First-In-Man Study Of Genome Editing Using Sangamo's ZFN Technology Published In New England Journal Of Medicine

RICHMOND, Calif., March 5, 2014 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced today the publication in the New England Journal of Medicine of the first clinical study of its proprietary zinc finger nuclease (ZFN)-based genome editing technology in humans. Data from the study, carried out in HIV-positive subjects, demonstrate that the T-cell genome can be safely engineered to mimic a naturally occurring mutation that provides resistance to HIV infection. ZFN-modified T-cells are well tolerated when reinfused and treatment is associated with decreased viral loads (VLs) in several subjects who were taken off their antiretroviral therapy (ART) including one whose viral load became undetectable. The study demonstrates the feasibility of this novel genome editing approach to achieve functional control of HIV.

Additional data on the ongoing SB-728-T ongoing clinical trials in HIV will be presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2014), which is taking place in Boston, March 3-6, 2014.

"We have used Sangamo's ZFN technology to safely genetically engineer an HIV-infected individual's own T-cells and to make those cells resistant to infection by the virus," said Carl June, M.D., Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania, and a senior author of the paper.  "This study demonstrates that ZFN-modified cells can be safely administered back to the individual; are able to persist and circulate throughout the body to key reservoirs of HIV infection; and show preferential survival over unmodified cells when antiviral drugs are withdrawn, potentially keeping the virus under control without the use of drugs. Our experience reinforces our belief that an immunological approach is a promising approach to enable functional control of HIV infection and eliminate the need for lifelong ART."

Summary of Study Results
In the study, T-cells from HIV subjects were isolated and edited with ZFNs to make them resistant to the virus by knocking out the CCR5 gene which encodes a coreceptor required for HIV infection.  After modification, the cells (SB-728-T) were returned to the subject, in a so-called "autologous infusion," and subjects were monitored for safety and a variety of immunological parameters.  The modified cells readily engrafted and were able to traffic throughout the body to key sites of HIV persistence such as the gut-associated lymphoid tissue. The data demonstrate that the modified cells persist and moreover appear to have a selective advantage, showing a preferential survival compared to unmodified cells when exposed to HIV during a planned interruption of ART. SB-728-T treatment was associated with an increase in the levels of total circulating CD4 T-cells and was well tolerated.

One of six subjects undergoing a treatment interruption experienced the longest delay in rebound of viral load when ART was withdrawn and achieved a decrease in VL to undetectable levels during the 12-week period. This subject was later found to carry a natural mutation of CCR5, CCR5 delta-32, in one of the two CCR5 genes (making the individual a CCR5 delta-32 heterozygote).  Thus, following exposure to the ZFNs targeting CCR5, at baseline this subject to had a greater percentage of T-cells that were modified at both sites (biallelic modification) and were fully resistant to HIV infection. Preliminary analyses suggest that the levels of circulating cells with biallelic modification of CCR5 may correlate with control of viral load.  Sangamo has ongoing clinical studies in CCR5 delta-32 heterozygotes (SB-728-902, Cohort 5) and in subjects undergoing Cytoxan pre-conditioning (SB-728-1101) to further study this relationship.

"The publication of this study in the New England Journal of Medicine represents a milestone in the development of ZFN-mediated genome editing as a new therapeutic approach," stated Edward Lanphier, Sangamo's president and chief executive officer. "Our ZFN technology functions at the DNA level, enabling us to make precise and persistent changes to the properties of cells that result in therapeutic benefit. Our goal is to use this powerful technology to engineer genetic cures for diseases that have thus far been treated as chronic conditions, including HIV and a wide range of monogenic diseases. The study represents an important first step in our development of this novel immunological therapy for HIV.  However, we now have clinical data from additional trials that confirm and extend the data presented in this early clinical trial.  We look forward to providing an update on our ongoing clinical trials at CROI and to providing guidance as to the future direction of this program."

Study Design
The study was an open-label, Phase 1 study of a single dose of approximately 10 billion ZFN-modified autologous T-cells in 12 HIV-infected subjects whose virus was well controlled by antiretroviral medications. Subjects were divided into two cohorts of six subjects each. Subjects in Cohort 1 were identified as immune responders who had demonstrated adequate recovery of CD4 T-cells after ART (>450 cells /mm³).Subjects in Cohort 2 were identified as individuals who had demonstrated inadequate recovery of CD4 T-cells after ART (200-500 cells /mm³), so-called immunologic non-responders.  Four weeks after SB-728-T treatment, Cohort 1 subjects underwent an interruption from ART of up to 12 weeks.  Cohort 2 remained on their ART throughout the study. The primary objective of the study was to assess safety and tolerability of administration of a single dose of SB-728-T.  Secondary outcomes included measures of immune reconstitution and HIV resistance. The study was carried out at the Hospital of the University of Pennsylvania and the Jacobi Medical Center, Albert Einstein College of Medicine and was supported in part by an NIAID Program Project Grant.

N.Eng. J. Med. 2014: 370:897-906 "Gene Editing of CCR5 in Autologous CD4 T-cells of Persons Infected with HIV." In addition to scientists and clinicians Perelman School of Medicine at the University of Pennsylvania, coauthors included researchers from the Albert Einstein School of Medicine and Sangamo BioSciences. Dr. June reports no financial disclosures related to Sangamo BioSciences.

About SB-728-T
SB-728-T is an autologous CD4+ T-cell product in which the gene for CCR5, a co-receptor for HIV entry, is modified via ZFN-mediated genome editing to disrupt the CCR5 protein.  T-cells with a disrupted CCR5 protein are resistant to infection by the most common strain of HIV.

About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic Cures^TM for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic^® for the treatment of HIV/AIDS (SB-728-T) and NGF-AAV for Alzheimer's disease (CERE-110). Sangamo's other therapeutic programs are focused on monogenic and rare diseases.  The company has formed a strategic collaboration with Shire International GmbH to develop therapeutics for hemophilia, Huntington's disease and other monogenic diseases, and with Biogen Idec for hemoglobinopathies, such as sickle cell disease and beta-thalassemia. It has also established strategic partnerships with companies in non-therapeutic applications of its technology, including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the Company's website at www.sangamo.com.

ZFP Therapeutic^® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo's current expectations. These forward-looking statements include, without limitation, references relating to research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo's ZFP technology platform for the treatment of HIV/AIDS, including a potential functional cure for HIV/AIDS, the ability of a ZFP Therapeutic to control HIV infection and projected timing of release of SB-728-T clinical data. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo's ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo's public filings with the Securities and Exchange Commission, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.

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