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本帖最后由 StephenW 于 2015-10-4 15:49 编辑
2007
TKM-HBV, a Novel RNA Interference Treatment for
Chronic Hepatitis B, Rapidly Reduces Surface Antigen
and other Viral Proteins in both Intrahepatic and Peripheral
Compartments
Amy C. Lee, Emily P. Thi, Luying Pei, Xin Ye, Jennifer Cross,
Sandie Y. Du, Ammen P. Dhillon, Janet R. Phelps, Kevin McClintock,
Michael Abrams, Ian MacLachlan; Tekmira Pharmaceuticals,
Burnaby, BC, Canada
TKM-HBV is a novel RNA interference (RNAi) therapeutic intervention
against hepatitis B virus (HBV) and currently in Phase 1
clinical development. It is designed to reduce the viral antigen
load in chronically infected patients and allow the body to
escape the state of immune repression imposed by the virus.
A mixture of three different oligonucleotide duplexes encapsulated
within a lipid nanoparticle delivery system, TKM-HBV acts
directly on all HBV RNAs (pregenomic RNA as well as viral
mRNA) via nucleotide sequence-specific cleavage. Because it
prevents the synthesis of viral proteins and reduces the overall
antigen load in the body, this mode of drug action may
present advantages over other approaches that seek to block
viral protein secretion into the bloodstream thereby potentially
causing intracellular build-up and ER stress. A hydrodynamic
injection (HDI) immunodeficient NOD.CB17-Prkdcscid/J mouse
model of HBV was used to characterize viral RNA targeting
and the time course of viral antigen reduction following a single
administration of TKM-HBV and its effective distribution
to its target organ, the liver. HBV RNA was measured using
branched DNA assays, HBV DNA was quantitated via QPCR,
and HBV proteins were detected using ELISA and immunohistochemistry
methods. Over 92% reduction of total HBV RNA in
the liver was observed as soon as 2 days after treatment, with
a slightly more moderate effect on the 3.5 kb species alone
suggesting this molecule is less accessible to the cellular RNAi
machinery than other HBV transcripts. Onset of serum HBV
DNA reduction was also highly rapid, with the nadir of >98%
inhibition detected at Day 2. Maximal treatment effects were
essentially reached at Day 4 for intrahepatic and serum HBsAg
(98% and 97%, respectively) whereas reduction of intrahepatic
HBcAg appeared to be a more gradual process, continuing to
decrease beyond Day 4 with a nadir reached at Day 7. Taken
together, these data suggest that the peripheral compartment is
a dynamic environment with rapid turnover of viral markers in
the blood stream whereas the turnover of viral proteins within
the intracellular compartment of liver cells occurs more slowly.
The kinetics of viral marker turnover may differ in a more
immunocompetent system. In summary, TKM-HBV effectively
removed viral antigens from both the intrahepatic and peripheral
compartments within days after a single treatment dose
in HDI mice. These viral elements include immunomodulatory
surface and core proteins which are implicated in mediating
the immune-repressed condition of chronic HBV infection.
Disclosures:
Amy C. Lee - Employment: Tekmira
Emily P. Thi - Employment: Tekmira Pharmaceuticals
Xin Ye - Employment: Tekmira Pharmaceuticals Corporation
Kevin McClintock - Employment: Tekmira Pharmaceuticals, Tekmira Pharmaceuticals,
Tekmira Pharmaceuticals, Tekmira Pharmaceuticals
The following authors have nothing to disclose: Luying Pei, Jennifer Cross, Sandie
Y. Du, Ammen P. Dhillon, Janet R. Phelps, Michael Abrams, Ian MacLachlan
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发表于 2015-10-4 15:47
