412
Antisense Oligonucleotides as Potential Drugs
Tab. 1
Antisense drug pipeline.
Target
Lead indication
Company
Product
Phase
CMV
CMV-retinitis
ISIS
Vitravene
Drug
PKC-
α
Cancer-NSCLC
ISIS/Lilly
AfFnitac
III
C-RA±
Cancer-ovarian
ISIS
ISIS 5132
II
H-ras
Cancer-pancreatic
ISIS
ISIS 2503
II
ICAM-1
Crohn’s disease
ISIS
ISIS 2302/Alicaforsen
III
ICAM-1
Tropical psoriasis
ISIS
ISIS 2302/Alicaforsen
II
ICAM-1
Ulcerative colitis
ISIS
ISIS 2302/Alicaforsen
II
HCV
Hepatitis C
ISIS
ISIS 14803
II
TN±-
α
Crohn’s disease
ISIS
ISIS 104838
II
TN±-
α
Topical psoriasis
ISIS
ISIS 104838
II
c-myc
Cancer, restenosis
AVI-Biopharm
Resten-NG
III
bcl
Cancer
Genta /Aventis
Genasense
III
HIV
AIDS
Enzo Biochem
HGTV43
II
Adenosine A1
Respiratory disease
EpiGenesis
EPI2010
II
PKA
Cancer
Hybridon
Gem 231
II
Rib. reductase
Cancer
Lorus Terapeutics
GTI2040
II
TG±-
β
2
Cancer
Antisense Pharma
AP 12009
I/II
VEG±R1
Cancer
Ribozyme Pharmaceuticals
Angiozyme
II
HCV
Hepatitis C
Ribozyme Pharmaceuticals
Heptazyme
I
HER2
Cancer
Ribozyme Pharmaceuticals
Herzyme
I
name of Novartis, certainly a fantastic
achievement. However, the number of
patients with CMV-retinitis has grown
lesser and lesser because of the suc-
cessful treatment of AIDS at least in
the Western hemisphere. ICAM-1 from
the same company, as a medication for
Crohn’s disease, has not been approved
yet but is pursued further under the
trade name Alicaforsen. Very far ad-
vanced is the Genta anti-
BCL2
oligonu-
cleotide Genasense for the treatment of
malignant melanoma in conjunction with
chemotherapy. Genasense is in phase
III clinical trial, developed together with
Aventis.
AfFnitac is a potent inhibitor of PKC
α
i
nn
o
n
sm
a
l
lc
e
l
ll
u
n
gc
a
n
c
e
r
,w
h
i
c
h
shows almost double survival times (16
instead of 8 months) in combination with
carboplatin/taxol. The main objective is
to obtain a good synergistic proFle by
the combination with chemotherapeutic
a
g
en
t
s
,a
si
sth
eg
o
a
lw
i
thG
en
a
s
en
s
e
,
with taxol in this case. AfFnitac is also
tested in a single-agent (phase II) trial
against non-Hodgkin’s lymphoma. Here,
a codevelopment together with Eli Lilly is
under way.
7
RNA Interference
Inhibition of gene expression by RNA
interference is a rapidly growing area
of research and has already found con-
siderable application for gene functional
analysis. It differs from the antisense
method fundamentally. It is a natural
process in plants undergoing transgene-
or virus-induced posttranscriptional gene
silencing (PTGS). Here, short double-
stranded
oligoribonucleotides
are
pro-
cessed from long dsRNA for the inhibi-
tion of expression of the foreign gene.
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