Amsterdam Molecular Therapeutics Research Demonstrates AAV Delivery May Be Key Success Factor for Therapeutic Promise of RNAi

May 23, 2011

AMSTERDAM, May 23, 2011 /PRNewswire-FirstCall/ — Amsterdam Molecular
Therapeutics (Euronext: AMT), a leader in the field of human gene therapy,
announced today the results from studies exploring the role of
adeno-associated viral (AAV) vectors for the efficient delivery of short and
micro RNA to inhibit disease by RNA interference. Data related to the future
development of an RNAi gene therapy for hypercholesterolemia and Huntington’s
disease were presented at the recent American Society of Gene and Cell
Therapy 14th Annual Meeting in Seattle, USA.

“Our results demonstrate a robust long-term knock-down of ApoB by
AAV-delivered miApoB in murine liver, thus providing an excellent candidate
for the development of RNAi-based gene therapy,” stated Dr Harald Petry, Head
of Research at AMT. “RNAi-based therapeutic strategies are considered highly
promising in the industry, but thus far, effective delivery has been elusive.
Our research has value in several therapeutic areas, such as
hypercholesterolemia and associated cardiovascular disease. In addition, in
Huntington’s disease, progress is being made quickly through in vivo studies
and we anticipate proof of concept data in animal models by the end of 2011
for this indication.”


Apolipoprotein B (ApoB) is a primary component of low-density lipoprotein
cholesterol (LDL-C). Serum levels of LDL-C are considered to be proportionate
to the risk of atherosclerotic vascular disease. AMT has conducted
proof-of-concept studies in vivo, with AAV delivery of both short-hairpin RNA
(AAV-shApoB) and microRNA (AAV-miApoB) to decrease ApoB gene expression,
thereby successfully reducing cholesterol levels in serum.

AMT initially developed and screened 19 shRNAs targeting conserved
sequences in human, mouse, and macaque ApoB mRNAs (shApoB) and subsequently
narrowed the focus to one candidate, shApoB10, for in vivo inhibition
studies. To compare the intrinsic inhibitory properties and long-term
efficacy of shRNA and miRNA, we expressed shApoB10 from a miRNA scaffold
(miApoB) using the liver-specific LP1 promoter. Self-complementary
adeno-associated virus vector of serotype 8 (scAAV8) was used for long-term
transduction of murine liver with shApoB and miApoB.

In a comparative study, ApoB expression was significantly decreased in
murine livers transduced with AAV-shApoB and AAV-miApoB. Expression of the
AAV-shApoB and AAV-miApoB resulted in 90% ApoB protein knock-down, associated
with 80% cholesterol decrease in murine plasma for the first 6 weeks.
However, after 6 weeks the inhibitory effect of AAV-shApoB started to wear
off, while AAV-miApoB retained a more stable inhibitory profile. At 27 weeks
post-injection, ApoB and plasma cholesterol were still decreased to 50% from
baseline. Ongoing research at AMT aims to determine the mechanism underlying
the differences seen between long-term AAV-shApoB and AAV-miApoB efficacy in
murine livers using different AAV doses. The longer-term inhibitory effect of
AAV-miApoB could be due to its lower toxicity and off-target properties
compared to AAV-shApoB because expression of miApoB is specifically limited
to hepatocytes.

Huntington’s disease (HD)

One particularly promising focus of AMT in the development of artificial
and cellular miRNAs targets several genes involved in HD, a rare and
incurable neurodegenerative disease caused by poly-CAG expansions in the
Huntington (Htt) gene. Initial studies have focused on optimizing the
inhibitory RNA molecules to achieve highest allele specificity and efficacy
against the mutant Htt gene. If the preliminary results are borne out by the
proof of concept data, the HD program would constitute an excellent program
for a co-development agreement.

About Amsterdam Molecular Therapeutics

AMT is a world leader in the development of human gene based therapies.
The company’s lead product Glybera(R), a gene therapy for lipoprotein lipase
deficiency (LPLD), is currently under review by the European Medicines Agency
(EMA). If approved, Glybera will be the first gene therapy product to be
marketed in Europe. AMT also has a product pipeline of several gene therapy
products in development for hemophilia B, Duchenne muscular dystrophy, acute
intermittent porphyria, Parkinson’s disease, and SanfillipoB. Using
adeno-associated viral (AAV) derived vectors as the delivery vehicle of
choice for therapeutic genes, the company has been able to design and
validate probably the world’s first stable and scalable AAV manufacturing
platform. This proprietary platform can be applied to a large number of rare
(orphan) diseases caused by one faulty gene and allows AMT to pursue its
strategy of focusing on this sector of the industry. AMT was founded in 1998
and is based in Amsterdam. Further information can be found at

Certain statements in this press release are “forward-looking statements”
including those that refer to management’s plans and expectations for future
operations, prospects and financial condition. Words such as “strategy,”
“expects,” “plans,” “anticipates,” “believes,” “will,” “continues,”
“estimates,” “intends,” “projects,” “goals,” “targets” and other words of
similar meaning are intended to identify such forward-looking statements.
Such statements are based on the current expectations of the management of
AMT only. Undue reliance should not be placed on these statements because, by
their nature, they are subject to known and unknown risks and can be affected
by factors that are beyond the control of AMT. Actual results could differ
materially from current expectations due to a number of factors and
uncertainties affecting AMT’s business. AMT expressly disclaims any intent or
obligation to update any forward-looking statements herein except as required
by law.

SOURCE Amsterdam Molecular Therapeutics B.V

Source: newswire

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