Preclinical Animal Data Demonstrates Promising Therapeutic Strategy for HIV/AIDS RICHMOND, Calif., June 30
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.
SOURCE Sangamo BioSciences, Inc.
