Data Demonstrate ZFN-dependent CCR5 Modification of Long-lived Central Memory and Stem-like T-cells
RICHMOND, CA, USA I November 4, 2013 I Sangamo BioSciences, Inc. (SGMO) announced today the presentation of clinical data from its program to develop a ZFP Therapeutic® for HIV/AIDS. The data demonstrate a reduction in the HIV DNA reservoir since receiving SB-728-T in seven of nine HIV-infected subjects on long-term anti-retroviral therapy (ART), despite a median duration of HIV infection of 21 years and baseline CD4 T-cell counts prior to SB-728-T treatment of The Lancet and Cell publications and entitled, “What Will it Take to Achieve an AIDS-Free World?” which is being held in San Francisco, November 3-5, 2013.
“These data are very promising and demonstrate the important link between SB-728-T treatment and immune reconstitution of central memory and total CD4 T cells and lower HIV DNA levels in subjects at 12 months,” said Rafick-Pierre Sekaly, Ph.D., Co-Director & Chief Scientific Officer, The Vaccine & Gene Therapy Institute of Florida (VGTI Florida), who presented the data and whose laboratory carried out the immunologic analyses.
ART successfully suppresses viral load in most subjects, but a significant proportion, so called immunologic non-responders (INR), do not restore normal CD4 counts above 500 cells/µl. HIV-infected subjects who were classified as INR, enrolled in Sangamo’s ongoing SB-728-902 clinical trial (Cohorts 1-3), received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells associated with increases in ZFN-modified CD4 central memory T-cells, specifically memory and stem cell-like cells (TSCM) which provide a long-lasting source of CCR5-modified CD4 T-cells. Notably, despite the increase in total CD4 T-cells, a long-term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir was observed, as measured by proviral DNA using a sensitive assay technique.
“Our goal is to develop an immunologic approach to HIV that should enable the patient’s immune system to attack HIV infection at the level of both the HIV DNA viral reservoir and circulating viral load, and our data suggest that we are seeing these effects in SB-728-T treated subjects,” stated Geoff Nichol, M.B., Ch.B., Sangamo’s executive vice president of research and development. “In previous clinical studies, a decline in the HIV reservoir in subjects on long-term ART has not been observed. In addition, any increase in the levels of CD4 cells in HIV-infected subjects is often associated with a concomitant increase in the size of the reservoir. In contrast, a single SB-728-T treatment of subjects on long-term ART produced a significant and durable improvement in CD4 count and, in the majority of subjects, a notable decrease in the HIV reservoir over time. In addition to data on reduction of the viral reservoir, we recently presented data at the Annual Meeting of the European Society of Gene and Cell Therapy (ESGCT) that demonstrated sustained ongoing control of viral load at or below the level of detection of HIV through 14 weeks in an SB-728-T- treated HIV-infected subject who was not on ART.”
Dr. Nichol continued, “Immunologic analyses suggest that SB-728-T treatment protects long-term central memory CD4 T-cells from HIV-infection. We have also identified key immunologic markers of inflammation that correlate with the degree of engraftment and can potentially aid in the selection of subjects for which SB-728-T may be most effective. In our ongoing studies, we will continue to investigate these parameters including the threshold engraftment levels of biallelically modified T-cells and the types of HIV-reactive cells necessary to mount an immune response to the virus. We look forward to presenting the results of our SB-728-902 Cohort 5 and SB-728-1101 studies in December 2013, at the Sixth International Workshop on HIV Persistence, Reservoirs and Eradication Strategies.”
Summary of Clinical Data Presented at the Lancet Meeting
SB-728-0902 Cohorts 1-3 (INR)
Subjects in this trial, so-called INR, have lower than expected total CD4 counts (
We observed that:
- Treatment of HIV subjects with a single infusion of SB-728-T leads to long-term increases in CD4 counts (up to 3 years in some subjects)
- Long-term increases in CD4 counts correlate with increased CD4 central memory, memory stem cells (TSCM)-like and increased ZFN CCR5 protected central memory T-cells
- Seven of nine subjects show decreased levels of HIV DNA at Month 12 post infusion
- An inflammatory environment pre-infusion appears to be an important predictor of CD4 reconstitution post-infusion
- Higher levels of inflammation correlate with poor immunological response and suggest a mechanism for altered survival of CM cells
Summary of Clinical Trial Design
About SB-728-902 Cohorts 1-3
The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of single infusions of an escalating dose of an autologous (a patient’s own) CD4+ T-cell product genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial enrolled nine HIV-infected subjects (three cohorts of three subjects each) who have sub-optimal T-cell levels and no detectable viral load on long-term ART. Subjects remained on their existing antiviral therapy while receiving treatment with SB-728-T.
About Sangamo
Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. As part of its acquisition of Ceregene Inc., Sangamo acquired a fully-enrolled and funded, double-blind, placebo-controlled Phase 2 trial to evaluate NGF-AAV (CERE-110) in Alzheimer’s disease. Sangamo’s other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington’s disease and hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire to develop therapeutics for hemophilia, Huntington’s disease and other monogenic diseases and has 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.
SOURCE: Sangamo Biosciences
Post Views: 171
Data Demonstrate ZFN-dependent CCR5 Modification of Long-lived Central Memory and Stem-like T-cells
RICHMOND, CA, USA I November 4, 2013 I Sangamo BioSciences, Inc. (SGMO) announced today the presentation of clinical data from its program to develop a ZFP Therapeutic® for HIV/AIDS. The data demonstrate a reduction in the HIV DNA reservoir since receiving SB-728-T in seven of nine HIV-infected subjects on long-term anti-retroviral therapy (ART), despite a median duration of HIV infection of 21 years and baseline CD4 T-cell counts prior to SB-728-T treatment of The Lancet and Cell publications and entitled, “What Will it Take to Achieve an AIDS-Free World?” which is being held in San Francisco, November 3-5, 2013.
“These data are very promising and demonstrate the important link between SB-728-T treatment and immune reconstitution of central memory and total CD4 T cells and lower HIV DNA levels in subjects at 12 months,” said Rafick-Pierre Sekaly, Ph.D., Co-Director & Chief Scientific Officer, The Vaccine & Gene Therapy Institute of Florida (VGTI Florida), who presented the data and whose laboratory carried out the immunologic analyses.
ART successfully suppresses viral load in most subjects, but a significant proportion, so called immunologic non-responders (INR), do not restore normal CD4 counts above 500 cells/µl. HIV-infected subjects who were classified as INR, enrolled in Sangamo’s ongoing SB-728-902 clinical trial (Cohorts 1-3), received a single infusion of SB-728-T which resulted in a durable increase in total CD4 T-cells associated with increases in ZFN-modified CD4 central memory T-cells, specifically memory and stem cell-like cells (TSCM) which provide a long-lasting source of CCR5-modified CD4 T-cells. Notably, despite the increase in total CD4 T-cells, a long-term decrease in the peripheral blood mononuclear cell (PBMC) HIV reservoir was observed, as measured by proviral DNA using a sensitive assay technique.
“Our goal is to develop an immunologic approach to HIV that should enable the patient’s immune system to attack HIV infection at the level of both the HIV DNA viral reservoir and circulating viral load, and our data suggest that we are seeing these effects in SB-728-T treated subjects,” stated Geoff Nichol, M.B., Ch.B., Sangamo’s executive vice president of research and development. “In previous clinical studies, a decline in the HIV reservoir in subjects on long-term ART has not been observed. In addition, any increase in the levels of CD4 cells in HIV-infected subjects is often associated with a concomitant increase in the size of the reservoir. In contrast, a single SB-728-T treatment of subjects on long-term ART produced a significant and durable improvement in CD4 count and, in the majority of subjects, a notable decrease in the HIV reservoir over time. In addition to data on reduction of the viral reservoir, we recently presented data at the Annual Meeting of the European Society of Gene and Cell Therapy (ESGCT) that demonstrated sustained ongoing control of viral load at or below the level of detection of HIV through 14 weeks in an SB-728-T- treated HIV-infected subject who was not on ART.”
Dr. Nichol continued, “Immunologic analyses suggest that SB-728-T treatment protects long-term central memory CD4 T-cells from HIV-infection. We have also identified key immunologic markers of inflammation that correlate with the degree of engraftment and can potentially aid in the selection of subjects for which SB-728-T may be most effective. In our ongoing studies, we will continue to investigate these parameters including the threshold engraftment levels of biallelically modified T-cells and the types of HIV-reactive cells necessary to mount an immune response to the virus. We look forward to presenting the results of our SB-728-902 Cohort 5 and SB-728-1101 studies in December 2013, at the Sixth International Workshop on HIV Persistence, Reservoirs and Eradication Strategies.”
Summary of Clinical Data Presented at the Lancet Meeting
SB-728-0902 Cohorts 1-3 (INR)
Subjects in this trial, so-called INR, have lower than expected total CD4 counts (
We observed that:
- Treatment of HIV subjects with a single infusion of SB-728-T leads to long-term increases in CD4 counts (up to 3 years in some subjects)
- Long-term increases in CD4 counts correlate with increased CD4 central memory, memory stem cells (TSCM)-like and increased ZFN CCR5 protected central memory T-cells
- Seven of nine subjects show decreased levels of HIV DNA at Month 12 post infusion
- An inflammatory environment pre-infusion appears to be an important predictor of CD4 reconstitution post-infusion
- Higher levels of inflammation correlate with poor immunological response and suggest a mechanism for altered survival of CM cells
Summary of Clinical Trial Design
About SB-728-902 Cohorts 1-3
The study is an open-label Phase 1 clinical trial to evaluate the safety and tolerability of single infusions of an escalating dose of an autologous (a patient’s own) CD4+ T-cell product genetically modified at the CCR5 gene by CCR5-specific ZFNs (SB-728-T). The trial enrolled nine HIV-infected subjects (three cohorts of three subjects each) who have sub-optimal T-cell levels and no detectable viral load on long-term ART. Subjects remained on their existing antiviral therapy while receiving treatment with SB-728-T.
About Sangamo
Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and genome editing. The Company has ongoing Phase 2 and Phase1/2 clinical trials to evaluate the safety and efficacy of a novel ZFP Therapeutic® for the treatment of HIV/AIDS. As part of its acquisition of Ceregene Inc., Sangamo acquired a fully-enrolled and funded, double-blind, placebo-controlled Phase 2 trial to evaluate NGF-AAV (CERE-110) in Alzheimer’s disease. Sangamo’s other therapeutic programs are focused on monogenic diseases, including hemophilia, Huntington’s disease and hemoglobinopathies such as beta-thalassemia and sickle cell anemia. Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). Engineering of ZFPs that recognize a specific DNA sequence enables the creation of sequence-specific ZFP Nucleases (ZFNs) for gene modification and ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function. Sangamo has entered into a strategic collaboration with Shire to develop therapeutics for hemophilia, Huntington’s disease and other monogenic diseases and has 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.
SOURCE: Sangamo Biosciences
Post Views: 171
