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704
LIVER-TARGETED INHIBITION OF PAPD5 AND PAPD7 LEADS
TO SUSTAINABLE HBsAg REDUCTION IN THE AAV-HBV MOUSE
MODEL.
Xue Zhou1, Youjun Yu1, Anais Lopez2, Josephine Felber2,
Helene Gylling3, Gitte Friis3, Soren Ottosen3 and Henrik
Mueller2, (1)Roche Pharma Research and Early Development,
Roche Innovation Center Shanghai, Shanghai, China, (2)
Roche Pharma Research and Early Development, Roche
Innovation Center Basel, Basel, Switzerland, (3)Roche
Pharma Research and Early Development, Roche Innovation
Center Copenhagen, Hørsholm, Denmark
Background: PAPD5 and PAPD7 have recently been
identified as host factors for Hepatitis B virus (HBV) and
are required for viral RNA stability It has been shown that
simultaneous inhibition of both proteins leads to a strong
inhibition of HBV gene expression in vitro. Here we evaluated
the combination of two locked nucleic acid antisense
oligonucleotides (LNA ASOs) targeting PAPD5 and PAPD7 in
the AAV-HBV mouse model. Methods: LNA ASOs targeting
mouse PAPD5 and PAPD7 were identified and covalently
linked to a cluster of N-acetylgalactosamine-moieties to
ensure hepatocyte-specific uptake. Both LNA ASOs were
administered subcutaneously in AAV-HBV mice one day apart
either once, weekly (5 doses) or bi-weekly (3 doses) at doses
ranging from 2 5mg/kg to 10mg/kg Mice were followed up for
a minimum of eight weeks after last dose. Viral, immunological
and safety parameters in serum were measured every week
Additional groups were terminated at intermediate time points
to allow assessment of target knockdown in liver Results:
After a single dose at 10mg/kg, HBsAg was reduced by
1 4log and returned back to baseline only 9 weeks after
dosing Mice that received weekly doses showed HBsAg
reduction up to 1 8log and antigen levels did not return back
to baseline by the end of the study Interestingly, dosing biweekly
for the same time period and concentration (5mg/
kg), showed even superior anti-viral effect On average,
HBsAg was reduced by 2 3log with four out of eight mice
displaying sustained HBsAg loss (<LLOQ) through the end
of the study This sustained anti-viral response correlated
with anti-HBs antibody induction Inhibition of PAPD5 and
PAPD7 in the liver was well-tolerated with no decrease in
body weight or ALT elevation Conclusion: It has previously
been shown that inhibition of PAPD5 and PAPD7 leads to a
strong reduction of HBV transcripts in vitro. However, this is
the first report providing evidence, that targeting PAPD5 and
PAPD7 also has a profound impact on viral gene expression
in vivo with infrequent dosing showing strong inhibition of viral
markers in combination with a long duration of action This
data underlines the importance of these two host factors for
the HBV transcription and emphasizes the potential of their
inhibition as a new therapeutic target for the HBV cure.
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发表于 2019-11-4 18:50