Sixera Pharma | scientific research
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scientific research

SCIENTIFIC RESEARCH

A growing number of genodermatoses (inheritable skin diseases) have been identified where the defective gene encodes a protease or protease inhibitor (de Veer et al. 2014). An important family of proteases in the granular and cornified layers of the epidermis is the kallikrein-related peptidases (KLKs).

KLK7 (previously known as stratum corneum chymotryptic enzyme (SCCE)) was the first KLK protease detected in active form in the stratum corneum (Egelrud and Lundström 1991, Hansson et al. 1994), followed by KLK5 (Brattsand and Egelrud 1999, Ekholm et al. 2000), and KLK14 (Stefansson et al 2006).

Sixera developed disease models including human skin zymography models and generated a KLK7 knock out mouse (Hansson et al. 2002) that has facilitated the selection of substances that can restore the balance in the affected skin of NS patients. Based on high throughput screening and molecular modelling a series of compounds selectively inhibiting the three proteases were developed. SXR1096 is a potent and highly selective compound that was selected for further development as a treatment for Netherton syndrome. SXR1096 is currently undergoing final pre-clinical development in preparation for further clinical testing.

Two of the founders of Sixera; Professor Torbjörn Egelrud and Dr Lennart Hansson and their colleagues at the Umeå University pioneered the research field and isolated, cloned and characterized some of the proteases that are active in the normal shedding of the stratum corneum of the skin; kallikrein 5 (KLK5), KLK7 and KLK14 (Brattsand et al, 2005).

Netherton syndrome is a rare genetic skin disease where the gene SPINK5, coding for the protease inhibitor LEKTI, is defect resulting in no or very low levels of LEKTI in the skin of these patients. In the normal skin LEKTI plays a role as an inhibitor of the stratum corneum proteases KLK5, KLK7 and KLK14 – and thereby maintaining a balance between build-up and shedding of the outermost layer of the skin. In the absence of LEKTI the proteases; KLK5,7 and 14 become overactive and this leads to exaggerated shedding of the outermost layer (stratum corneum) of the skin.