SCAD: A modular platform for efficient delivery of duplex RNA to the CNS and beyond

Area of Science:

• Biotechnology
• Molecular Biology
• Neuroscience

Background:

• Oligonucleotide therapeutics offer targeted gene modulation for various diseases.
• Effective delivery beyond the liver, especially to the central nervous system (CNS), remains a major hurdle.
• Current liver-targeting strategies like N-Acetylgalactosamine are insufficient for CNS applications.

Purpose of the Study:

• To develop a novel delivery platform for duplex RNA therapeutics targeting extrahepatic tissues, particularly the CNS.
• To optimize the platform for enhanced protein binding and cellular uptake.
• To evaluate the efficacy, biodistribution, and safety of the platform in preclinical models.

Main Methods:

• Development of the smart chemistry-aided delivery (SCAD) platform by conjugating duplex RNA with an accessory oligonucleotide.
• Screening for optimal SCAD architecture to enhance cell-free protein binding and in vitro activity.
• Administration of SCAD-siRNA conjugates in rodent models to assess CNS and extrahepatic tissue delivery, gene knockdown, and safety.

Main Results:

• The optimized SCAD architecture demonstrated superior cell-free protein binding and in vitro activity.
• Local administration in rodents led to widespread CNS biodistribution and sustained mRNA knockdown (>5 months).
• The SCAD platform showed efficient delivery to other extrahepatic tissues, including the eye, lung, and joint, with a favorable safety profile.

Conclusions:

• The SCAD platform is a versatile and effective tool for delivering duplex RNA therapeutics to the CNS and other extrahepatic tissues.
• SCAD technology addresses a critical unmet need for oligonucleotide delivery in non-hepatic indications.
• The modular design of SCAD allows for broad applicability to various duplex RNA therapeutics, advancing the field of oligonucleotide therapy.