Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells.
Leukocytes are central regulators of inflammation and the target cells of therapies for key diseases, including autoimmune, cardiovascular, and malignant disorders. Efficient in vivo delivery of small interfering RNA (siRNA) to immune cells could thus enable novel treatment strategies with broad applicability. In this report, we develop systemic delivery methods of siRNA encapsulated in lipid nanoparticles (LNP) for durable and potent in vivo RNA interference (RNAi)-mediated silencing in myeloid cells. This work provides the first demonstration of siRNA-mediated silencing in myeloid cell types of nonhuman primates (NHPs) and establishes the feasibility of targeting multiple gene targets in rodent myeloid cells. The therapeutic potential of these formulations was demonstrated using siRNA targeting tumor necrosis factor-α (TNFα) which induced substantial attenuation of disease progression comparable to a potent antibody treatment in a mouse model of rheumatoid arthritis (RA). In summary, we demonstrate a broadly applicable and therapeutically relevant platform for silencing disease genes in immune cells.
Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
Tatiana I
TI
Novobrantseva
Anna
A
Borodovsky
Jamie
J
Wong
Boris
B
Klebanov
Mohammad
M
Zafari
Kristina
K
Yucius
William
W
Querbes
Pei
P
Ge
Vera M
VM
Ruda
Stuart
S
Milstein
Lauren
L
Speciner
Rick
R
Duncan
Scott
S
Barros
Genc
G
Basha
Pieter
P
Cullis
Akin
A
Akinc
Jessica S
JS
Donahoe
K
K
Narayanannair Jayaprakash
Muthusamy
M
Jayaraman
Roman L
RL
Bogorad
Kevin
K
Love
Katie
K
Whitehead
Chris
C
Levins
Muthiah
M
Manoharan
Filip K
FK
Swirski
Ralph
R
Weissleder
Robert
R
Langer
Daniel G
DG
Anderson
Antonin
A
de Fougerolles
Matthias
M
Nahrendorf
Victor
V
Koteliansky