Ehlers-Danlos Syndrome Type Arthrochalasia (aEDS) is a very rare genetic disorder caused by dominant-negative mutations in COL1A1 or COL1A2 that affect type I collagen processing and cause systemic fragility of connective tissue. Protheragen specializes in end-to-end preclinical services to support target validation, developing therapies and performing mechanistic studies for aEDS, using the latest technologies aimed at investigating collagen biology and extracellular matrix (ECM) dysfunction.
Introduction to aEDS
Ehlers-Danlos Syndrome Type Arthrochalasia (aEDS) is an ultra-rare genetic disorder that affects <1 in 1,000,000 people aEDS is caused by dominant-negative variations in either COL1A1 and COL1A2 that prevent the biosynthesis of type I collagen. Subject matter experts have recently reported gene variants that skip exons in either of these genes that disrupt the cleavage of N-terminal propeptides of proalpha-1/I collagen, resulting in malformed collagen fibrils and weakening the cellular ECM.
Pathogenesis of aEDS
The pathogenesis of aEDS stems from dominant-negative mutations in COL1A1 or COL1A2, disrupting the cleavage of type I procollagen N-terminal propeptides, primarily due to exon-skipping variants. These mutations disrupt collagen fibrillogenesis and lead to irregular collagen fibril ultrastructure and compromised biomechanical properties of the ECM.
Researchers have also recently shown endoplasmic reticulum (ER) stress associated with malformed collagen leading to aberrant ECM function and drove signaling through dysregulated TGF-β pathways. There is also evidence that the dysregulation of collagens interaction with cell receptors (i.e., integrins) could also cue altered mechanotransduction, further destabilizing connective tissue homeostasis.
Fig.1 The genotype of WAe009-A-72 cell line. Predicted amino acid sequence were shown. (Ma
et al., 2022)
Therapeutics Development for aEDS
Research focus is to restore the pathogenic COL1A1/A2 mutations or to mitigate the downstream dysfunction of the ECM. Preclinical approaches will be via gene editing, antisense oligonucleotides (ASOs) to restore collagen processing, or using biomaterials for tissue reinforcement.
Table.1 Current Therapeutic Strategies for aEDS.
| Approach/Drug |
Target |
Mechanism |
Development Stage |
Challenges |
| Gene Therapy |
COL1A1/COL1A2 exon-skipping |
Correct collagen processing mutations |
Preclinical |
Off-target effects, delivery challenges. |
| ASOs (Exon Skipping) |
COL1A1 exon 6 |
Restore procollagen cleavage |
Preclinical |
Tissue-specific delivery. |
| PCPE1 Activators |
PCPE1 enzyme |
Enhance procollagen maturation |
Preclinical |
Selectivity for type I collagen. |
| LOXL2 Inhibitors |
LOXL2 enzyme |
Promote collagen crosslinking |
Preclinical |
Fibrosis risk. |
| Synthetic Collagen Scaffolds |
ECM structure |
Mechanically reinforce weakened tissues |
Preclinical |
Host integration. |
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 provides a comprehensive suite of services to bring therapies to aEDS. The team of experienced scientists, dermatologists and geneticists, will use their expertise and innovation to facilitate the progress of aEDS research, with specialized therapeutic development and disease model development services designed to facilitate your projects.
Therapeutic Development Platforms for aEDS
Disease Models Development for aEDS
Protheragen provides tailored 2D cell models and 3D skin models to investigate the pathology of aEDS including COL1A1/COL1A2-driven collagen abnormalities and dysregulated ECM remodeling. Protheragen's animal models reproduce key aEDS features such as joint hypermobility and dermal fragility to evaluate therapies targeting collagen biosynthesis or ECM stabilization.
- Patient-Derived Dermal Fibroblasts
- COL1A1ΔExon6 HEK293T Cells
- COL1A1-Edited Epidermal Organoids
- Multilayered Skin-ECM Constructs
- ECM Remodeling-on-a-Chip
- COL1A1Mov13 Knockout Mice
- COL1A2R789C Knock-In Mice
- TP63-COL1A1 Dual Reporter Mice
- Transgenic COL1A2R304W Zebrafish
- COL1A1AΔExon6 Zebrafish
Protheragen is a one-stop-shop for preclinical research services to develop therapeutics for rare skin diseases such as aEDS. Protheragen provides end-to-end solutions to develop therapeutics from target discovery and disease modeling through drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Ma, S., et al. "Generation of a Col1a2 Homozygous Knockout Stem Cell Line Via Crispr/Cas9 System." Stem Cell Res 59 (2022): 102652. Print.
- Martin-Martin, M., et al. "Ehlers-Danlos Syndrome Type Arthrochalasia: A Systematic Review." Int J Environ Res Public Health 19.3 (2022).
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
