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Zinc Finger Proteins Put Personalized HIV Therapy Within Reach

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J220:
From http://www.sciencedaily.com/releases/2008/06/080630093611.htm :

ScienceDaily (June 30, 2008) — Researchers at the University of Pennsylvania School of Medicine and collaborators are using minute, naturally occurring proteins called zinc fingers to engineer T cells to one day treat AIDS in humans.

"By inducing mutations in the CCR5 gene using zinc finger proteins, we've reduced the expression of CCR5 surface proteins on T cells, which is necessary for the AIDS virus to enter these immune system cells," explains first author Elena Perez, MD, PhD, Assistant Professor of Pediatrics at Penn. "This approach stops the AIDS virus from entering the T cells because it now has an introduced error into the CCR5 gene."

Some people are born with a mutation on their CCR5 gene and therefore do not have a working CCR5 receptor on the surface of their T cells. These rare individuals are immune to HIV infection and seemingly are not affected by the non-functional CCR5 protein. The zinc finger approach aims to mimic this natural immunity.

Perez performed the research while a postdoctoral fellow in the lab of senior author Carl June, MD, Director of Translational Medicine at the Abramson Family Cancer Research Institute, and a Professor of Pathology and Laboratory Medicine at Penn. Perez is also an attending physician with the Children's Hospital of Philadelphia in the Division of Allergy and Immunology.

Normally, zinc fingers bind to different bases in the DNA sequence to regulate the activity of genes. The zinc fingers used in this experiment were designed to bind to specific DNA sequences in the CCR5 gene. The CCR5 protein is one of the two cell-surface receptors needed for HIV to gain entry into a T cell in order to replicate.

In this study, the zinc finger protein brings a DNA enzyme to the CCR5 gene to cut a portion of its sequence, but due to the repair process a new mutation arises in the CCR5 protein, rendering it non-functional. Without a functional CCR5 protein on the cell's surface, HIV cannot enter, presumably leading to resistance to HIV infection.

The researchers demonstrated this process in cell culture and in a mouse model. For the animal part of the study, the investigators used healthy human CD4 T cells and added DNA that expresses the zinc fingers, which modifies the CCR5 co-receptor. They grew the engineered cells in tissue culture flasks and transferred them into immune-deficient mice infected with HIV. "We followed them over time and showed that those mice that received the zinc-finger-treated cells showed less viral load than controls and improved CD4 counts," says Perez.

The researchers are planning a clinical trial in humans in which T cells from HIV patients would have their CCR5 gene deliberately knocked out. These modified T cells could then be infused back into the patients to re-establish their immune system and decrease their viral load.

Dr. Perez and Dr. June have no financial relationship with Sangamo.

NYCguy:
Sangamo previously claimed that there would be a trial in 2007.  Let's hope they start one soon, rather than sending out more press releases.

bimazek:
http://www.sciencenews.org/view/generic/id/33799/title/HIV_knockout

a little more science detail on this discovery if you are into that

my hope is that in 5 years we will all have some non toxic treatment

haart may still be arround in some cases like mutated virus that is resistant

maybe 7 years is my hope

bimazek:
this looks like it could be a major major breakthrough - lets hope that there rapid movement forward - lot of detailed science here

Find a specific gene and then  turn it on or off.
ZFP-Therapeutics are designed to activate or repress specific genes relevant to human diseases. More...
http://www.sangamo.com/index.php

TEN DIAGRAMS TO EXPLAIN HOW IT WORKS
http://www.sangamo.com/tech/our_tech_ex.html
 Engineering Transcription Factors to Regulate Genes
Transcription factors are naturally occurring proteins that function within the nucleus of a cell to regulate gene expression. Transcription factors function by binding to specific sites on DNA and causing nearby genes to be turned on or off. (fig. A)

PDF on how they have had success with AIDS
http://files.shareholder.com/downloads/SGMO/351574819x0x209704/40e1ddfe-7186-4503-8904-8751b5b3fe55/SGMO_News_2008_6_30_General_Releases.pdf

www.sangamo.com  is the company that invented all this!!


details on technology of ZPT
http://www.sangamo.com/tech/tech.html
how USLCA is using sagamo ZPT tech to treat aids
http://www.sangamo.com/human/human_thera_overview.html#HIV



Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)
HIV infection results in the death of immune system cells and thus leads to AIDS, a condition in which the body’s immune system is depleted to such a degree that the patient is unable to fight off common infections and ultimately  succumbs to opportunistic infections or cancers.  CCR5 is the co-receptor for HIV entry into T-cells and without CCR5 expressed on their surface, HIV cannot infect these cells.  A population of individuals has been identified that is immune to HIV infection, despite multiple exposures to the virus. They have a natural mutation, CCR?532, that results in the expression of a shortened, non-functional CCR5 protein. This mutation appears to have no observable deleterious effect on the growth or survival or these individuals. We are using our ZFN-mediated gene disruption technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection.  The aim is to provide a population of HIV-resistant cells that can fight opportunistic infections. In collaboration with scientists at the University of Pennsylvania and the University of Los Angeles California, UCLA, we are pursuing both ex- and in vivo approaches in T-cells and hematopoietic. Sangamo anticipates filing an IND for this therapeutic in 2008.

cute guys who helped invent this technology
http://www.sangamo.com/discovery/discovery.html


http://www.nature.com/nbt/journal/vaop/ncurrent/abs/nbt1410.html
Article abstract
Nature Biotechnology
Published online: 29 June 2008 | doi:10.1038/nbt1410
Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Abstract
Homozygosity for the naturally occurring Delta32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted approx50% of CCR5 alleles in a pool of primary human CD4+ T cells. Genetic disruption of CCR5 provided robust, stable and heritable protection against HIV-1 infection in vitro and in vivo in a NOG model of HIV infection. HIV-1-infected mice engrafted with ZFN-modified CD4+ T cells had lower viral loads and higher CD4+ T-cell counts than mice engrafted with wild-type CD4+ T cells, consistent with the potential to reconstitute immune function in individuals with HIV/AIDS by maintenance of an HIV-resistant CD4+ T-cell population. Thus adoptive transfer of ex vivo expanded CCR5 ZFN–modified autologous CD4+ T cells in HIV patients is an attractive approach for the treatment of HIV-1 infection.


http://investor.sangamo.com/stockquote.cfm?benchmark1=&Event1=&DisplayType=Area&Period=560&CustomFromDate=6%2F20%2F2004&CustomToDate=10%2F30%2F2004

John2038:
Milestone Achieved A Year Ahead of Schedule (Jan 12, 2009)

Sangamo BioSciences, Inc. (Nasdaq: SGMO) today announced it has reached a major production capacity milestone as part of its agreement with Sigma-Aldrich Corporation (Nasdaq: SIAL) to commercialize zinc finger nuclease reagents (ZFNs) for research applications. The milestone triggers a payment of $1.0 million to Sangamo.

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