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On Demand

Advancing Nose-to-Brain Delivery of Nucleic Acids through Localization


Mar 25, 2022 10:00am ‐ Mar 25, 2022 10:00am


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Description

Advancing Nose-to-Brain Delivery of Nucleic Acids through Localization

Samantha M. Sarett1, Zhefeng Li1, Anisha D’Souza3, Hao-Cheng Chueh1, Christopher Wiethoff1, Peng Fang1, Erica Mondo1, Christina Zhang1, Claire Moront1, Ryan C. Hill1, Sarah Dicker1, Benjamin S. Bleier2, Mansoor Amiji3, Michelle Lynn Hall1
Eli Lilly and Company1; Massachusetts Eye and Ear Institute2; Northeastern University3

Nucleic acids like short interfering RNA (siRNA) are an emerging class of drugs with the capability of addressing previously untreatable (central nervous system) CNS diseases at the genetic level. However, broad clinical application of nucleic acid drugs has been hampered by their inherently poor delivery properties. To date, the only clinically validated option for CNS delivery of nucleic acids is a highly invasive direct injection.
Nose-to-brain delivery (N2B) is a minimally invasive approach that circumvents the BBB and could effectively deliver siRNA to the CNS. Deposition at the olfactory epithelium (located in the upper nasal cavity) allows transport of drugs alongside the olfactory and trigeminal nerves to the brain. However, the fundamental biological differences between rodent and human nasal biology have historically hindered development of drugs that leverage the N2B pathway. For example, 95% of the rodent nasal epithelial surface area allows N2B transit compared to 5 – 8 % for humans. Thus, we hypothesized that a key issue for N2B delivery could be inefficient / variable localization and retention at the target area.
In our investigation of the potential for N2B delivery of nucleic acids, we confirmed the validity of the transit pathway for siRNA therapeutics using pipet-based intranasal instillation in rats. However, absent more efficient localization of dose, magnitude of siRNA delivery was low (1x10-3 – 1x10-2 % ID/g in olfactory bulb and trigeminal nerve). Subsequently, we improved the consistency and degree of siRNA distribution to the CNS through localization by two distinct methods. First, we used catheter-based intranasal infusion in rats to localize the dose to the back of the nasal cavity. Second, we evaluated a translatable approach that both localizes and retains the dose at the rodent epithelium via implantation of a minimally invasive nasal depot (MIND). In both cases, distribution to the brain increased by >10-fold in the olfactory bulb and trigeminal nerve, and siRNA was also quantified in deeper brain regions (e.g., frontal cortex, hippocampus, striatum). RNAScope data depicting siRNA distribution to the olfactory bulb and surface layers of the cortex supported siRNA’s transit through the distinct N2B pathway. In pilot studies, N2B-delivered siRNA also achieved knockdown in regions along that pathway (trigeminal nerve (25%), brain stem (50%), and rostral frontal cortex (20%)).
This data highlights the necessity of efficient localization and retention of siRNA at the olfactory epithelium for effective N2B delivery. Our data shows that addressing this challenge (e.g., via the simple, endoscopic application of MIND in human patients) could bridge the translatability gap for the N2B route. This motivates a continued investigation of the minimally invasive N2B route for delivery of nucleic acid therapeutics to the CNS.

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