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Monday, 06/30/2008 8:38:49 AM

Monday, June 30, 2008 8:38:49 AM

Post# of 252588
AIDS Treatment - Is the Paradigm Shifting?

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/06-30-2008/0004840885&EDATE=

>> Sangamo BioSciences Announces Nature Biotechnology Study Demonstrating the Use of Zinc Finger Nucleases to Generate HIV Resistant T Cells

Preclinical Animal Data Demonstrates Promising Therapeutic Strategy for
HIV/AIDS

RICHMOND, Calif., June 30 /PRNewswire-FirstCall/ -- Sangamo
BioSciences, Inc. (Nasdaq: SGMO) announced today the publication of data
demonstrating that human immune system cells (CD4 T-cells) can be made
resistant to HIV infection by treatment with zinc finger DNA-binding
protein nucleases (ZFN(TM)). The data suggest that the ZFN approach, which
results in the permanent modification of the CCR5 gene encoding an
important receptor for HIV infection, is a promising strategy for the
treatment of HIV/AIDS.

The work, which was carried out in the laboratory of Carl June, M.D.,
Director of Translational Research at the Abramson Family Cancer Research
Institute at the University of Pennsylvania School of Medicine, in
collaboration with Sangamo scientists, was published as an Advance Online
Publication in Nature Biotechnology

(http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1410.html).

"A ZFN approach represents the 'next generation' of HIV-entry blocking
agents and a potentially promising class of anti-HIV compounds," said, Dr.
June who is the senior author of the study. "These proof of principle data,
together with experience from individuals that carry a natural mutation in
their CCR5 gene suggest that permanent 'knock-out' of the of CCR5 gene is
important and clinically relevant for long-term resistance to HIV infection
and, we believe, may prove to be more effective than temporary 'knock down'
approaches based on small molecule inhibitors, antibodies, antisense or
RNAi."

Sangamo's ZFNs are designed to permanently modify the DNA sequence
encoding CCR5, a co-receptor that enables HIV to enter and infect cells of
the immune system. Individuals carrying a naturally occurring mutation of
their CCR5 gene, a variant known as CCR5-delta32, have been shown to be
resistant to HIV infection.


"The data described in this paper are an important demonstration of the
potential therapeutic properties of our product," commented Dale Ando,
M.D., Sangamo's vice president of therapeutic development and chief medical
officer. "We have demonstrated that a single treatment with our
CCR5-specific ZFNs generates a population of HIV-resistant human T-cells
similar to the situation in individuals carrying the natural CCR5-delta32
mutation. ZFN-modification of these cells is permanent and makes them
resistant to HIV. The modified cells preferentially survive and expand in
an animal after HIV infection, providing a reservoir of healthy and
uninfectable immune cells. Furthermore, we observed that animals given the
ZFN-modified cells had increased numbers of CD4 cells and substantially
lower levels of HIV in their blood compared to animals given non-modified
cells demonstrating statistically significant protection from the virus. In
an HIV-infected patient, such modified cells could be available as a
protected reservoir within the immune system to fight both opportunistic
infections and HIV itself."

Several major pharmaceutical companies have initiated programs to
develop small molecule or monoclonal antibody approaches to block the
binding of HIV to CCR5. However, a small molecule or antibody approach
requires the constant presence of a sufficiently high concentration of
these drugs or antibody to block therapeutically relevant numbers of the
CCR5 protein, which is present in thousands of copies on the surface of
each T-cell and other tissues in the body. One such drug has been approved
by the US Food and Drug Administration with a "black box" warning, the
strongest for prescription drugs, concerning the risk of liver toxicity and
the possibility of heart attacks.

Sangamo's ZFN technology represents a means of potentially
circumventing these limitations or risks by specifically modifying only CD4
T-cells, the principal target of HIV pathology, in a one-time exposure of
the cells to ZFNs. This results in permanent modification of the CCR5
protein such that HIV cannot enter and infect the cells. This approach
could potentially enable the generation of a reservoir of protected CD4
T-cells that are available to fight the opportunistic infections that are
characteristic of AIDS as well as HIV itself. Sangamo expects to initiate a
clinical trial to evaluate this approach by the end of the year.


Data Reported in the Nature Biotechnology Paper

The reported results demonstrate that a one-time exposure to
CCR5-specific ZFNs resulted in the generation of an HIV-resistant
population of human primary T-cells by the permanent genetic modification
of the CCR5 gene. These ZFN-modified CD4 T-cells expanded stably in
HIV-infected cultures for several weeks and appeared to behave identically
to untreated T-cells except that they were resistant to infection by HIV.
ZFN treated primary CD4 T-cells and transformed CD4 cell lines resisted
infection with R5-tropic HIV (virus that uses the CCR5 co-receptor to enter
cells), resulting in enrichment of ZFN- generated CCR5-disrupted cells in
the population upon long-term exposure to virus (>50 days). Importantly, in
the presence of HIV, ZFN-modified CD4 T- cells also preferentially expanded
in a mouse model. The modified cells were infused into mice that lack a
normal immune system and thus do not reject human cells. After 33 days, the
mice were sacrificed and analyzed for the presence of ZFN-modified cells.
Researchers determined that ZFN-modified cells engrafted normally in the
mouse and that the proportion of modified cells present at the end of the
experiment was greater than two to three fold higher in mice in the
presence of HIV infection (p=0.008). In a second experiment it was
determined that 50 days after infection, mice given the ZFN- modified cells
had increased numbers of CD4 cells and a statistically significant
reduction in viral load in their peripheral blood (P<0.001) compared to
mice given control cells. These data suggest that, in the presence of HIV,
the ZFN-modified cells have a selective advantage allowing them to evade
infection and destruction leaving them able fight opportunistic infections
and HIV itself.

About HIV/AIDS and CCR5

HIV stands for Human Immunodeficiency Virus. HIV infection kills or
impairs cells of the immune system, progressively destroying the body's
ability to fight infections and certain cancers resulting in AIDS (Acquired
Immune Deficiency Syndrome). Individuals diagnosed with AIDS are
susceptible to life-threatening diseases called opportunistic infections,
which are caused by microbes that usually do not cause illness in healthy
people. According to Worldaidsday.org, over 3 million people were infected
with HIV in 2005. There are now over 40 million people living with HIV and
AIDS worldwide.

CCR5 is the chemokine receptor that HIV uses as a co-receptor to gain
entry into immune cells. CCR5 is perhaps the most important of the known
co- receptors for HIV, since the most commonly transmitted strains of HIV
are strains that bind to CCR5 -- so-called "R5" strains. A small fraction
of the population carries a mutation in their CCR5 gene, called the delta32
mutation. This mutated version of the gene results in a truncated CCR5
protein which cannot be used by HIV as a co-receptor. Individuals that have
mutant delta 32 versions of both of their CCR5 genes are resistant to
infection by R5 HIV strains.

About Sangamo

Sangamo BioSciences, Inc. is focused on the research and development of
novel DNA-binding proteins for therapeutic gene regulation and
modification. The most advanced ZFP Therapeutic(TM) development program is
currently in Phase 2 clinical trials for evaluation of safety and clinical
effect in patients with diabetic neuropathy. Phase 1 clinical trials are
ongoing to evaluate a ZFP Therapeutic for peripheral artery disease. Other
therapeutic development programs are focused on ALS, cancer, HIV/AIDS,
neuropathic pain, nerve regeneration, Parkinson's disease and monogenic
diseases. Sangamo's core competencies enable the engineering of a class of
DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By
engineering ZFPs that recognize a specific DNA sequence Sangamo has created
ZFP transcription factors (ZFP TF(TM)) that can control gene expression
and, consequently, cell function. Sangamo is also developing
sequence-specific ZFP Nucleases (ZFN(TM)) for gene modification. Sangamo
has established strategic partnerships with companies outside of the human
therapeutic space including Dow AgroSciences, Sigma-Aldrich Corporation and
several companies applying its ZFP Technology to enhance the production of
protein pharmaceuticals. For more information about Sangamo, visit the
company's web site at http://www.sangamo.com.

This press release may contain forward-looking statements based on
Sangamo's current expectations. These forward-looking statements include,
without limitation, references to the research and development of novel ZFP
TFs and ZFNs as ZFP Therapeutics, applications of Sangamo's ZFP technology
platform, the therapeutic potential of ZFNs for the treatment of HIV/AIDS,
strategic partnerships with collaborators and clinical trials of ZFP
Therapeutics. Actual results may differ materially from these
forward-looking statements due to a number of factors, including
technological challenges, uncertainties relating to the initiation and
completion of stages of ZFP Therapeutic clinical trials, Sangamo's ability
to develop commercially viable products and technological developments by
our competitors. See the company's SEC filings, and in particular, the risk
factors described in the company's Annual Report on Form 10-K and its most
recent Quarterly Report on Form 10-Q. Sangamo BioSciences, Inc. assumes no
obligation to update the forward-looking information contained in this
press release. <<

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