Back HIV Treatment Search for a Cure CROI 2013: Zinc Finger Gene Therapy Leads to Durable T-Cell Recovery, Sangamo Says

CROI 2013: Zinc Finger Gene Therapy Leads to Durable T-Cell Recovery, Sangamo Says


Modification of CD4 T-cells using zinc finger technology designed to render cells resistant to HIV led to durable immune reconstitution, while a different gene therapy technique may make cells less susceptible to viral infection, according to 2 studies presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week in Atlanta.

Sangamo BioSciences is evaluating a technique in which T-cells are collected from a patient's blood via apheresis, a zinc finger nuclease is used to disrupt CCR5 gene expression, and the altered cells -- known as SB-728-T -- are allowed to multiply and infused back into the body.

CCR5 is one of the 2 main gateways HIV uses to enter cells, and the hypothesis is that CD4 cells that have this receptor removed will be protected from infection by virus that uses this co-receptor. The approach was inspired in part by the Berlin Patient, who appears to be free of HIV several years after receiving stem cell transplants from a bone marrow donor with a natural CCR5-deletion mutation. Helping T-cells resist infection is one of many avenues of HIV cure research currently being explored.

At the 2011 Retrovirus conference, researchers reported that the procedure appeared safe and well-tolerated, modified SB-728-T cells engrafted and distributed themselves as expected in the body, and treated patients showed sustained T-cell gains. Further data presented at CROI 2012 and at ICAAC 2012 showed that the procedure was associated with long-term CD4 cell gains among HIV positive people with poor immunological recovery on antiretroviral therapy (ART).

Researchers have now reported that this immune reconstitution appears durable out to 3 years, while a laboratory study looking at a different gene manipulation technique suggests that modified cells were protected against HIV infection, according to conference abstracts and a press release issued by Sangamo.

Below is an edited excerpt from the recent Sangamo press release. The full version is available online.

Sangamo Presents New Clinical Data at CROI 2013 Demonstrating Persistent Immune System Improvements After Treatment With ZFN Therapeutic SB-728-T

  • Data Demonstrate that SB-728-T Possesses Necessary Immunologic Properties to Support a "Functional Cure" for HIV/AIDS

Richmond, Calif.-- March 6, 2013 -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced new data from its program to develop a "functional cure" for HIV/AIDS in two presentations at the 20th Conference on Retroviruses and Opportunistic Infections (CROI), held in Atlanta from March 3 to 6, 2013. 

The first presentation described data from the SB-728-T Phase 1 study (SB-728-902, Cohorts 1-3) demonstrating that SB-728-T treatment of HIV-infected subjects leads to durable reconstitution of the immune system driven by increases in total CD4+ central memory T-cells (TCM) and CCR5-protected TCM. TCM are long-lived, self-renewing cells that have the ability to remember and react against foreign antigens including HIV. The data also showed that certain cell surface marker and gene expression profiles may predict which patients will likely respond best to SB-728-T treatment.

"These important data extend our understanding of why SB-728-T treatment improves the immune system as well as the conditions required for optimal engraftment of ZFN-modified T-cells," said Dale Ando, MD, Sangamo's vice president of therapeutic development and chief medical officer. "They confirm that SB-728-T meets the key immunologic requirements for immune reconstitution in HIV-infected individuals. In addition, analysis of cell surface marker and gene expression profiles of immune system cells in subjects who show superior responses to treatment in terms of increased T-cell counts provides us with important indicators that will aid us in the optimization of our clinical trials."

"The ability of SB-728-T to durably reconstitute the immune system in HIV-infected subjects after a single treatment has never been observed before with any other therapeutic approach," commented Rafick-Pierre Sekaly, PhD, Co-Director and Chief Scientific Officer, the Vaccine and Gene Therapy Institute of Florida (VGTI Florida), whose laboratory carried out the analysis. "Improvement in the overall health of the immune system of HIV-infected individuals, as demonstrated by treatment with SB-728-T, is a key step along the path to developing an immunologic approach to controlling and potentially eliminating the virus. We have analyzed the cells that constitute this unprecedented elevation of total CD4+ cell counts, extending our previous observations that the increase is primarily due to durable expansion of the central memory T-cells. Importantly, the level of ZFN-dependent CCR5 gene disruption is sustained in these cells, which is critical for the durable success of this approach."

HIV destroys the immune system by killing CD4+ T cells. The current standard of care for HIV/AIDS is daily treatment with antiretroviral therapy (ART), which suppresses viral load in the blood of most subjects but does not eliminate the reservoir of HIV-infected cells. In addition, a significant proportion of treated HIV-infected individuals do not experience a restoration of CD4+ T-cell counts to normal levels.  SB-728-T treatment, by eliminating the co-receptor, CCR5, which is necessary for HIV entry to CD4+ cells, is designed to provide a CCR5-negative population of CD4+ T-cells that cannot be infected by HIV but are able to fight opportunistic infections and enable the immune system to control and eliminate the virus. Sangamo's clinical studies have demonstrated successful ZFN-dependent CCR5 gene modification of T-cell populations, including critical cell types such as the T CM.  Studies to date have demonstrated that engraftment of SB-728-T is safe, the modified cells are durable and demonstrate prolonged trafficking and dynamic immunological responsiveness in the gut mucosa, an important HIV reservoir. The data presented today demonstrate that SB-728-T treatment leads to unprecedented durable increases in total CD4+ T cells that are correlated with increases in TCM and ZFN-mediated CCR5-modified TCM

"These exciting data support our development program for SB-728-T as a potential functional cure for HIV/AIDS," stated Edward Lanphier, Sangamo's president and CEO. "We have ongoing Phase 2 clinical trials designed to build on our early studies in which we observed a significant correlation between the number of infused CD4+ T cells in which both copies of the CCR5 gene are modified, so-called biallelic modification, and reduction in viral load during a treatment interruption. We intend to present data from these trials this year."

The first of these ongoing trials (SB-728-902 Cohort 5) evaluates the approximate doubling of bi-allelic engraftment that can be achieved in individuals that have a natural mutation of one of their CCR5 gene copies, CCR5 delta-32 heterozygotes, and seeks to confirm an observation of the occurrence of aviremia during ART treatment interruption (TI). The second trial (SB-728-1101) examines the ability of a lymphopenic preconditioning regimen to enhance bi-allelic engraftment and reduce viral load during a TI in subjects in which CCR5 is not mutated. 

Sangamo expects to present preliminary data in the first half of 2013 and the full data set from both trials by the end of 2013.

Data Summary

Abstract #126 "The Central Memory T-cell is the Critical Component for Sustained CD4+ Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4+ T-cells (SB-728-T)" -- Wednesday, March 6, 2013

HIV-infected subjects were enrolled in a Phase 1 clinical trial (SB-728-902, Cohorts 1-3) and received a single dose of SB-728-T (5 to 30 billion cells). All subjects were on ART and had stably controlled undetectable levels of HIV in their blood.

The study evaluated safety and tolerability, changes in CD4+ T-cell counts and the ratio of CD4+ to CD8+ T-cells, as well as persistence of SB-728-T in the blood and trafficking of these ZFN-modified cells into gut-associated lymph tissue.

Analysis of data from subjects in the study presented today demonstrated:

  • Treatment of HIV subjects with SB-728-T leads to both acute and long term increases in total CD4+ T-cell counts.
  • Observed level of CD4+ T-cell reconstitution is significantly greater than in previously published T-cell infusion studies without CCR5 modification.
  • Long term increases in total CD4+ T-cell counts correlate with increased TCM and increased ZFN-mediated CCR5 disrupted TCM.
  • Levels of CCR5 disrupted TCM were stable or increased over time compared to other T-cell sub-populations.
  • In addition, analysis of immune cells of treated individuals provided a specific cell-surface marker profile and "gene expression signature" that characterized individuals who showed superior responses to treatment in terms of increased CD4+ T-cell counts.

In the same oral session, data were also presented from a research stage study conducted in collaboration with scientists in the laboratory of Dr. James A. Hoxie, Professor of Medicine at the University of Pennsylvania and Director of the Penn Center for AIDS Research.

Abstract #129 "T-Cells Edited to Express CCR5 or CXCR4 Fused to the C34 Peptide from gp41 Heptad Repeat-2 Exhibit Robust Protection from Diverse HIV-1 Isolates" -- Wednesday, March 6, 2013  

The data demonstrate potent inhibition of HIV infection in cells expressing a chimeric protein comprising a portion of the HIV envelope fused to either the CXCR4 or CCR5 HIV co-receptors. Scientists fused the C34 peptide from the gp41 portion of the HIV envelope to the amino terminus of either the CXCR4 (C34-X4) or CCR5 (C34-R5) proteins. Importantly, both C34-X4 and C34-R5 demonstrated potent inhibition of infection by either an X4-tropic or R5-tropic HIV-1 isolate in primary CD4+ T cells, the natural target of HIV.

Webcasts of all the presentations at CROI 2013 can be accessed via the following link:

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 research and development of novel DNA-binding proteins for 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. 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 AG 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



J Zeidan, G Lee, J Lalezari, et al. Central Memory T Cell Is the Critical Component for Sustained CD4 Reconstitution in HIV Subjects Receiving ZFN CCR5 Modified CD4 T Cells (SB-728-T). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 126.

G Leslie, J Wang, B Haggarty, et al. T Cells Edited to Express CCR5 or CXCR4 Fused to the C34 Peptide from gp41 Heptad Repeat-2 Exhibit Robust Protection from Diverse HIV-1 Isolates. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 129.

Other Source

Sangamo BioSciences. Sangamo Presents New Clinical Data at CROI 2013 Demonstrating Persistent Immune System Improvements After Treatment With ZFN Therapeutic SB-728-T. Press release. March 6, 2013.