Alnylam has set out how it plans to deliver siRNA to the central nervous system and other tissues beyond the liver. Writing in Nature Biotechnology, the RNA specialist shared details of how the conjugation of its drug candidates enabled the therapeutic silencing of target genes around the body in preclinical studies.
Lipid nanoparticles and GalNAc conjugates already support the delivery of siRNA to the liver, enabling the development of approved treatments that target the organ. However, other delivery systems are needed if Alnylam and its rivals are to realize the full potential of siRNA and treat the array of diseases around the body that are potentially amenable to gene silencing.
Alnylam advanced its extrahepatic delivery strategy earlier this year when it kicked off a phase 1 trial of a potential treatment for Alzheimer’s disease. The new research paper sheds light on the delivery system that underpins the Alzheimer’s candidate.
To get siRNA to organs beyond the liver, Alnylam has conjugated 2′-O-hexadecyl (C16) to the molecules. The C16 approach builds on a history of using lipophilic moieties to improve the delivery and uptake of siRNA molecules. Alnylam saw an opportunity to optimize the lipophilicity of chemically modified siRNA to aid intracellular delivery.
The preclinical studies suggest Alnylam is onto something. After showing the delivery system can cause knockdown in the CNS, the eye and the lung in animals, the biotech ran a study in a mouse model of Alzheimer’s. Knockdown of the target gene lasted three months and was associated with reductions in an isoform of amyloid beta. Kevin Fitzgerald, Ph.D., chief scientific officer at Alnylam, discussed the findings.
“Diseases of the CNS are some of the most difficult to treat. Thus, we are encouraged by these preclinical findings as they suggest siRNAs may have a role in treating diseases impacting the CNS, the eye, and the lung. Our CNS delivery platform provides long durability, which is particularly advantageous in settings of intrathecal administration, where infrequent dosing is desirable,” Fitzgerald said in a statement.