Biotech Values

[HobGlobulin]

HIV Foiled by Spreading the CCR5 delta32 Mutation Around?

Has this approach been discussed here before?

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/10-28-2008/0004913439&EDATE=


>> Sangamo BioSciences Presents Data at ICAAC Demonstrating 'In Vivo' Protection Against HIV Infection by CCR5-ZFN Therapeutic

Preclinical Animal Data Demonstrates Selective Survival Advantage of
ZFN-Treated Immune Cells after HIV Infection and Reduced Viral Loads

WASHINGTON and RICHMOND, Calif., Oct. 28 /PRNewswire-FirstCall/ --
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the presentation
of data demonstrating that human CD4 T-cells can be made permanently
resistant to HIV infection by treatment with zinc finger DNA-binding
protein nucleases (ZFN(TM)) resulting in an increase in CD4 T-cell counts
and a reduction in viral load in an animal model of HIV infection. The
presentation, entitled, "Establishment of HIV Resistant CD4 T-cells Using
Engineered Zinc Finger Protein Nucleases (ZFNs)" is taking place today at
the joint meeting of the Interscience Conference on Antimicrobial Agents
and Chemotherapy (ICAAC) and the Infectious Diseases Society of America
(IDSA) in Washington, DC.

"We are very excited about these data and our collaboration with
Sangamo to develop an HIV/AIDS therapeutic," said Carl June, M.D., Director
of Translational Research at the Abramson Family Cancer Research Institute
at the University of Pennsylvania School of Medicine, and a co-author of
the study. "The ability to prevent immune cells from becoming infected by
HIV has the potential to provide long term control of both the
opportunistic infections characteristic of AIDS as well as the virus
itself. We look forward to bringing this program into the clinic."

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.

"These data provide good support for the evaluation of our first
ZFN-based ZFP Therapeutic in man," commented Dale Ando, M.D., Sangamo's
vice president of therapeutic development and chief medical officer. "It
was observed more than ten years ago that individuals carrying the natural
CCR5-delta32 mutation were highly resistant to infection by HIV.
Consequently, a variety of small molecule and antibody approaches have been
tested as potential therapeutics. However, a small molecule or antibody
approach requires the constant presence of a sufficiently high
concentration of drug 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. We believe that our ZFN technology
provides an approach that circumvents the dosing and potential toxicity
issues of a systemic therapy. By specifically modifying only CD4 T-cells,
the principal target of HIV pathology, in a one-time exposure of the cells
to ZFNs, we can generate a population of R5-tropic HIV-resistant T-cells.

We have shown that these ZFN-modified human cells are made permanently
resistant to infection by HIV. Furthermore, the cells selectively survive
and expand in an animal after HIV infection, providing a reservoir of
healthy and uninfectable immune cells. In a patient, such cells could be
available to fight both opportunistic infections characteristic of AIDS and
HIV itself. The modified cells exhibited the expected properties of normal
CD4 T-cells. These data also demonstrate that ZFN-modified human CD4
T-cells can be produced in the quantities required for the translation of
this program into the clinic. We intend to file an investigational new drug
(IND) application for this ZFP Therapeutic this year and begin a clinical
trial as soon as possible."

Data Reported in the ICAAC/IDSA Presentation

The reported results demonstrate that a one-time exposure to
CCR5-specific ZFNs resulted in the generation of an HIV-resistant
population of primary human 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 exposure to virus. 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). It was also determined that 50 days after infection,
mice given the ZFN-modified cells had increased numbers of CD4 cells and a
statistically significant seven-fold reduction in viral load in their
peripheral blood (P<0.001) compared to mice given control cells. A high
level of specificity of the CCR5-ZFNs for their target site was
demonstrated by immunochemistry and direct genomic sequence analysis of
ZFN-treated human CD4 T-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.

In addition, Sangamo and its collaborators have demonstrated successful
ZFN-modification of clinical-scale quantities of human CD4 T-cells and that
these modified cells exhibited the expected properties of normal T-cells.
This demonstrates that ZFN-modified human CD4 T-cells could be produced in
quantities required for the translation of this program into the clinic.

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
individuals. According to UNAIDS/WHO, over 2.7 million people were infected
with HIV in 2007. There are now over 33 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 produces malformed CCR5
proteins, which cannot be used by HIV as a co-receptor. Individuals that
have two copies of this mutant form of CCR5 (delta32) 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 and ALS. Other therapeutic
development programs are focused on 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. <<