Rescue of non-human primates from advanced Sudan ebolavirus infection with lipid encapsulated siRNA.
Although significant progress has been made in developing therapeutics against Zaire ebolavirus, these therapies do not protect against other Ebola species such as Sudan ebolavirus (SUDV). Here, we describe an RNA interference therapeutic comprising siRNA targeting the SUDV VP35 gene encapsulated in lipid nanoparticle (LNP) technology with increased potency beyond formulations used in TKM-Ebola clinical trials. Twenty-five rhesus monkeys were challenged with a lethal dose of SUDV. Twenty animals received siRNA-LNP beginning at 1, 2, 3, 4 or 5 days post-challenge. VP35-targeting siRNA-LNP treatment resulted in up to 100% survival, even when initiated when fever, viraemia and disease signs were evident. Treatment effectively controlled viral replication, mediating up to 4 log10 reductions after dosing. Mirroring clinical findings, a correlation between high viral loads and fatal outcome was observed, emphasizing the importance of stratifying efficacy according to viral load. In summary, strong survival benefit and rapid control of SUDV replication by VP35-targeting LNP confirm its therapeutic potential in combatting this lethal disease.
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Emily P
EP
Thi
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Amy C H
AC
Lee
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Joan B
JB
Geisbert
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Raul
R
Ursic-Bedoya
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Krystle N
KN
Agans
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Marjorie
M
Robbins
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Daniel J
DJ
Deer
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Karla A
KA
Fenton
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Andrew S
AS
Kondratowicz
Arbutus Biopharma Corporation, Burnaby, British Columbia V5J 5J8, Canada.
Ian
I
MacLachlan
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Thomas W
TW
Geisbert
Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA.|Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Chad E
CE
Mire
D000818:Animals; D000914:Antibodies, Viral; D004195:Disease Models, Animal; D004339:Drug Compounding; D029043:Ebolavirus / Q000302:isolation & purification / Q000472:pathogenicity; D019142:Hemorrhagic Fever, Ebola / Q000628:therapy* / Q000821:virology; D056945:Hep G2 Cells; D006801:Humans; D008055:Lipids; D008253:Macaca mulatta; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D013397:Sudan; D019562:Viral Load / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism; D014766:Viremia / Q000628:therapy; D014779:Virus Replication
D000914:Antibodies, Viral; D008055:Lipids; D034741:RNA, Small Interfering; C080980:VP35 protein, filovirus; D054334:Viral Regulatory and Accessory Proteins
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