Dermatosparaxis Ehlers-Danlos Syndrome (dEDS) is an extremely uncommon genetic disorder caused by mutations in the ADAMTS2 gene that results in abnormal collagen processing, extreme skin fragility, and hypermobile joints. Protheragen provides complete preclinical drug and therapy development services for dEDS. We utilize advanced models and technologies to accelerate translational breakthroughs.
Introduction to Dermatosparaxis Ehlers-Danlos Syndrome
Fig.1 Vascular complications in nonvascular EDS. (D'Hondt, Van Damme and Malfait, 2018)
Ehlers-Danlos SyndromeDermatosparaxis EDS (dEDS) is a recessive subtype of Ehlers-Danlos Syndrome with bi-allelic mutants in ADAMTS2, a procollagen peptidase that serves a key role in collagen fibril assembly. It has a characteristic presentation of poorly organized bundles of collagen and leads to extreme skin fragility, delayed healing of skin wounds, and laxity at joints. The syndrome is commonly recognized as one of the rarest subtypes of EDS, with an estimated prevalence of <1 in 1,000,000 individuals. Recent studies have highlighted dysregulated TGF-β signaling and dysregulated extracellular matrix (ECM) remodeling as important pathophysiological drivers.
Biomarkers Development for Dermatosparaxis Ehlers-Danlos Syndrome
- Genetic Biomarkers: Recent advances in next-generation sequencing (NGS) and long-read sequencing technologies are permitting the identification of critical ADAMTS2 mutant identification; such as deep intronic and accessory mosaic mutants that are important in confirming the diagnosis of dEDS. Studies are examining the relationship between specific mutation types, such as deep intronic mutants, and the severity of certain phenotypes, providing the possibility for prognostic biomarkers of disease progression and severity.
- Collagen Metabolism Biomarkers: Abnormal processing of collagen leads to clear changes in the components of the ECM in dEDS. Several serum- or tissue-based assays will detect increased levels of immature procollagen type I N-terminal propeptide (PINP) and decreased levels of the major collagen crosslink metabolites, such as pyridinoline, provide highly reliable and quantitative biomarkers of disease activity and treatment response.
Therapeutics Development for Dermatosparaxis Ehlers-Danlos Syndrome
Enzyme Replacement
Strategies
Enzyme Replacement Strategies: Specific therapeutic strategies for enzyme replacement aim to alleviate deficient ADAMTS2 activity using recombinant protein delivered via lipid nanoparticles (LNP) to target skin. The LNPs are often surface modified to allow skin targeting. Upon release, ADMATS2 functions to cleave procollagen N-terminal propeptides to restore collagen accumulation.
ECM-Targeted
Interventions
ECM-Targeted Interventions: Small molecules identified to target ECM remodeling are currently being developed to reduce tissue fragility. LOXL2 inhibitors (e.g., PAT-1251) allow for collagen flexibility by limiting excessive crosslinking. TGF-β inhibitors (e.g., Galunisertib) dampen MMP-driven collagen degradation.
Our Services
Protheragen provides a full range of services to support advancing therapies for dEDS. Our team of expert scientists, dermatologists, and geneticists employ advanced technologies to drive progress, supported by targeted therapeutic development and disease model development survey.
Therapeutics Development Platforms for Dermatosparaxis Ehlers-Danlos Syndrome
Disease Models Development for Dermatosparaxis Ehlers-Danlos Syndrome
Protheragen offers tailored in vitro 2D cell models and 3D skin models to study dEDS molecular pathological features. These features include defectively processed collagen, ECM destabilization, and impaired activity of the ADAMTS2 enzyme. Our animal models can specifically recapitulate the hallmark phenotypes of dEDS enabling robust validation of therapeutic strategies focusing on genetic correction, enzyme replacement, and ECM targeting.
2D Cell Models & 3D Skin Models
- ADAMTS2-KO human dermal fibroblasts
- 3D dEDS skin equivalents with ADAMTS2 knockdown
- Patient-derived dermal fibroblast-keratinocyte co-cultures
Animal Models Development
- ADAMTS2−/− global knockout mice
- ADAMTS2 conditional knockout mice
- ADAMTS2−/− zebrafish
- ADAMTS2 point mutations mice
By combining gene-edited disease models, multi-omics, and high-throughput screening we provide actionable data, and to de-risk your therapeutic development pipeline. Contact us to explore how our end-to-end preclinical expertise can advance your dEDS research.
References
- Al Sayed, A., and C. Sumrall. "Dermatologic, Orthopedic, and Cardiovascular Manifestations and Management in a Geriatric Patient with Dermatosparaxis-Type Ehlers-Danlos Syndrome: A Case Report." Cureus 16.11 (2024): e73211.
- D'Hondt, S., T. Van Damme, and F. Malfait. "Vascular Phenotypes in Nonvascular Subtypes of the Ehlers-Danlos Syndrome: A Systematic Review." Genet Med 20.6 (2018): 562-73.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
