Ingredient-Level In Silico Analysis of RNAi Therapeutics Linking Gene Knockdown to Bradykinin-Driven Angioedema in Hereditary Angioedema

Partner Description

Alnylam Pharmaceuticals
Alnylam Pharmaceuticals is a leading biopharmaceutical company pioneering RNA interference (RNAi) therapeutics. The company focuses on translating siRNA-mediated gene silencing into clinically meaningful treatments, including programs targeting hereditary angioedema (HAE), a rare and potentially life-threatening disorder with significant unmet medical need.

Challenge

Hereditary angioedema is a chronic, recurrent condition characterized by episodic swelling of subcutaneous or submucosal tissues. In HAE, dysregulation involving factor XII and/or C1 inhibitor results in excessive bradykinin production, driving increased vascular permeability and acute swelling attacks.

While siRNA represents a powerful therapeutic ingredient capable of selectively suppressing disease-relevant genes, its development in HAE is challenged by fragmented mechanistic understanding across the contact activation and bradykinin pathways. Experimental evidence is often siloed at the level of individual biomolecules, making it difficult to quantitatively connect gene knockdown to downstream bradykinin response. This lack of integration limits optimization of target selection, dosing strategies, and rational evaluation of combination RNAi approaches.

How CytoSolve® Helped

CytoSolve® collaborated with Alnylam to perform an ingredient-level, in silico analysis of RNAi therapeutics within the biological context of HAE. CytoSolve® converted the contact activation cascade and bradykinin production pathways into mechanistic computational models capable of simulating dynamic system behavior rather than relying on isolated biomarker correlations.

The integrated modeling framework enabled systematic evaluation of how perturbations at different nodes—representing siRNA-mediated gene knockdown—propagate through interconnected pathways to influence bradykinin levels. Sensitivity analyses identified which molecular components exert the greatest control over clinically relevant outputs. Model behavior was rigorously validated against independent in vitro and in vivo findings from the scientific literature, ensuring biological plausibility and robustness. Simulation outputs aligned with outcomes observed in Alnylam’s in vivo studies, reinforcing confidence in the predictive value of the ingredient-level analysis.

Key Benefits Realized

  • Established a quantitative, systems-level connection between RNAi ingredient activity and bradykinin-driven biological outcomes
  • Identified pathway leverage points most sensitive to gene knockdown, supporting informed target prioritization
  • Cross-validated model predictions using independent in vitro and in vivo experimental evidence
  • Demonstrated predictive alignment with Alnylam’s in vivo results, enabling more confident preclinical decision-making
  • Created a mechanistic foundation for rational exploration of multi-target and combination RNAi strategies

Outcome

Through collaboration with CytoSolve®, Alnylam translated complex contact activation and bradykinin biology into a validated in silico systems architecture suitable for ingredient-level analysis of RNAi therapeutics. By quantitatively linking siRNA-mediated gene suppression to downstream pathway response, the model provided a predictive framework for accelerating target selection, optimizing knockdown strategies, and rationally designing combination RNAi approaches aimed at improving therapeutic control of hereditary angioedema.