Franklin Biolabs Achieves CLIA Certification for AAV NAb Testing
Learn more

Pharmacodynamics of siRNA Therapeutics in NHP Models of Hereditary Angioedema

PROVEN INTELLIGENCE ACCELERATING NEXT-GENERATION THERAPIES

Pharmacodynamics of siRNA Therapeutics in NHP Models of Hereditary Angioedema

Pharmacodynamics of siRNA in NHP Models of Hereditary Angioedema

CELL & GENE | RNA | BIOLOGICS

Frequently Asked Questions

    How do you quantify target engagement for siRNA therapeutics in NHP models of HAE?

    A: We quantify target engagement by measuring the reduction of plasma kallikrein activity and protein levels using validated methods. This is supplemented by direct measurement of target mRNA knockdown in liver biopsies via qPCR to confirm the mechanism of action at the molecular level.

    What is the typical study duration for an NHP pharmacodynamic study for an siRNA-based HAE therapeutic?

    A: A typical single-dose pharmacodynamic study in non-human primates runs from 30 to 90 days post-dose. This duration allows for comprehensive characterization of the onset, magnitude, and duration of target knockdown, which informs clinical dose selection and frequency.

    How do you address the translation of LNP delivery systems from discovery models to NHPs?

    A: We recognize that LNP performance can vary across species. Our approach involves leveraging scalable production methods, such as those using parallelized microfluidic devices, to ensure consistent particle characteristics. We evaluate the LNP’s biodistribution and safety profile in NHPs to confirm that the delivery system performs as expected before initiating pivotal pharmacodynamic assessments.

    What are the key pharmacodynamic endpoints for an siRNA HAE therapeutic in NHPs?

    A: Key endpoints include the dose-dependent reduction of plasma kallikrein protein and activity over time. Molecular-level target engagement is confirmed by quantifying target mRNA knockdown in liver tissue. Comprehensive safety assessments, including clinical observations and histology, are also integrated endpoints.

A promotional graphic for Franklin BioLabs showcasing a list of their notable scientific publications in preclinical and translational research.

Executive Summary

Non-human primate (NHP) models are the definitive system for evaluating the pharmacodynamics of siRNA therapeutics for Hereditary Angioedema (HAE). The biological conservation of the kallikrein-kinin system between NHPs and humans provides highly translatable data on target engagement and duration of action. Key readouts include the quantification of plasma kallikrein reduction and direct measurement of target mRNA knockdown in the liver. The success of these programs depends on robust, scalable lipid nanoparticle (LNP) formulation and a framework for generating GxP-compliant data to support an 18-24 month IND timeline.

Evaluating siRNA-Mediated Kallikrein Knockdown in HAE Models

For siRNA therapeutics targeting Hereditary Angioedema, NHP studies provide the most predictive data for human clinical outcomes. The primary pharmacodynamic objective is to demonstrate potent, durable, and dose-dependent reduction of plasma kallikrein, the serine protease central to HAE pathophysiology. Our study designs focus on serial sampling to precisely map the time course of target protein suppression.

This biological assessment is paired with molecular-level confirmation.

  • Target mRNA Quantification: We measure target mRNA levels in liver tissue to verify the siRNA mechanism of action.

  • Biomarker Analysis: We monitor related biomarkers to understand the broader physiological response to treatment.

  • Safety Assessment: Comprehensive safety and toxicology evaluations, including clinical observations and histology, are integrated into all study designs.

A marketing fact sheet from Franklin Biolabs about the scientific benefits of Mauritian cynomolgus macaques for preclinical research, featuring a photo of the primates.

A stylized rendering of a DNA double helix on the left side of a light blue gradient background.

The Impact of LNP Formulation on In Vivo Potency

The delivery vehicle is as important as the siRNA payload itself. The consistency and scalability of lipid nanoparticle production directly influence in vivo potency and the translational potential of a therapeutic candidate. As research on scalable microfluidic devices demonstrates, manufacturing methods that produce LNPs with superior delivery characteristics can significantly enhance therapeutic efficacy ([PMID: 34189917]). This principle underscores the need for rigorous characterization of the LNP delivery system in a relevant large animal model before advancing a program.

Franklin Biolabs operates a >100,000 sq ft facility equipped to handle these complex programs. While the Franklin Biolabs brand launched in 2024, our core scientific team brings a 100% IND-enabling success rate on programs initiated since 2019.

Supporting Complex Therapeutic Supply Chains

Executing these advanced studies requires sophisticated infrastructure and operational excellence. The logistical framework for next-generation therapeutics involves specialized expertise in formulation, handling, and analysis.

A close-up, blue-toned image of scientific glassware, featuring vials placed in a dish filled with clear, spherical beads, suggesting a laboratory or research setting.

Animal Welfare and Regulatory Compliance

Through our strategic partnership with Bioculture Group, all animal studies are conducted in AAALAC-accredited facilities in full compliance with USDA regulations. We are committed to the highest standards of animal welfare, strictly adhering to the 3Rs principles:

  • Replacement: Using non-animal methods where scientifically valid.

  • Reduction: Minimizing the number of animals used per study.

  • Refinement: Optimizing procedures to enhance animal well-being.

Scientific Process Diagram

This content is for informational purposes. For guidance specific to your therapeutic program, please contact our team for a consultation.

Explore More Capabilities