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

By Amsterdam Molecular Therapeutics B.v, PRNE
Sunday, May 22, 2011

AMSTERDAM, May 23, 2011 -

- RNAi Data for Hypercholesterolemia Presented at ASGCT Annual Meeting

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,

"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
, 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

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.


For further enquiries: Jorn Aldag, CEO, AMT, Tel : +31-20-566-7394, j.aldag at; Mike Sinclair, Partner, Halsin Partners, Tel : +44-20-7318-2955, msinclair at

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