Porphyria pertains to an uncommon range of metabolic disorders marked by the excessive accumulation of porphyrins and their precursors due to enzyme deficiencies in the heme biosynthesis pathway. Protheragen incorporates advanced molecular knowledge and custom disease models into therapeutic development, offering comprehensive porphyria preclinical drug and therapy services to expedite therapeutic innovations.
Introduction to Porphyria
There are eight major subtypes of the disorder, each referred to as hepatic or erythropoietic, depending on the site of enzyme deficiency in located. Mutations in HMBS, ALAS2 or CPOX genes are associated with acute hepatic porphyrias, whereas cutaneous forms are associated with UROD or FECH mutations. AIP is the most common acute subtype and, through recent migratory studies, has a prevalence rate of 1-5 per 100,000. The advancement in genetic profiling has elucidated the correlations between genotype and phenotype, highlighting modifier genes that determine the severity of the disorder.
Fig.1 Organization of the UROS gene. (Singal, 2019)
Pathogenesis of Porphyria
Porphyria is a result of the impaired heme biosynthesis pathway and accumulation of its intermediates like δ-aminolevulinic acid (ALA), porphobilinogen (PBG), or porphyrins. In acute porphyrias, HMBS mutations block heme production, causing ALA/PBG neurotoxicity and autonomic dysfunction. Cutaneous porphyrias involves the deficiency of uroporphyrinogen decarboxylase, leading to porphyrin deposition in skin and photosensitivity. Oxidative stress and hepatic iron overload exacerbate symptoms alongside hormonal aggravation, with newer research indicating some secondary role from mitochondrial dysfunction.
Fig.1 Heme biosynthesis and porphyria. (Dickey, Leaf and Balwani, 2024)
Therapeutics Development for Porphyria
Gene Therapy
Functional HMBS or URODgenes are delivered to hepatocytes via AAV (Adeno-associated virus) vectors in gene therapy, where enzymes are restored and toxic porphyrin precursor accumulations are reduced. Phase I/II trials in AIP demonstrate persistent biochemical correction and decrease neurovisceral attacks. AAV capsids targeting the liver increase the efficacy of transduction while controlling immune responses on the body.
RNA-Based Therapies
n advanced hepatic porphyrias, Givosiran, an approved siRNA therapy, inhibits the production of δ-aminolevulinic acid (ALA) and Porphobilinogen (PBG) by silencing ALAS1 mRNA through RNA interference at the liver level. Subcutaneous administration once a month reduces the frequency of attacks in Phase III trials. Novel antisense oligonucleotides (ASOs) aimed against ALAS1 splice variants are undergoing preclinical assessment.
Small-Molecule Therapies
Hematin restores heme concentration, decreases ALAS1 expression and thereby reduces attacks. However, it's useful for very short periods due to potential risk of iron overload. For erythropoietic protoporphyria (EPP) patients, increasing FECH enzyme activity leads to lower protoporphyrin IX and photosensitivity levels. Shifting peroral FECH activators and heme mimetics from developmental stages is expected to aid as better therapeutics.
Our Services
Protheragen offers comprehensive solutions for porphyria including therapeutic development and disease model development aimed at accelerating innovation for the alleviation of porphyria.
Therapeutic Development Platforms for Porphyria
Protheragen undertakes comprehensive advanced porphyria therapy development, including preclinical services, which center on the pathophysiological mechanisms of heme biosynthesis disorder by employing gene therapy, RNA intervention, and small molecule drug development for appropriate enzyme replacements, mitigating toxic metabolite effects.
Disease Model Development for Porphyria
Protheragen's preclinical portfolio is porphyria-focused and includes 2D cell models, 3D skin models, as well as animal models, all designed to achieve true disease pathologies and promote method therapeutics progression.
| 2D Cell Models & 3D Skin Models |
| Protheragen utilizes 2D cell models and advanced 3D skin models to study the molecular pathways of porphyria. This allows in vitro testing of multiple candidate drugs on the skin for safety and efficacy evaluation during the preclinical phase of drug development. |
| Optional Models |
- HMBS-KO HepG2 Cells
- FECH-Deficient Erythroid Progenitors
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- UROD-Knockdown Hepatocytes
- Skin Equivalents with Keratinocyte-Fibroblast Co-Cultures
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| Animal models |
| Protheragen's preclinical in vivo studies employ animal models, including genetically engineering models tailored to Porphyria, to evaluate therapeutic safety and efficacy while ensuring biological relevance to disease mechanisms. |
| Optional Models |
- Hmbs p.Arg167Gln Knock-In Mice
- Fechm1Pas/m1Pas Mutant Mice
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- UROD Conditional Knockout Mice
- alas2 CRISPR Mutants Zebrafish
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| Optional Species |
Mice, Rats, Non-human primates, Others |
Protheragen offers support in therapeutic innovation for rare skin diseases, including porphyria. As a specialized research service provider, we offer complete services from target discovery, disease modeling, drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Prasad, B., et al. "Congenital Erythropoietic Porphyria: The Overlooked Inherited Disorder." BMJ Case Rep 18.3 (2025).
- Dickey, A. K., R. K. Leaf, and M. Balwani. "Update on the Porphyrias." Annu Rev Med 75 (2024): 321-35.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
