Ichthyosis Hystrix of Curth-Macklin (IHCM) is one of the most severe subtypes of ichthyosis, which is a hereditary skin condition marked by the presence of thick and scaly skin. Protheragen is fully devoted to preclinical drug and therapy development services for IHCM which accelerates the steps from discovery to translating science through target identification to IND-enabling studies.
Overview of Ichthyosis Hystrix of Curth-Macklin
The genetic basis of IHCM primarily lies in heterozygous frameshift mutation in Keratin 1 (KRT1) gene. KRT1 provides instructions for making keratin 1, a vital component in maintaining the architecture of keratinocytes – the predominant cell type in the skin's outer layer. It is believed that these mutations impair the customary processes of skin cell differentiation and desquamation, resulting in a keratin blockade.
Fig.1 Confocal ultrastructural analysis. (Terrinoni
et al., 2018)
Pathogenesis of Ichthyosis Hystrix of Curth-Macklin
Ichthyosis Hystrix of Curth-Macklin is driven by autosomal dominant mutations in the KRT1 gene, encoding keratin 1, which disrupt keratin intermediate filament formation in epidermal cells. These mutations impair epidermal differentiation and cell-cell adhesion, leading to hyperkeratosis, acanthosis, and pathognomonic "double-edged" nuclear membranes on histology. The resultant defective desquamation manifests clinically as progressive verrucous plaques and palmoplantar keratoderma.
Therapeutics Development for Ichthyosis Hystrix of Curth-Macklin
Active preclinical therapeutic development for IHCM focuses on several approaches considered promising, including attempts to correct the KRT1 mutation through gene therapy and the use of small molecule drugs to target specific pathways altered by the mutations.
Table.1 Therapeutic Development of IHCM.
| Therapeutic Strategy |
Target |
Mechanism |
Key Research Focus |
Development Stage |
| Gene Therapy |
KRT1 gene |
Delivery of functional KRT1 gene constructs; gene editing approaches |
Vector design optimization, gene delivery strategies, in vitro and in vivo efficacy studies |
Preclinical |
| Small Molecule Therapies |
Downstream targets in affected pathways |
Modulation of pathways impacted by KRT1 mutations; reducing hyperkeratosis |
High-throughput screening, in vitro assays, in vivo model testing for efficacy and safety |
Preclinical |
| Topical Agents |
Keratinocytes, skin barrier |
Enhancement of skin barrier function; reduction of scaling and inflammation |
Formulation development, in vitro permeability studies, preclinical efficacy testing |
Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen focuses on building an ecosystem to prepare for the preclinical trials and builds integrated solutions aimed accelerating the preclinical development of IHCM. From therapeutic development, diagnostics development to disease model development, our specialists use sophisticated tools to provide all-sides assistance.
- Patient-Derived Keratinocytes with KRT1 Mutations
- HaCaT-KRT1V176D
- 3D Epidermal Equivalents
- Conditional Epidermal Krt1 Knockout Mice
- Humanized KRT1 p.V176D Transgenic Mice
Bridging the gap between discovery and development, Protheragen concentrates on preclinical research with the purpose of expediting the discovery of potential drugs and therapies for IHCM. We provide complete in vitro and in vivo studies, including drug safety evaluation and DMPK services to make sure you make the best selection from your numerous drug candidate pools with the help of our sophisticated facilities and our scientific team.
Partner with us to IHCM research into viable therapeutic innovations. For inquiries regarding our comprehensive services, please contact us.
References
- Terrinoni, A., et al. "Role of the Keratin 1 and Keratin 10 Tails in the Pathogenesis of Ichthyosis Hystrix of Curth Macklin." PLoS One 13.4 (2018): e0195792.
- Yang, Z., et al. "A Novel Frameshift Truncation Mutation in the V2 Tail Domain of Krt1 Causes Mild Ichthyosis Hystrix of Curth-Macklin." Clin Exp Dermatol 45.6 (2020): 719-21.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
