation partners to generate, establish, and validate 3D full-thickness skin models mimicking human skin from healthy controls and patients with a skin disorder. Models underwent characterisations following Europe an and international standards.
Today these models are used to replace animals in the development of protein replacement therapies (PRT) for congenital ichthyosis and other keratinisation disorders. Our main interest is the replacement of transglutaminase-1, 12R-LOX and eLOX-3, encoded by TGM1, ALOX12B and ALOXE3, respectively. Mutations in the TMG1 and the both LOX-genes together account for roughly 50% of all ARCI patients in Europe. Recently we gained first proof-of-concept results for nanoparticle based PRT using transglutaminase-1 deficient skin models.
To further enhance our interest in reducing animal experiments while developing new pharmaceuticals for rare skin disorders, we are currently developing 3D skin models for more complex diseases of the skin, especially for those also affecting pigmentation.
Another approach is to integrate cells generated through fate-specific differentiation from induced pluripotent stem cells (iPSCs). We gained first promising results for iPSC-derived melanocytes from healthy and diseased sources. Melanocyte enriched 3D model systems can help us understand the pathomechanisms of rare pigmentation disorders and are an excellent platform for pharmaceutical /cosmetic testing to specifically simulate the skin of our patients prior to clinical testing.
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