HIV Gene Therapy Data Update

HIV Gene Therapy Data Update

HIV Gene Therapy Data Reported This Month

Sangamo Says Experimental Therapy Kept HIV Level Low
By Rob Waters – January 19, 2010 16:05 EST
Jan. 19 (Bloomberg) — Sangamo BioSciences Inc., a company developing gene-based therapies for AIDS and other conditions, said an experimental treatment kept down levels of HIV, the virus that causes AIDS, in the first patient tested in a study.
The patient interrupted his antiviral medications after infection-fighting cells that are targets of the virus were treated with the Sangamo product. His viral levels didn’t rise for six weeks, two weeks to four weeks later than typical patients who halt medication, Richmond, California-based Sangamo said today in a statement.
The therapy uses an engineered protein called a zinc finger nuclease to try and neutralize a receptor called CCR5 that HIV uses to enter and infect immune cells. This approach aims to replicate the immunity to HIV infection enjoyed by 1 percent to 2 percent of people whose own CCR5 genes are mutated.
The zinc finger technology “provides a totally new approach to HIV/AIDS with the aim of providing a reservoir of functional T-cells that are resistant to infection by HIV and available to fight opportunistic infections,” Dale Ando, Sangamo’s chief medical officer, said in the statement. “These data are an early indication that this may be possible.”

Sangamo’s Bet Against AIDS: Gene Therapy – “The bottom line: Sangamo BioSciences is testing a gene therapy for AIDS inspired by a cured patient. The first results come this month.”

Inspired by one man’s cure, the biotech tweaks patients’ genes

“preliminary data will be reported on Feb. 27 at a medical conference in Boston. Moussatos says that if the data are strong, Sangamo may attract partnerships with larger drugmakers that it will need to help finance larger trials.”
Video Interview with patient:
Feb 10, 2011, By Rob Waters
Timothy Brown may be the only person cured of AIDS. Brown, who lives in San Francisco, in 2007 received a stem-cell transplant in Berlin that transferred genetic material to him from one of the up to 2 percent of humans with a natural immunity to the disease. He has been off treatment since then, and no traces of the AIDS virus have been found in his body, says his hematologist, Gero Hütter, now with the German Red Cross in Mannheim. His case has encouraged tiny Sangamo BioSciences (SGMO) to develop a new form of gene therapy that could offer others the same result.
While there’s no guarantee Brown, 44, will remain virus-free, his case has spurred scientists to try to duplicate the result without a dangerous stem-cell transplant. Sangamo, a Richmond (Calif.) biotechnology company, will report data late this month on a gene therapy that’s likely to be less risky. If the results are a success, and the method is eventually approved, it may generate $750 million a year in U.S. sales, says Liana Moussatos, a biotech analyst at Wedbush Securities. “It’s high-risk, but definitely high-reward,” she says. “If this is a cure for HIV that prevents or reduces the lifelong need for drugs, that’s a huge accomplishment.”
Sangamo’s stock has more than doubled since July 6, when the company, with no products on the market, reported success of its gene therapy approach in mice in the journal Nature Biotechnology. One reason for the enthusiasm: The therapy, using a new technology that acts like biological scissors to cut into genes at precise points, may also treat other diseases, such as hemophilia, Parkinson’s, and neuropathy, the nerve damage caused by diabetes, says Sangamo Chief Executive Officer Edward Lanphier. An approved treatment for neuropathy alone, which has no cure, may generate $6 billion a year, Moussatos says.
Sangamo is conducting two studies of its HIV therapy in 21 people. Both are in the first stage of testing usually required to win U.S. regulatory approval. Its preliminary data will be reported on Feb. 27 at a medical conference in Boston. Moussatos says that if the data are strong, Sangamo may attract partnerships with larger drugmakers that it will need to help finance larger trials.
There are 1.1 million Americans living with the AIDS-causing HIV virus, and 34 million are infected worldwide, according to the U.S. Centers for Disease Control and Prevention. Antiviral drugs, led by Atripla and Truvada, made by Gilead Sciences (GILD) and Bristol-Myers Squibb’s (BMY) Reyataz, generated $15.1 billion in worldwide sales last year, according to industry researcher IMS Health.
AIDS first emerged in 1981 and, in the early years, killed most of those infected within a year of diagnosis. In 1996 doctors began combining three different families of drugs to overcome HIV’s ability to become resistant. That extended lives of patients in North America and Europe by at least 13 years on average, according to a 2008 study. Still, the drugs aren’t a cure, since the virus rebounds when their use stops. They are taken daily, often cause nausea, and can trigger kidney damage. They also need to be regularly adjusted as the virus mutates, gaining resistance in the body.
In the Sangamo process, doctors draw patients’ blood and remove infection-fighting white blood cells. They are then modified using naturally occurring proteins called zinc fingers that cut into patients’ DNA at selected points. Chopping the DNA in the middle of a gene called CCR5 eliminates a receptor that HIV uses to gain entry to cells. The modified cells are then returned to the patient through an infusion.
“This approach shows the most promise of any that I know of,” says Jay A. Levy, a researcher at the University of California in San Francisco who helped identify HIV as the source of AIDS in 1984. “It’s a terrific way of looking for a long-term functional cure for the virus.”
One person who hopes it will prove effective is Matt Sharp, 54, an AIDS educator who was diagnosed in 1988 and today takes a daily regimen of three antivirals. He learned about the Sangamo trial a year ago and enrolled. Since last summer, when Sharp received an infusion of his own gene-modified T-cells, blood cells that help the immune system fight infection, the number of those cells has doubled, he says. “I’m just hoping I could get an infusion once a year that would keep HIV under control and I won’t have to deal with the effects of taking medication.”
CCR5 isn’t a new target. The gene pathway was first noticed in the mid-1990s by scientists studying people immune to HIV infection. In these people, including the donor who contributed stem cells to Brown, the CCR5 gene is mutated and inactive, keeping the virus from gaining a foothold in the immune system. For most HIV patients, however, a stem-cell transplant is impractical and risky. It requires finding a donor with the CCR5 mutation and whose tissues and blood match the patient’s—and carries about a 30 percent risk of death, says Levy.
That’s too high a risk for most AIDS patients who have access to proven antiviral medicines. Brown, previously known in medical circles only as “the Berlin patient,” was willing to take the chance because he also had developed a potentially fatal case of leukemia—a blood cancer that can also be treated by stem-cell transplants. When chemotherapy stopped controlling his leukemia, Brown and his doctors decided to find a donor with genetic characteristics that would allow treatment of both conditions simultaneously. Brown underwent two stem-cell transplants. Afterward he developed neurological problems and other side effects and spent a year in the hospital, at some points near death. He eventually recovered and was released in early 2009.
“If I hadn’t survived, I kind of doubt that the work towards a cure would have gone this far,” Brown says. Now he hopes scientists will be able to develop new therapies based on his treatment “so people can be cured of HIV without having to go through what I went through.”

Zinc Fingers Disrupts CCR5/HIV Entry; Sangamo and the University 

Dec 28, 2009  Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that its collaborators at the University of Pennsylvania have opened a Phase 1

Sangamo BioSciences Initiates Phase 1 Trial of CCR5-ZFP 

Feb 3, 2009  Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that its collaborators at the University of Pennsylvania have opened a Phase 1

New Gene Therapy Zinc Fingers Research Published: ‘doctors may someday control HIV virus using stem cells without using anti-retroviral drugs’ ……’Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo’ in Nature Biotevhnology July 2 2010……

New Gene Therapy Zinc Fingers Research Published: ‘doctors may 

Jul 2, 2010  Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo

Can HIV be cured with stem cell therapy? commentary

by SG Deeks – 2010 –Can HIV be cured with stem cell therapy? commentary. Steven G Deeks and Joseph M McCune. Nature Biotechnology July 2010 full text of study in
Sangamo BioSciences Initiates Phase 1 Trial of CCR5-ZFP Therapeutic to Treat HIV/AIDS
RICHMOND, Calif., Feb 03, 2009 — Therapeutic Approach Provides HIV-Resistant Immune Cells
Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today that its collaborators at the University of Pennsylvania have opened a Phase 1 clinical trial to evaluate SB-728-T for the treatment of HIV/AIDS.
Based on Sangamo’s zinc finger DNA-binding protein nuclease (ZFN) technology, SB-728-T has been shown in an animal model of HIV infection to lead to an increase in CD4+ T-cell counts, a reduction in viral load and expansion of CCR5-modified T-cells, suggesting resistance to HIV.
“This is the first time that we have had the ability to make a patient’s T-cells permanently resistant to infection by CCR5-specific strains of HIV and we are very excited to begin a clinical trial of this novel ZFN-based therapy,” said Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine. “The ability to protect immune cells from infection with HIV and the expansion of CCR5-modified T-cells has the potential to provide long-term control of both the virus itself and eventually the opportunistic infections characteristic of AIDS.”
CCR5 is a co-receptor that enables HIV to enter and infect cells of the immune system. About ten years ago, it was observed that individuals carrying a natural mutation of their CCR5 gene, CCR5-delta32, were highly resistant to infection by HIV. These individuals, lacking a functional CCR5 (approximately 1-2% of the general population), are immunologically “normal”. A variety of small molecule and antibody antagonists of CCR5 binding have been tested and developed as potential therapeutic agents for the treatment of HIV infection. In addition, there is a recent report of a patient who had both HIV infection and leukemia and received a bone marrow transplant from a donor carrying the CCR5 mutation. After the successful bone marrow transplant, HIV treatment was discontinued and the virus could not be found in the circulating blood several months after the procedure. Sangamo’s ZFNs are designed to modify the DNA sequence encoding CCR5. This modification can occur directly in T-cells with only a brief exposure to the ZFNs. Once the modification is made to the T-cell’s CCR5 gene it is permanently disrupted.
“Our ZFN approach is very well-validated by naturally occurring mutations in man and the recent bone marrow transplant report,” commented Dale Ando, M.D., Sangamo’s vice president of therapeutic development and chief medical officer. “However, allogeneic bone marrow transplantation (bone marrow taken from a different person) is not widely applicable as a therapeutic approach for HIV as it is a risky procedure requiring irradiation and ablation of the immune system and matched donors who also carry the CCR5-delta32 mutation are likely to be rare. Small molecule or antibody antagonists require the constant presence of a high concentration of drug in order to block therapeutically relevant numbers of the CCR5 protein.
In contrast, we believe that our ZFN technology provides an approach that circumvents the dosing and potential toxicity issues of a systemic therapy and provides a simpler approach than a transplant. We specifically modify the patient’s own CD4+ T-cells, the principal target of HIV infection, with a one-time exposure of the cells to CCR5-specific ZFNs. This generates a population of T-cells that lack the CCR5 receptor, are resistant to HIV and can be infused back into the patient to provide a reservoir of HIV-resistant functional immune cells and, more importantly, may expand and provide an HIV immune response.”
“Our ZFP technology functions at the DNA level and, as this application demonstrates, enables us to address highly validated therapeutic targets that have proven difficult to drug at the protein and RNA levels,” commented Edward Lanphier, Sangamo’s president and CEO. “ZFPs can be engineered to regulate or modify any gene, in any cell type, which provides numerous opportunities for its therapeutic applications. This trial is another important step in establishing our ZFP technology as a major new therapeutic product development platform.”
About the SB-728-T Clinical Trial
The study is an open-label Phase 1 clinical trial of the safety and tolerability of a single infusion of autologous (a patient’s own) CD4+ T cells genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). A total of twelve subjects with HIV will be enrolled in this trial in two treatment cohorts. The first cohort to be treated comprises six subjects who have failed two or more HAART (Highly Active Antiretroviral Therapy) regimen. The first three subjects in this cohort will be treated sequentially and monitored for the first 21-days post treatment before an additional subject is treated. After this period of evaluation and monitoring has passed successfully, the next three subjects will be treated. The second cohort comprises six subjects who are responsive to their current therapy regimen who will be treated with CCR5-modified T-cells and undergo a structured therapy interruption (STI) or therapy “break”. The primary objective of the study is to evaluate the safety and tolerability of SB-728-T. In addition to safety monitoring, data will be collected on the expansion and persistence of ZFN-modified cells, CD4+ cell counts and viral load. Individuals interested in participating in this trial should visit or contact Larisa Zifchak, R.N. at 215-349-8091 (, Joe Quinn at 215-349-8091 ( or Pablo Tebas, M.D. at 215-349-8091.
Preclinical Data
Preclinical data on SB-728-T were published in the journal Nature Biotechnology (Perez E. E. et al., Nat Biotechnol. 2008 Jul; 26(7):808-16.) and presented 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 in October 2008. The 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 additional experiments 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 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.
Dr. June is not affiliated with Sangamo BioSciences in any capacity beyond his role as a clinical collaborator on this project. 

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