Targeted Genetics Announces Publication of Preclinical Data Supporting the Use of AAV Vectors to Deliver siRNA
09 4월 2008 - 8:30PM
Marketwired
SEATTLE, WA today announced the publication of preclinical data
characterizing the novel use of Adeno-Associated Viral (AAV)
vectors to deliver small interfering RNA (siRNA) for the treatment
of Huntington's disease. The goal of this research is to assess the
use of interfering RNA to silence the mutant huntingtin gene and
thus, reduce the level of the defective protein.
siRNAs are a powerful way to silence genes in mammalian cells.
siRNAs generally function by causing messenger RNAs (mRNAs) for
certain genes to be cleaved and thus prevent protein synthesis.
Similarly, a second class of small RNAs, microRNAs (miRNAs), also
regulate gene expression. These small RNAs represent a new
therapeutic approach to many diseases, such as Huntington's
disease, caused by dominant genetic mutations. Delivery of siRNAs
to cells as oligonucleotides is inefficient because they are taken
up into cells poorly. In addition, these oligonucleotide RNAs bind
to certain receptors on the cell and invoke deleterious
non-specific immune signals and inflammation. This delivery problem
for siRNA can be solved by expressing interfering RNA (short
hairpin RNA or shRNA) from vectors, such as AAV, that can be
delivered efficiently and specifically to the cell nucleus.
However, this approach may still lead to non-specific toxicity with
some RNAs.
This publication describes the development of a generally
applicable approach to addressing the toxicity problem. The study,
titled, "Artificial miRNAs mitigate shRNA-mediated toxicity in the
brain: implications for the therapeutic development of RNA
interference," by McBride, Boudreau, et.al., is now available
online, and will appear in the April 15th issue of Proceedings of
the National Academy of Sciences of the United States of America
(PNAS).
"We have developed AAV-RNAi vectors that efficiently abrogate
disease in mouse models of Huntington's disease. However, many
shRNAs are inefficiently processed and can cause non-specific
toxicity due to metabolic or off-target effects. The team has
developed an approach to overcome these hurdles by embedding the
expressed shRNA in an artificial miRNA," stated Barrie J. Carter,
Ph.D., executive vice president and chief scientific officer of
Targeted Genetics. "These new AAV-RNAi vectors thus retain the
efficiency of delivery and biologic efficacy while having a greatly
enhanced safety profile. We believe this new design concept is of
great importance and general applicability to the entire RNA
therapeutic field."
"These findings represent a significant advance in our
preclinical evaluation of AAV-RNAi vectors and expands our
understanding of use of artificial miRNA expression systems to
mitigate shRNA-mediated toxicity in the brain, the implications of
which are crucial to the development of RNAi for both basic
biological and other therapeutic applications," stated Beverly L.
Davidson, Ph.D., Roy J. Carver professor of Internal Medicine and
vice chair of basic research in the Department of Internal Medicine
at the University of Iowa. "The long-term expression capabilities
of AAV vectors allow for infrequent dosing, which is highly
desirable when administering a therapeutic directly to the brain.
These preclinical data show that the mammalian brain can tolerate
at least a 50% reduction of the Huntingtin gene expression for at
least 4 months. Even more exciting is the additional ongoing
research we are conducting that shows expression over prolonged
periods of a year or more."
About Targeted Genetics and University of Iowa and Collaborative
Effort
Scientists from Targeted Genetics and the University of Iowa are
working together to develop AAV-RNAi vectors that efficiently
abrogate disease in mouse models of Huntington's disease. In 2005,
Targeted Genetics formed a collaboration to develop HD therapeutics
using an AAV delivered RNAi approach to target the HD gene with
Sirna Therapeutics, which included the work by University of Iowa
researchers. In April, 2008, Targeted Genetics Corporation
announced that it has acquired full exclusive rights to its
preclinical Huntington's disease (HD) program from Sirna
Therapeutics, a wholly owned subsidiary of Merck & Co., Inc. As
part of this acquisition, Targeted Genetics obtained a licensing
agreement with the University of Iowa that covers certain IP
developed by Dr. Beverly Davidson's laboratory related to RNA
interference (RNAi) including Adeno-Associated Virus (AAV)
expressed RNAi.
Dr. Beverly Davidson at the University of Iowa has published
preclinical data demonstrating that the delivery of siRNA to the
brain using an AAV vector efficiently inhibited gene expression in
an animal model of neurodegenerative disease (Nature Medicine,
2004); and also has conducted studies in which AAV vectors were
used to express siRNAs and were directly injected into the brains
of mice with HD. Results of these studies demonstrate nearly normal
movement in the mice and significant improvements in characteristic
neurological damage compared to untreated mice. The study also
demonstrated that levels of toxic HD protein in siRNA-treated mice
were reduced to 40 percent of normal levels (PNAS, 2005).
About Huntington's Disease
HD is a devastating, inherited, neurodegenerative disorder that
results from a mutation in the gene that codes for the huntingtin
protein. HD generally shows onset in mid-life and, according to the
Huntington's Disease Society of America, one of out of every 10,000
Americans has HD and an additional 200,000 are at risk of onset.
The disease-causing gene produces a defective huntingtin protein
that is toxic to certain brain cells and the subsequent neuronal
damage leads to the movement disorders, psychiatric disturbances
and cognitive decline that characterize this disease.
About Targeted Genetics
Targeted Genetics Corporation is a biotechnology company
committed to the development of innovative targeted molecular
therapies for the prevention and treatment of acquired and
inherited diseases with significant unmet medical need. Targeted
Genetics' proprietary Adeno-Associated Virus (AAV) technology
platform allows it to deliver genes that encode proteins to
increase gene function or RNAi to decrease or silence gene
function. Targeted Genetics' product development efforts target
inflammatory arthritis, AIDS prophylaxis, congestive heart failure
and Huntington's disease. To learn more about Targeted Genetics,
visit Targeted Genetics' website at www.targetedgenetics.com.
Safe Harbor Statement under the Private Securities Litigation
Reform Act of 1995:
This release contains forward-looking statements regarding the
Company's liquidity and financial resources, its ability to fund
ongoing and future operations, its business strategy and product
development, including statements regarding the data collected in
the HD program, the timing, continuance or results of trials
related to the HD program, the potential impact of the HD program
on our results of operations and other statements about the
Company's plans, objectives, intentions and expectations. These
statements involve current expectations, forecasts of future events
and other statements that are not historical facts. Inaccurate
assumptions and known and unknown risks and uncertainties can
affect the accuracy of forward-looking statements. Factors that
could affect actual future events or results include, but are not
limited to, payments anticipated by the Company under product
development collaborations and contracts, the Company's actual
expenses, the Company's ability to raise capital when needed, the
timing, nature and results of the Company's clinical trials,
potential development of alternative technologies or more effective
products by competitors, the Company's ability to obtain and
maintain regulatory or institutional approvals, the Company's
ability to maintain its listing on the NASDAQ Capital Market and
the Company's ability to obtain, maintain and protect its
intellectual property, as well as other risk factors described in
its filings with the Securities and Exchange Commission (SEC),
including in "Item 1A. Risk Factors" in the Company's most recent
annual report on Form 10-K for the year ended December 31, 2007
filed with the SEC. You should not rely unduly on these
forward-looking statements, which apply only as of the date of this
release. The Company undertakes no duty to publicly announce or
report revisions to these statements as new information becomes
available that may change the Company's expectations.
Investor and Media Contact: Stacie D. Byars WeissComm Partners
415.946.1072 Email Contact Carolyn Wang WeissComm Partners
415.946.1065 Email Contact
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