This approach employs targeted reduction of β-catenin expression or activity in the liver to alleviate porphyria by correcting dysregulated heme biosynthesis. Delivery modalities include RNA interference agents (siRNA, DsiRNA in lipid nanoparticles), antisense oligonucleotides, small molecule inhibitors of Wnt/β-catenin transcription, and PORCN inhibitors. By downregulating early enzymes like aminolevulinic acid synthase and inhibiting heme oxygenase-1, it prevents the buildup of porphyrin intermediates and preserves heme levels. Additional benefits include reduced aggregation of nuclear intermediate filament proteins and enhanced protein clearance through unfolded protein response and autophagy pathways, collectively mitigating liver injury hallmarks such as ductular reactions and fibrosis.
Description
This technology stands out by addressing multiple nodes within the heme synthesis and degradation pathways, whereas existing therapies like givosiran focus solely on aminolevulinic acid synthase 1. Its multi-pronged modulation of enzyme expression, heme degradation, and proteostasis offers broader disease control, reducing both porphyrin accumulation and heme deficiency. Moreover, reversible β-catenin suppression allows for cyclical treatment regimens that balance efficacy with safety, representing a more comprehensive and adaptable strategy for managing porphyria.
Applications
- Chronic porphyria treatment drugs
- Acute porphyria therapy
- Liver fibrosis therapeutics
- RNAi liver delivery platform
- Wnt pathway inhibitor development
Advantages
- Targets multiple steps in the heme biosynthesis pathway for a more comprehensive therapeutic effect
- Reduces porphyrin accumulation and alleviates porphyria symptoms
- Protects against liver injury and lowers serum markers of liver damage (ALP, ALT)
- Preserves heme levels and prevents heme depletion
- Decreases protein aggregation and enhances protein clearance mechanisms
- Adaptable to diverse delivery methods (RNAi, antisense, small molecules)
- Offers potential advantages over single-enzyme treatments like givosiran
Invention Readiness
In vivo data
IP Status
https://patents.google.com/patent/US10961534B2
