Porphyrias are a subgroup of complex genetic disorders associated with the metabolism of heme, the most prevalent being porphyria cutanea tarda (PCT). Protheragen has developed novel drug and treatment frameworks for PCT and aims to cure the disorder's complexity with sophisticated technologies that deal with its root causes and symptoms.
Introduction to Porphyria Cutanea Tarda
Porphyria Cutanea Tarda (PCT) results from a photosensitivity disorder of the skin. Its symptoms involve blisters, lesions on skin surfaces, and other hepatic dysfunctions due to inadequate activity of uroporphyrinogen decarboxylase (UROD), resulting in a toxic build-up of uroporphyrins. It has sporadic (Type I, accounts for 80% of cases) or familial (Type II) subtypes. Frequently triggers involve excess iron, alcohol, inflammation from the hepatitis C virus, or estrogen. With a global prevalence of ~1 out of 10,000 people affected, PCT is more rampant in HCV endemic regions.
Pathogenesis of Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) is caused by cell intrinsic and extrinsic factors. Deficiency of UROD activity accumulates carboxylated porphyrins in the liver and skin, causing photosensitivity and subsequent skin blistering. Heme biosynthesis is disrupted in conjunction with mitochondrial dysfunction and impaired iron homeostasis, which enhance porphyrin toxicity and precipitate cutaneous and hepatic tissue damage. Hepatic iron overload is also a contributor as it causes additional oxidative stress by inactivating UROD through reactive oxygen species (ROS).
Fig.1 Mechanism of skin damage by porphyrins in porphyria cutanea tarda. (Singal, 2019)
Therapeutics Development for Porphyria Cutanea Tarda
| Therapeutic Strategy |
Target / Intervention |
Key Findings / Rationale |
Development Stage |
| Gene Therapy |
UROD Gene Restoration |
AAV8-UROD vector: Delivers functional UROD gene to hepatocytes via adeno-associated virus, restoring enzyme activity in mice. |
Preclinical |
| RNA Interference (siRNA) |
HFE Gene Silencing |
LNPs-siRNA-HFE: Lipid nanoparticles deliver siRNA targeting HFE mRNA, reducing hepatic iron uptake. Early trials show serum ferritin reduction. |
Phase I Trials |
| Hepcidin Mimetics |
Ferroportin Inhibition |
LJPC-401: Synthetic hepcidin analog suppresses ferroportin, lowering dietary iron absorption. Phase II data show serum ferritin reduction in PCT patients. |
Phase II Trials |
| Recombinant UROD (PEGylated) |
Enzyme Replacement Therapy |
PEG-UROD: Intravenous PEGylated recombinant UROD reduces hepatic porphyrins by 70% in preclinical models. |
Preclinical |
| Antifibrotic Agents |
TGF-β Pathway |
Pirfenidone: Inhibits TGF-β-mediated collagen deposition, reducing porphyrin accumulation in PCT-derived hepatoids. |
Preclinical |
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 integrates full-scope therapeutic development and disease model development services to improve porphyria cutanea tarda therapy. Our dermatologists, geneticists, and physician scientists work with advanced technologies tailored to the disorder for the development of effective therapies.
Therapeutic Development Platforms for Porphyria Cutanea Tarda
Protheragen has proprietary platforms that combine small molecule therapeutics aimed at modulating excess porphyrin accumulation, gene therapy approaches directed at UROD replacement to restore normal enzyme activity, and biologics that mitigate tissue damage and enhance the condition of the skin, mucous membranes, and other structures affected by cutaneous porphyria.
Disease Model Development for Porphyria Cutanea Tarda
Protheragen developed preclinical models for porphyria cutanea tarda which include 2D cell models, 3D skin models, and animal models with pathophysiologic relevance, and designed to aid in therapeutic development.
- UROD-Knockout Hepatocyte
- Patient-Derived Skin Fibroblast
- HFE-Mutant Hepatocyte
- Skin-on-a-Chip with Porphyrin Deposition
- UROD+/- Knockout Mice with Iron Overload Mice
- UROD Conditional Knockout Mice
- HFE C282Y Transgenic Mice
- HCV-Transgenic PCT Mice
Protheragen offers preclinical research services focused on studying the pathogenesis and therapy of UROD deficiency coupled with iron overload porphyria cutanea tarda. We offer full services spanning from target discovery to disease modeling as well as drug safety evaluation and DMPK services.
References
- Singal, A. K. "Porphyria Cutanea Tarda: Recent Update." Mol Genet Metab 128.3 (2019): 271-81.
- Chaiyabutr, C., et al. "Porphyria Cutanea Tarda in Scotland: Underlying Associations and Treatment Approaches." Int J Dermatol 63.12 (2024): 1707-12.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
