Hemophilia management is currently undergoing a paradigm shift from traditional protein replacement to RNA modalities and their delivery. This review provides a critical analysis of RNA-based therapeutics (specifically siRNA, mRNA, and CRISPR/Cas9) as a versatile paradigm distinct from DNA ones. We synthesize clinical and preclinical data to contrast these modalities: siRNA strategies (e.g., fitusiran) have indicated ∼90% reductions in bleeding rates by rebalancing hemostasis independent of factor deficiency; LNP-mRNA platforms offer tunable, transient factor production without genomic integration risks; and CRISPR-based editing aims for permanent correction (up to 170% FIX expression in preclinical studies) but necessitates rigorous monitoring for off-target effects. Crucially, this article dissects the non-viral delivery landscape determining the clinical viability of these cargos. We evaluate lipid nanoparticles (LNPs) as the current clinical gold standard for hepatic delivery, contrasting them against emerging polymeric systems, aptamer-conjugates, and exosomes designed to overcome rate-limiting barriers such as endosomal entrapment and renal clearance. By juxtaposing the immunogenic limitations of viral vectors, we conclude that next-generation RNA therapeutics, enabled by LNPs and GalNAc-conjugation, offer a strategic pathway to overcome the durability gap observed in Hemophilia A and expand treatment access to patients currently excluded by viral seroprevalence.
Zangi et al. (Mon,) studied this question.
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