Cutis Laxa is an uncommon disorder of connective tissue resulting in loose, saggy skin along with multisystem involvement presenting involvements the cardiovascular, pulmonary, and musculoskeletal systems. Protheragen provides seamless preclinical development services to advance next generation targeted therapies and diagnostics for Cutis Laxa utilizing state-of-the-art technologies in preclinical disease-specific models.
Introduction to Cutis Laxa
Cutis Laxa, a group of genetic disorders marked by impaired elastic fiber formation, lead to skin laxity, vascular aneurysms, and emphysema. Current publications have classified cutis laxa into autosomal dominant, autosomal recessive and X-linked forms, most commonly with pathogenic variants in ELN (elastin), FBLN5 (fibulin-5) and LOX (lysyl oxidase). The estimated global incidence ranges from 1 in 500,000 to 1 in 2,000,000, with phenotypic variability depending on the mutated gene and mutation type.
Pathogenesis of Cutis Laxa
Cutis Laxa occurs as genetic defects in elastic fiber assembly, primarily involving mutations in ELN (elastin), FBLN5 (fibulin-5), or LOX (lysyl oxidase), which disrupt cross-linking and stabilization of extracellular matrix (ECM) components. Impaired elastogenesis leads to fragmented elastic fibers, reducing tissue resilience and causing systemic effects such as vascular aneurysms and pulmonary emphysema. Recent studies identified dysregulated TGF-β signaling and MMP-mediated ECM degradation as secondary drivers of disease progression, exacerbating connective tissue fragility.
Fig.1 The molecular pathomechanism in cutis laxa syndromes. (Beyens, A.,
et al., 2021)
Therapeutics Development for Cutis Laxa
Current strategies for treating elastic fiber defects in cutis laxa include gene editing, protein replacement, and small molecule modulation; preclinical studies have demonstrated potential efficacy for each to restore extracellular matrix integrity, which we have previously described.
Table.1 Current Therapeutic Development for Cutis Laxa.
| Therapy Type |
Target/Pathway |
Development Stage |
Mechanism of Action |
| Gene Therapy |
ELN, FBLN5 |
Preclinical |
CRISPR correction of FBLN5 mutations in patient-derived fibroblasts restored elastin deposition in vitro. |
| Protein Replacement |
Fibulin-5 |
Preclinical |
Recombinant fibulin-5 injected subcutaneously in Fbln5-/- mice improved skin elasticity. |
| Small Molecules |
LOX activation |
Preclinical |
Copper supplementation enhanced LOX activity in ATP6V0A2-mutant fibroblasts, improving elastin cross-linking. |
| Cell Therapy |
iPSC-derived fibroblasts |
Preclinical |
Gene-corrected iPSC-derived fibroblasts from Cutis Laxa patients secreted functional fibulin-5 in 3D ECM models. |
| Antioxidants |
Oxidative stress pathways |
Preclinical |
N-acetylcysteine (NAC) reduced oxidative stress in ELNmut fibroblasts, delaying ECM degradation. |
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 full suite of services to advance therapeutics for cutis laxa. Our team of scientists, dermatologists, and geneticists leverage cutting-edge technologies and methodologies to progress your project through targeted therapeutic development and disease model development services.
Therapeutic Development Platforms for Cutis Laxa
At Protheragen, we provide integrated, end-to-end solutions to develop therapies for ELN/FBLN5- driven elastic fiber defects and ECM dysfunction in cutis laxa across the small molecule, gene therapy, and biologic platforms as well as cell therapy.
Disease Models Development for Cutis Laxa
Protheragen provides a full suite of preclinical models to advance cutis laxa research, including 2D cell models, 3D skin models and animal models development model disease pathology and accelerate therapeutic development.
| 2D Cell Models & 3D Skin Models |
| Protheragen's preclinical research services for cutis laxa disease are designed to provide a comprehensive platform for understanding the efficacy of novel therapeutics. We provide in vitro studies using 2D cell models and 3D skin models to uncover potential molecular mechanisms of action of cutis laxa. |
| Optional Models |
- ELN mutant fibroblasts
- iPSC-derived fibroblasts
|
- Air-Liquid Interface (ALI) 3D epidermis
- Cutis Laxa-specific skin organoids
|
| Animal models |
| In vivo preclinical studies are also a key part of our services, we utilize, such as genetically engineering models, to test the safety and efficacy of potential therapeutics. Animal models are selected based on their ability to mimic the human condition of cutis laxa. |
| Optional Models |
- Fbln5-/- knockout mice
- Eln+/- heterozygous mice
|
- Humanized skin xenografts
- Eln mutant zebrafish
|
| Optional Species |
Mice, Rats, Non-human primates, Others |
Protheragen is a one-stop shop for facilitating the preclinical research services for a rare skin disease, cutis laxa. Protheragen provides end-to-end solutions for target discovery, modeling, thorough drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Beyens, A., et al. "Cutis Laxa: A Comprehensive Overview of Clinical Characteristics and Pathophysiology." Clin Genet 99.1 (2021): 53-66.
- Samal, A., et al. "Acquired Cutis Laxa Type 2 (Marshall's Syndrome) Associated with Sweet's Syndrome: A Rare Entity." Indian J Dermatol 69.5 (2024): 423.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
