AI Insight
This study demonstrates that camelid-derived single-domain antibodies (VHHs) targeting transferrin receptor 1 (TfR1) can effectively deliver siRNAs across the blood-brain barrier into deep brain structures following systemic administration. Tested across wild-type mice, humanized TfR1 transgenic mice, and non-human primates, VHH-siRNA conjugates achieved 50-80% target gene knockdown at both mRNA and protein levels, with an effective dose 50 below 1 mg/kg. The conjugates showed favorable pharmacokinetics, including rapid receptor-dependent brain distribution and durable gene silencing at low nanomolar concentrations in neural cells.
Why it matters
Many neurological disorders such as Huntington's disease, Parkinson's disease, and ALS involve dysregulated gene expression in deep brain regions that are notoriously difficult to target therapeutically. This platform could enable non-invasive, systemically administered RNA interference therapies at clinically relevant doses, potentially replacing more burdensome intrathecal or intracranial delivery methods.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Despite their therapeutic potential across a wide range of central nervous system (CNS) disorders, nucleic acid-based therapeutics are limited by inefficient delivery to deep brain regions at clinically viable doses. Transferrin receptor 1 (TfR1) has emerged as an attractive target for receptor-mediated transcytosis across the blood-brain barrier (BBB), enabling systemic delivery of biologics such as lysosomal enzymes and monoclonal antibodies. In this study, we demonstrated the translational potential of recently described TfR1-targeting camelid-derived single-domain antibodies (VHHs) for CNS delivery of siRNAs. When conjugated 1:1 to different tool siRNAs, these VHHs promote rapid and robust intracellular uptake, resulting in potent RNAi activity at low nanomolar concentrations in neural cells. Systemic administration of VHH-siRNA conjugates in wild-type mice, hTfR1 transgenic-mice and non-human primates revealed a favourable pharmacokinetic profile characterized by rapid TfR-dependent distributional clearance and efficient functional uptake in deep brain structures. This translated into durable target knockdown of 50-80% at both mRNA and protein levels and with ED50 below 1 mg/kg siRNA. Collectively, these findings establish our TfR1 targeting VHHs as a fit-for-purpose platform for the systemic delivery of therapeutic oligonucleotides to deep brain structures at clinically relevant doses, opening new avenues for the treatment of diverse CNS disorders.