Classic Ehlers-Danlos Syndrome (cEDS) is an uncommon inherited connective tissue disorder that is notable for skin hyperextensibility, hypermobility of the joints, and the abnormal healing of tissues. cEDS is estimated to occur in 1 in 20,000 to 1 in 40,000 births, necessitating the need for focused therapeutic development. Protheragen offers comprehensive preclinical drug and therapy development services for cEDS to expedite your research process.
Introduction to Classic Ehlers-Danlos Syndrome
Classic Ehlers-Danlos Syndrome (cEDS) is hereditary, primarily caused by pathogenic variants in the COL5A1 or COL5A2 genes that code for the type V collagen, which is required in the extracellular matrix (ECM). Recent research demonstrates how these mutations interfere with the process of collagen fibrillogenesis and subsequent mechanical properties, leading to compromised integrity of the skin and stability of the joints. There is a global prevalence of this disorder, with the most severe manifestations often attributed to dominant-negative COL5A1 mutations. Recent research has also revealed that dysregulated TGF-β signaling and ECM remodeling enzymes contribute to tissue fragility and instability.
Fig.1 Clinical features of TNX-related clEDS and clEDS-related phenotypes of Tnxb
−/−mice. (Foy
et al., 2022)
Biomarkers Development for Classic Ehlers-Danlos Syndrome
- Collagen Metabolites: Serum levels of pro-collagen V N-terminal propeptide (P5CP) indicate aspect of patients with collagens V turnover in the context of cEDS and provides a non-invasive biomarker to aid in determination of disease progression and therapeutic response. More recent research has also established the utility of P5CP as a surrogate biomarker to monitor the response to interventions targeting collagen stabilization.
- Proteomic Signatures: Proteomic analysis of skin biopsies in patients with cEDS has yielded diminished expression of decorin and lumican respective proteoglycans required for appropriate organization of collagen fibrils. Baseline levels of decreased proteoglycans overall feature and correlate to ultrastructural defects in collagen. Proteomic profiles can determine a subtype of mechanistic features and assist in establishing potential and appropriate ECM-modulating therapies.
- Genetic Biomarkers: The use of third-generation long-read sequencing can detect pathogenic deep intronic variants in COL5A1/2 that are undetected by traditional NGS. This genetic innovation allows for increased diagnostic accuracy and subsequently specific therapeutic measures, overcoming traditional difficulties to implement treatment of genetically undetected cases.
Therapeutics Development for Classic Ehlers-Danlos Syndrome
AAV-delivered
COL5A1
AAV-delivered COL5A1: The use of AAV9 vectors delivered intravenously carrying a functional copy of COL5A1 resulted in restored collagen V biosynthesis in preclinical models, including in vivo reduced skin fragility and improved skin integrity overall. CRISPR base editing enables specifically correct COL5A2 splice-site mutations in patient-derived cells, which results in improved biosynthesis and reformed collagen fibril organization as demonstrated in 3D skin models.
Protein
Replacement
Protein Replacement: Delivery of recombinant decorin subcutaneously improves collagen crosslinking and collagen tensile strength in humanized skin grafts, by offsetting any inherent instability in ECM. The use of small-molecule TGF-β inhibitors have also shown to inhibit over-expressed matrix metalloproteinases (MMPs) which allowed for decreased overall matrix degradation and maintained connective tissue integrity seen in preclinical studies.
Our Services
Protheragen offers the full range of services to advance therapeutics for classic ehlers-danlos syndrome. Our team of expert scientists, geneticists and dermatologists apply your innovations to advance options with cutting edge and innovative therapeutic development and disease model development services to support your projects.
Therapeutic Development Platforms for Classic Ehlers-Danlos Syndrome
Disease Models Development for Classic Ehlers-Danlos Syndrome
Protheragen offers tailored in vitro (2D cell models and 3D skin models) investigate molecular pathologies associated with cEDS, focusing on collagen biosynthesis defects and extracellular matrix destabilization. Our animal models also replicate landmark disease characteristics to skin hyperextensibility, joint-hyper mobility, and impairment in healing which allows for wide-range evaluation of preclinical therapeutic targeting organizing connective tissue integrity.
- Patient-Derived Fibroblasts
- COL5A1/2 KO Cells
- 3D Skin Equivalents
- Microfluidic ECM-on-a-Chip
- Keratinocyte-Fibroblast Co-cultures
- COL5A1+/− Mice
- Zebrafish COL5A2 Mutants
- Conditional COL5A1 Knockout Rats
- Rabbit Tendon Injury Models
- Guinea Pig Skin Fragility Models
As a consolidated and capable preclinical research services provider, Protheragen is dedicated to driving therapeutic options for rare skin disorders such as classic ehlers-danlos syndrome. full range of service seamlessly from target identification to drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Foy, M., et al. "Classical Ehlers-Danlos Syndrome with Severe Kyphoscoliosis Due to a Novel Pathogenic Variant of Col5a2." Clin Case Rep 10.11 (2022): e06338.
- Okuda-Ashitaka, E., and K. I. Matsumoto. "Tenascin-X as a Causal Gene for Classical-Like Ehlers-Danlos Syndrome." Front Genet 14 (2023): 1107787.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
