Alnylam and CytoSolve® Build a Predictive In Silico Systems Architecture Linking RNAi 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 organization focuses on translating siRNA-driven gene silencing into clinically meaningful therapies, including programs targeting hereditary angioedema (HAE), a rare disease with significant unmet medical need.

Challenge

Hereditary angioedema is a chronic, recurrent disorder characterized by episodic, non-pruritic swelling of subcutaneous or submucosal tissues. In HAE, dysregulation involving factor XII and/or C1 inhibitor leads to excessive bradykinin production, driving vascular permeability and acute swelling attacks.

Although siRNA therapeutics offer a powerful means to suppress genes implicated in HAE, development is complicated by limited mechanistic integration across the contact activation and bradykinin pathways. Experimental evidence is often fragmented across individual biomolecules, making it difficult to quantitatively connect gene knockdown to downstream bradykinin response. This fragmentation constrains optimization of target selection, dosing strategies, and rational design of combination RNAi approaches.

How CytoSolve® Helped

CytoSolve® collaborated with Alnylam to construct a mechanistic, in silico systems architecture capturing the interconnected biology underlying HAE. CytoSolve® converted the contact activation cascade and bradykinin production pathways into quantitative computational models capable of simulating dynamic pathway behavior rather than relying on isolated biomarker interpretation.

The modeling framework enabled systematic evaluation of how perturbations at different nodes—representing siRNA-mediated gene knockdown—propagate through the network to influence bradykinin production. Sensitivity analyses clarified which pathway components exert the greatest control over clinically relevant outputs. Model behavior was validated against independent in vitro and in vivo findings from the literature, ensuring biological plausibility and robustness. Importantly, simulation results aligned with outcomes observed in Alnylam’s in vivo studies, strengthening confidence in the model’s predictive utility.

Key Benefits Realized

  • Established a quantitative, systems-level link between siRNA target knockdown and bradykinin-driven pathway response.
  • Identified pathway leverage points with the greatest influence on bradykinin production to support target prioritization.
  • Cross-validated model behavior using independent experimental evidence from published in vitro and in vivo studies.
  • Demonstrated predictive alignment with Alnylam’s in vivo results, supporting more confident preclinical decision-making.
  • Created a mechanistic foundation for rational exploration of multi-target and combination siRNA strategies.

Outcome

Through collaboration with CytoSolve®, Alnylam translated complex contact activation and bradykinin biology into a validated in silico systems architecture capable of connecting siRNA-mediated gene suppression to downstream pathway outcomes. The resulting computational model provided a practical, predictive framework for accelerating target selection, optimizing knockdown strategies, and exploring combination RNAi approaches aimed at improving therapeutic control of life-threatening hereditary angioedema.