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Updated: Apr 27, 2026

Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes

Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes

Published on: July 23, 2016

Divalent siRNA for prion disease.

Juliana E Gentile¹, Taylor L Corridon¹, Fiona E Serack¹

¹Program in Brain Health, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States.

Nucleic Acids Research

|April 25, 2026

Summary

This summary is machine-generated.

Researchers developed a potent new drug candidate, 2439-s4, using divalent short interfering RNA (siRNA) to lower prion protein (PrP) levels. This novel siRNA therapy shows promise for treating prion diseases, with a new drug candidate entering clinical trials.

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Area of Science:

Neuroscience and Pharmacology
Oligonucleotide Therapeutics
Prion Disease Research

Background:

Prion protein (PrP) lowering is a validated strategy for prion disease treatment, but more potent drug candidates are needed.
Divalent short interfering RNA (siRNA) offers enhanced potency and duration for central nervous system (CNS) drug development.

Purpose of the Study:

To discover and develop novel, potent PrP-lowering drug candidates using divalent siRNA technology.
To evaluate the efficacy and safety of a lead candidate, 2439-s4, for potential human prion disease treatment.

Main Methods:

Identification and characterization of mouse Prnp-targeting divalent siRNA (1682-s4) in wild-type and prion-infected mice.
Generation of transgenic mouse models (Tg25109, Tg26372) expressing human PRNP for in vivo screening.
Discovery and optimization of human PRNP-targeting siRNA (2439) across various divalent siRNA chemical scaffolds.

Main Results:

Mouse siRNA 1682-s4 significantly increased survival time in prion-infected mice.
Human siRNA 2439, particularly in scaffold s4, demonstrated superior PrP knockdown in transgenic mice.
A single dose of 2439-s4 significantly reduced human PrP levels in the brain, with favorable toxicology and FDA IND clearance.

Conclusions:

Divalent siRNA scaffold s4 enhances PrP lowering potency, offering a promising therapeutic approach.
2439-s4 represents a potent and safe drug candidate for human prion diseases, advancing to clinical trials.