Amsterdam Molecular Therapeutics Successfully Lowers Cholesterol In Vivo With Enhanced Novel MicroRNA AAV Gene Therapy
AMSTERDAM, October
25, 2010/PRNewswire-FirstCall/ -- Amsterdam Molecular Therapeutics
(AMT) Holding N.V. (Euronext: AMT), a leader in the development of
gene based therapies, today announced that its gene therapy product
incorporating siRNA sequences into microRNA scaffolds to silence
Apolipoprotein B100 (AAV-miApoB) was able to significantly lower
plasma cholesterol levels in vivo over a period of 18 weeks. These
preliminary results suggest that this approach could lead to a
treatment for high cholesterol in humans.
"Successful
hepatocyte-specific delivery of microRNA (miRNA) and significant
demonstration of gene silencing again illustrates the strength of
AMT's AAV platform. We announced previously success with our short
hairpin RNA targeting ApoB (shApoB) gene product but our newest
data suggests our miRNA product is proving to be even better and
safer," stated Jorn Aldag, CEO of AMT. "Certainly of the two
approaches, the natural characteristics of miRNA, such as prolonged
stable long term expression, undetectable toxicity profile, tissue
specificity, as well as the significant efficacy, suggest a more
favorable route to a viable treatment for high cholesterol. This
future application of our technology may circumvent some of the
delivery issues with the RNA approach. We intend to seek partners
to exploit the full AAV technology potential in the RNA
field."
Using its proprietary
adeno-associated viral vectors (AAV), a single injection of
AAV-miApoB transduced murine hepatocytes almost entirely and
resulted in a reduction of total plasma cholesterol of 60-80% for
an 18 week period. AAV delivery of miRNA, expressed from a
liver-specific promoter, constitutes the second powerful approach
by which AMT has demonstrated to lower plasma cholesterol, together
with AMT's AAV shApoB gene therapy product tested in the same model
of the disease. In our new approach, we went one step further and
limited the expression of the inhibitory miApoB molecule only to
the hepatocytes, which provides a higher safety profile, a feature
very important for future clinical applications. Data were
presented at the Hepatocyte User Group and Medicon Valley
Hepatocyte User Forum (22-23 October) in Montpellier, France, and
at the European Society for Gene and Cell Therapy Annual Conference
(22-25 October) in Milan, Italy.
In the new study,
mice received intra-venous injections with equal doses of 1011 gc
per animal AAV-shApoB or AAV-miApoB and were examined for 18 weeks.
Expression of the shApoB and miApoB resulted in 90% ApoB protein
knock-down, associated with 80% cholesterol decrease in murine
plasma for the first 6 weeks. However, after 8 weeks the effect of
the shApoB started to wear off, while miApoB remained effective in
ApoB and cholesterol reduction for up to 18 weeks. Ongoing research
aims to determine the mechanism for the differences seen between
long-term AAV-shApoB and AAV-miApoB efficacy in murine livers. We
believe that the long-term stability of the miApoB is due to its
lower toxicity and off-target properties compared to shApoB because
expression of miApoB is specifically limited to hepatocytes.
ApoB100 is the
structural protein of Low Density Lipoprotein (LDL) particles that
carry cholesterol. Silencing the activity of ApoB100 with miRNA or
shRNA lowers plasma LDL-cholesterol by 60-80% and has the potential
to be used to treat hypercholesterolemia and associated
cardiovascular disease.
About Amsterdam
Molecular Therapeutics
AMT is a leader in
the development of human gene based therapies. 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 what is probably the first stable and
scalable AAV production platform. This proprietary platform can be
applied to a large number of rare (orphan) diseases that are caused
by one faulty gene. Currently, AMT has a product pipeline with
several AAV-based gene therapy products in LPLD, Hemophilia B,
Duchenne Muscular Dystrophy, Acute Intermittent Porphyria, and
Parkinson's Disease at different stages of research or development.
AMT was founded in 1998 and is based in Amsterdam.
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
For further
enquiries: Jorn Aldag, CEO, AMT, Tel: +31-20-566-7394,
j.aldag@amtbiopharma.com; Mike Sinclair, Partner, Halsin Partners,
Tel: +44-20-7318-2955, msinclair@halsin.com
Posted: October 2010
