Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells

Area of Science:

• Immunology
• Molecular Biology
• Nanotechnology

Background:

• Leukocytes are crucial in inflammation and disease, making them key therapeutic targets.
• Current therapies face challenges in efficient in vivo delivery to immune cells.
• Targeting leukocytes offers potential for novel treatments in autoimmune, cardiovascular, and malignant disorders.

Purpose of the Study:

• To develop systemic delivery methods for small interfering RNA (siRNA) using lipid nanoparticles (LNPs).
• To achieve durable and potent in vivo RNA interference (RNAi)-mediated gene silencing in myeloid cells.
• To establish a therapeutic platform for targeting immune cells in various diseases.

Main Methods:

• Encapsulation of siRNA within lipid nanoparticles (LNPs) for systemic delivery.
• Demonstration of siRNA-mediated silencing in myeloid cell types of nonhuman primates (NHPs).
• Validation of targeting multiple gene targets in rodent myeloid cells.

Main Results:

• First demonstration of siRNA-mediated gene silencing in NHP myeloid cells.
• Successful targeting of multiple genes in rodent myeloid cells.
• siRNA targeting tumor necrosis factor-α (TNFα) significantly reduced disease progression in a rheumatoid arthritis mouse model, comparable to antibody treatment.

Conclusions:

• A broadly applicable and therapeutically relevant LNP-based platform for in vivo gene silencing in immune cells has been developed.
• This platform enables durable and potent RNAi-mediated gene silencing in myeloid cells.
• The findings support the potential of this technology for novel therapeutic strategies against inflammatory, autoimmune, and malignant diseases.