Executive Summary: Designing preclinical efficacy models for RNA therapeutics in rare genetic disorders requires a tailored, science-driven strategy. Standard templates are insufficient. The approach must account for the specific RNA modality (mRNA, siRNA, tRNA), the non-viral delivery system (e.g., Lipid Nanoparticle), and the unique pathophysiology of the indication. Success depends on leveraging deep expertise in in vivo delivery, biodistribution, and complex biological responses, supported by GxP-compliant processes aligned with MHRA and global regulatory expectations.

A Foundation in Complex In Vivo Systems

The scientific and regulatory path for RNA therapeutics, particularly for rare diseases, requires a deep understanding of how to achieve targeted biological effects in vivo. While the delivery vehicle may be a non-viral LNP, the fundamental challenges of biodistribution, target engagement, and functional protein expression share principles with other advanced therapies.

Our team’s historical work in de-risking viral vector platforms provides a robust framework for addressing these challenges. For instance, demonstrating stable, long-term cholesterol reduction in nonhuman primate models via AAV-delivered meganucleases (PMID: 29985478) establishes a clear precedent in managing complex liver-directed therapies. Similarly, optimizing vector efficacy for gain-of-function protein expression in metabolic disease models (PMID: 25023731) informs our approach to mRNA-based protein replacement strategies. This track record, which contributes to our 100% successful IND rate since 2019, was established by our core scientific leadership prior to the formal launch of Franklin Biolabs in 2024.

Tailoring Efficacy Models for RNA Payloads

A preclinical strategy for an RNA therapeutic must be customized to the modality and its intended mechanism of action.

• mRNA Therapeutics: For protein replacement, efficacy models focus on quantifying the expression, activity, and duration of the therapeutic protein in target tissues. This involves developing phase-appropriate bioanalytical assays to measure functional outcomes.

• siRNA Therapeutics: For gene silencing, the primary endpoint is the specific knockdown of the target transcript and protein. Models must be sensitive enough to detect graded dose-responses and assess the duration of the silencing effect.

• LNP Delivery Systems: The lipid nanoparticle itself requires characterization. Efficacy studies are designed in parallel with safety assessments that evaluate the LNP’s distribution and potential immunogenicity, drawing on expertise from collaborations with leaders like Moderna.