Pseudoxanthoma Elasticum (PXE) is a distinct genetic condition brought about through mutation of the ABCC6 gene due to features including dysregulated calcification of elastic structures in the skin, eyes, and cardiovascular system. Protheragen is pioneering drug and therapy development for Pseudoxanthoma Elasticum and works towards fully integrated approaches to expedite the conversion of innovative ideas and methods into practical therapies.
Introduction to Pseudoxanthoma Elasticum
PXE is a notable illness of rare incidence such as an autosomal recessive disorder which stems from changes to the ABCC6 gene placed on 16p13.1 chromosome. Estimated at approximately 1 in 25 thousand to 100 thousand globally, PXE manifests in the form of progressive calcification of elastic fibers mainly concerning the skin, cardiovascular system and eyes. Mostly expressed in the liver and kidneys, the ABCC6 protein exerts control over extracellular levels of pyrophosphate (PPi), a key vascular calcification inhibitor.
Pathogenesis of Pseudoxanthoma Elasticum
Pseudoxanthoma elasticum stems from the loss-of-function mutations of the ABCC6 gene containing a transmembrane pyrophosphate (PPi) signaling sequence and a membrane bound transporter of a carrier. The ABCC6 misbalance interrupts the proper flow of ATP outside to the hepatocytes and proximal tubule renal cells, blocking the enzyme processes of ATP into PPi through ectonucleotide pyrophosphate phosphodiesterase I (ENPP1). Deficiency of PPi lowers the level of minerals and fails to control the action of tissue nonspecific alkaline phosphatase (TNAP) which causes untethered breakdown of PPi into phosphate with the following deposition of hydroxyapatite in elastic fibers.
Fig.1 The predicted two-dimensional topology of the ABCC6 protein. (Moitra
et al., 2017)
Therapeutics Development for Pseudoxanthoma Elasticum
| Therapeutic Strategy |
Mechanism/Target |
Key Findings/Results |
Development Stage |
| Chaperone Therapy (4-PBA) |
Corrects ABCC6 trafficking defects |
Restored ABCC6 membrane localization in mutant hepatocytes (specific to missense mutations). |
Preclinical |
| Bisphosphonates (Etidronate) |
PPi analog; inhibits mineralization |
Reduced arterial calcification in Abcc6−/− mice. In 74 PXE patients, 4% reduction in femoral calcification and fewer retinal events. |
Phase III |
| Oral PPi Supplementation |
Replenishes plasma PPi levels |
Elevated plasma PPi in mice and humans; inhibited mineralization in Abcc6−/− mice. |
Phase I/II |
| ENPP1 Protein Replacement |
Restores ATP→PPi conversion |
Overexpression of ENPP1 normalized PPi and reduced calcification in Abcc6−/− mice. |
Preclinical |
| TNAP Inhibitors (SBI-425) |
Inhibits PPi degradation |
Reduced calcification in Abcc6−/− mice; next-gen inhibitors under development. |
Preclinical |
| VEGF Antagonists |
Inhibits choroidal neovascularization |
Stabilized vision in PXE patients; does not reverse calcification. |
Approved |
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 offers full therapeutic development and disease model development services to aid in the development of pseudoxanthoma elasticum therapy. Our scientists, dermatologists, geneticists, and others utilize advanced disorder-specific technologies to aid and assist in effective therapy development.
Therapeutic Development Platforms for Pseudoxanthoma Elasticum
Protheragen's platforms include small molecule therapeutics for modifying abnormal calcification processes, gene therapy for specific ABCC6 modification aimed at restoring PPi homeostasis, and biologics to diminish ectopic calcification and enhance elastic fiber damage in skin and vascular tissues involved in pseudoxanthoma elasticum.
Disease Model Development for Pseudoxanthoma Elasticum
Protheragen offers pseudoxanthoma elasticum preclinical models including 2D cell models, 3D skin models, and animal models that recapitulate the relevant pathophysiological changes of the disease with the aim of interventions for possible therapeutic avenues.
- ABCC6-Knockout Hepatocyte Model
- Patient-Derived Fibroblast Model
- 3D Liver Organoid with ABCC6 Deficiency
- Abcc6−/− Knockout Mice
- Abcc6 Conditional Knockout Mice
- Vitamin D Diet-Induced Model
- Magnesium-Deficient Abcc6−/− Mice
Protheragen performs preclinical research services specifically aimed at the pathology of pseudoxanthoma elasticum. If interested in the service, we provide a full scope from discovery, through disease modeling, drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Luo, H., et al. "Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020." J Clin Med 10.1 (2020).
- Moitra, K., et al. "Abcc6 and Pseudoxanthoma Elasticum: The Face of a Rare Disease from Genetics to Advocacy." Int J Mol Sci 18.7 (2017).
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
