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Specialized NHP Tissue Collection for CNS Biodistribution of Oligonucleotide Therapies

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Specialized NHP Tissue Collection for CNS Biodistribution of Oligonucleotide Therapies

NHP Tissue Collection for Oligonucleotide CNS Biodistribution

CELL & GENE | RNA | BIOLOGICS

For oligonucleotide therapies administered to the central nervous system (CNS), a significant portion of the dose can distribute systemically, creating risks for non-target toxicity and complicating dose-response modeling. A robust IND-enabling package requires precise characterization of this biodistribution. Franklin Biolabs has developed specialized nonhuman primate (NHP) tissue collection and histology protocols designed to capture high-resolution data on both CNS and peripheral tissue exposure, directly supporting regulatory submissions and de-risking clinical development.

    How does your collection protocol differ for antisense oligonucleotides (ASOs) versus siRNAs in CNS studies?

    A: Our protocols are customized based on the specific oligonucleotide modality. For ASOs, we prioritize collection of tissues known for potential class-specific toxicities, such as the kidney and liver. For siRNAs, we expand collection to include tissues relevant to potential immunogenicity, such as the spleen and lymph nodes, while ensuring all protocols are optimized for RNA integrity.

    What specific CNS and peripheral tissues are prioritized for collection to assess non-target biodistribution?

    A: Beyond comprehensive CNS sampling (e.g., multiple spinal cord levels, cortex, cerebellum), we prioritize key peripheral tissues. Standard collection includes the liver, kidney, spleen, heart, and dorsal root ganglia (DRG). The final tissue list is always developed in consultation with the sponsor to align with the therapeutic’s specific mechanism and safety profile.

    What GxP standards apply to tissue collection and processing for IND-enabling biodistribution studies?

    A: All tissue collection, processing, and handling for IND-enabling studies are conducted within our GxP-compliant framework. This ensures data integrity, traceability, and adherence to the quality standards expected by regulatory authorities for pivotal safety and toxicology assessments.

    How do you mitigate RNA degradation during complex NHP necropsies?

    A: We employ rapid, optimized necropsy procedures performed by highly trained teams. Tissues are immediately stabilized using appropriate methods (e.g., flash-freezing in liquid nitrogen or immersion in RNAlater™) to preserve RNA integrity for subsequent molecular assays performed by our strategic partners.

Characterizing Systemic Exposure of CNS-Administered Oligonucleotides

Oligonucleotide therapies targeting the CNS present a unique biodistribution challenge. The assumption that intrathecal or intracerebroventricular administration confines the therapeutic agent to the CNS is incorrect. Data shows that a substantial fraction of a dose administered to the cerebrospinal fluid (CSF) can enter systemic circulation.

This phenomenon has direct implications for your program’s safety assessment. As demonstrated in studies of viral vectors administered to the CSF, a significant percentage of the dose can be detected systemically (PMID: 37624734). This systemic exposure profile necessitates a comprehensive evaluation of potential non-target tissue accumulation and associated toxicities to build a complete safety narrative for regulatory review.

A scientist in a lab coat and gloves looks through a microscope in a laboratory setting, with a blue color overlay.

A scientist pipetting a red liquid into a multi-well plate in a laboratory setting.

High-Resolution Histology and Tissue Collection Protocols

A successful IND submission depends on accurately characterizing this biodistribution. Our approach integrates specialized NHP necropsy with advanced histology to provide definitive data. This meticulous process provides the rapid pathology insights needed to accelerate preclinical readouts and build a robust safety package.

Our protocol design includes:

  • Comprehensive Tissue Sampling: We collect a wide array of CNS and peripheral tissues, including dorsal root ganglia, liver, kidney, and spleen, to create a complete map of therapeutic distribution.

  • Optimized Fixation and Processing: Tissues are processed using techniques specifically designed to preserve oligonucleotide integrity for downstream applications, including in situ hybridization (ISH) and other molecular assays.

  • Coordinated Sample Logistics: We work directly with the sponsor’s designated laboratories or our strategic partners to ensure seamless sample transfer and a fully documented chain of custody, preserving sample integrity up to the point of handoff.

  • GxP-Compliant Reporting: All data is generated and reported from our >100,000 sq ft facility to meet the stringent requirements for IND-enabling toxicology studies.

De-Risking the Path to IND

By providing a clear understanding of your oligonucleotide’s biodistribution profile, we help you anticipate and address potential regulatory questions. This proactive approach is central to our model, which supports an 18-24 month IND timeline. Since 2019, programs supported by our scientific leadership have achieved a 100% IND success rate, a track record we continue with the Franklin Biolabs brand launched in 2024.

Scientific Process Diagram

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

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