What is the therapeutic potential of FGF 19 in pediatric liver diseases?

Therapeutic Potential of FGF19 in Pediatric Liver Diseases

FGF19 shows promising therapeutic potential for pediatric cholestatic liver diseases through its regulation of bile acid metabolism, but its clinical application is limited by safety concerns regarding potential tumorigenicity that must be addressed through engineered non-tumorigenic variants.

Understanding FGF19 Biology in Pediatric Liver Development

• FGF19 is a gut-derived hormone that regulates CYP7A1, the rate-limiting enzyme in bile acid synthesis pathway 1
• In neonates, the FGF19-CYP7A1 gut-liver axis appears to be developmentally regulated, with CYP7A1 activity undetectable prior to 30 weeks' gestation 1
• Interestingly, FGF19 concentrations are elevated at birth in preterm infants and decrease over time, suggesting an extra-intestinal source of FGF19 during early development 1

Therapeutic Applications in Pediatric Cholestatic Diseases

• FGF19 has demonstrated potential in treating cholestatic liver diseases by reducing hepatic bile acid levels through modulation of bile acid synthesis 2
• Engineered FGF19 variants like M70 have shown efficacy in treating cholangiopathies in animal models by:
  • Inhibiting hepatic expression of Cyp7a1 and Cyp27a1 (enzymes responsible for bile acid synthesis) 3
  • Reducing the hepatic bile acid pool and blood levels of bile acids 3
  • Reversing liver injury and decreasing hepatic inflammation 3
  • Attenuating biliary fibrosis 3

Safety Concerns and Modified FGF19 Variants

• A major limitation of FGF19 therapy is its potential role in hepatocellular carcinogenesis 2
• Prolonged exposure to native FGF19 has been shown to lead to hepatocellular carcinoma formation in Mdr2-deficient mice 3
• Non-tumorigenic FGF19 variants (like M70) have been developed that maintain the beneficial effects on bile acid metabolism without the tumorigenic potential 2, 3
• These engineered variants represent a promising approach for treating cholestatic liver diseases while mitigating cancer risk 2

Molecular Mechanisms of FGF19 Action

• FGF19 requires both FGFR4 (fibroblast growth factor receptor 4) and KLB (Klotho beta) for its liver-specific activities 4
• The liver is the primary site of FGF19 action due to the unique co-expression of both FGFR4 and KLB 4
• FGF19 signaling in the liver leads to:
  • Repression of CYP7A1, reducing bile acid synthesis 4
  • Decreased expression of proteins involved in fatty acid synthesis (Fabp5, Scd1, Acsl3) 5
  • Increased expression of proteins involved in fatty acid oxidation (Acox1) 5

Challenges in Developing FGF19-Based Therapies for Children

• Many FGF19 targets have dual functions in both metabolism and cell proliferation (Pdk4, Apoa4, Fas, Stat3), making it difficult to fully uncouple metabolic benefits from mitogenic potential 5
• The developmental regulation of the FGF19-CYP7A1 axis in neonates suggests that supplemental FGF19 may not benefit preterm and term infants with cholestatic liver disease 1
• Careful consideration must be given to the developmental stage when designing FGF19-based interventions for pediatric patients 1

Potential Applications in Specific Pediatric Liver Diseases

• Progressive Familial Intrahepatic Cholestasis (PFIC): FGF19 variants could potentially benefit patients with BSEP disease who require liver transplantation 6
• Bile Acid Synthesis Disorders: While bile acid replacement therapy is the primary treatment, FGF19 variants might offer an alternative approach for patients with progressive disease 6
• Non-alcoholic Fatty Liver Disease (NAFLD): Given FGF19's role in lipid metabolism, it could potentially address the lack of effective pharmacological treatments for pediatric NAFLD 6

Future Research Directions

• Investigating the source and role of elevated FGF19 in preterm infants 1
• Developing FGF19 variants that completely separate metabolic benefits from proliferative effects 5
• Exploring the potential of FGF19-based therapies as alternatives to liver transplantation in specific pediatric liver diseases 2, 3
• Conducting clinical trials to establish safety and efficacy of engineered FGF19 variants in pediatric populations 2