HIV 1101 Study Recruitment Complete

Active, not recruiting

Dose Escalation Study of Cyclophosphamide in HIV-Infected Subjects on HAART Receiving SB-728-T Condition: HIV Intervention: Genetic: SB-728-T Latest press release mentioning the 1101 study:

February 24, 2016

Sangamo BioSciences Presents Phase 2 Immunological Data from SB-728-T ZFP Therapeutic® HIV Program at CROI 2016

Subjects from SB-728-1101 Cohort 3* Remain Off Antiretroviral Therapy for Over a Year
Immunologic and Reservoir Analyses Suggest Mechanism for Viral Load Control

RICHMOND, Calif., Feb. 24, 2016 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO), the leader in therapeutic genome editing, announced the presentation of immunological data from the Company's clinical trials of SB-728-T, a ZFP Therapeutic^® designed to provide functional control of HIV. Analysis of data from Sangamo's most recent SB-728-1101 study suggests key, potentially interrelated mechanisms for viral load (VL) control in treated subjects during a treatment interruption (TI) from their antiretroviral therapy (ART). The analysis was presented by Sangamo's collaborator, Rafick-Pierre Sékaly, Ph.D., Richard Fasenmeyer Chair in Immunopathogenesis, Case Western Reserve University, at the 2016 Annual Conference on Retroviral and Opportunistic Infections (CROI 2016). The meeting is being held in Boston from February 22-26, 2016.
A significant number of subjects treated with SB-728-T have experienced a striking control of their viral load for a sustained period in the absence of ART," stated Dr. Sékaly. "This is particularly notable in cohorts treated with optimal doses of Cytoxan^® in the SB-728-1101 study. Immunological and HIV reservoir analyses suggest that the best predictors for post-treatment viral control are higher levels of SB-728-T engraftment, specifically long-lived memory T-cells, evidence of polyfunctional antiviral CD8 responses during TI and lower HIV reservoir levels prior to TI. This may provide a model mechanism of action for SB-728-T and help identify HIV-infected individuals who will benefit most from this novel immune-based therapy."
"The evidence of sustained viral load control in subjects enrolled in the 1101 study is very encouraging," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "Four of nine subjects treated at Cytoxan doses of 1.0 and 1.5 g/m² remain on extended TI, including two of three treated subjects in Cohort 3* who were included in this analysis and have viral loads under 1,000. The data suggest that by mimicking the characteristics of the 'elite controller' HIV subpopulation it may be possible to develop a functional cure for HIV/AIDS. Based on our extensive clinical studies, we believe that we have identified both an SB-728-T manufacturing method and patient characteristics that will aid us and a future partner in the development of this therapeutic through pivotal studies."
Of the nine subjects pre-conditioned with Cytoxan doses of 1.0 and 1.5 g/m² (Cohorts 3, 3* and 5) six subjects demonstrated durable control of viremia (VL < 10,000) during an extended TI (14-26 months duration), with two subjects showing consistent ongoing VL measurements less than 1,000 (17 and 20 months at the time of analysis). Using a univariate linear regression model, the analysis demonstrated that greater levels of engrafted CCR5-modified cells before TI (p=0.03) and higher frequencies of long-lived CD4 memory T-cells (TSCM) during TI (p=0.01) correlated with lower VLs. The data suggest that an HIV resistant, long-lived CD4 TSCM compartment is likely to be critical in establishing VL control possibly by restoring immune homeostasis and providing help to HIV-specific CD8 T-cells. Multivariate analyses were used to determine parameters that further predict VL control during TI. Results indicate that higher CD4 TSCM levels, as well as a more robust polyfunctional anti-HIV gag CD8 response during TI (p=0.04) were associated with reduced VL. Furthermore, the analysis demonstrated that HIV reservoir size prior to TI showed a significant interaction with CD8 response in this model (p=0.03). These data suggest that a smaller HIV reservoir at the beginning of the TI coupled with a strong CD8 response resulted in better VL control.
In late 2015, Sangamo enrolled five additional subjects in Cohort 3* and expects to present that data at the end of 2016. Pending the data readout for SB-728-1101 Cohort 3*, the Company intends to partner the HIV program for pivotal studies and 

Fred Hutch article on HIV - Stem cell program

http://www.fredhutch.org/en/news/spotlight/imports/gene-therapy-and-genome-editing-strategies-for-hiv-resistance.html

Gene therapy and genome editing strategies for HIV resistance

April 18, 2016

– J Herman

With modern advances in combinatorial antiretroviral therapy (ART), HIV infection has become a manageable latent infection for many patients. This has largely extended patient lifetimes; however, in rare cases ART is not effective. Additionally, despite response to ART ongoing co-morbidities compromise lifespan. Thus researchers are working towards functional cures, where even in the absence of ART no HIV particles are produced in patient blood. Such a cure was reported after hematopoietic cell transplantation for AML. Thus members of the Kiem lab in the Clinical Research Division are working towards an autologous (from the subjects own marrow) transplant using genetically engineered, HIV resistant stem cells. With the rich history of marrow and stem cell transplant, Fred Hutch doctors and researchers are particularly well suited to pursue this approach.  Drs. Chris Peterson (research scientist), Kevin Haworth (postdoctoral fellow), and colleagues in the Kiem lab genetically modify stem cells to resist HIV infection. Two unique methods were used to achieve this gene editing, and were recently published in the journals Molecular Therapy – Methods & Clinical Development and Blood.
The first approach used to modify hematopoietic stem cells was actually to hijack HIV itself. When HIV infects human cells it inserts its own genes into human chromosomes, understanding this mechanism allowed scientists to exploit it for therapeutic uses. With standard molecular biology techniques, researchers replace the HIV genes with therapeutically relevant genes, then these engineered viral particles insert into human chromosomes. Cal-1, the therapeutic agent in this study, produces a small peptide after it has been inserted into the human cells and prevents HIV from fusing with the host cell, thus stopping infection. The first step in establishing this new therapy was to show that the transplanted cells persisted, and were safe.
Drs. Peterson and Haworth modified hematopoietic stem cells with Cal-1 and then determined how long the cells persisted in a clinically relevant animal model. Dr. Peterson outlined the approach for these experiments, "We evaluate all of our gene therapy methods in two ways. First, we perform transplants in an uninfected setting. This allows us to focus on the safety of the gene therapy intervention on its own, and optimize the protocol for engineering and engrafting the cells. Once that is established, we can then apply the identical therapy in infected subjects." For these initial studies, the gene therapy-modified cells were followed for up to six months after transplantation. No adverse events were observed during this period, and the Cal-1 modification was maintained in blood cells after this long time point. Excitingly, this gene modification was present not just in stem cells, but in many differentiated cell types. This differentiation is essential for Cal-1 to provide HIV protection, because HIV targets differentiated cells, such as T cells. Another safety concern when using this hijacked HIV mechanism is that the engineered virus inserts semi-randomly into human chromosomes; this could negatively affect the patient if it compromises normal growth and differentiation. If this were the case, a less diverse set of insertion sites would be observed over time. In this study researchers observed a high diversity of insertion sites were maintained immediately following transplant up to six months later. The modified stem cells demonstrate resistance to HIV infection as well. Following infection with a virus closely related to HIV, Cal-1 cells outcompeted non-modified cells and increased their representation in bone marrow.
There are many approaches to modify the human genome. For their other study, researchers in the Kiem lab employed zinc finger nucleases (ZFNs) to target HIV receptors with a gene editing strategy. ZFNs are engineered to target a very specific site of DNA and induce a double stranded break. If the error prone non-homologous end joining pathway rejoins these strands, it often causes a premature truncation of the gene product, resulting in a nonfunctional protein. Previous work found that loss of the cell surface protein CCR5 decreases HIV infectivity because CCR5 is one of the biomolecules HIV binds to enter cells. Thus ZFNs targeting CCR5 were used to delete this protein in hematopoietic stem cells. The safety of this gene editing approach was evaluated similarly to Cal-1 modified cells. CCR5 deletion could be detected more than six months after transplant in multiple progenitor cell types. The CCR5 targeting also resulted in a large diversity of deletion sequences, which were maintained over time, again suggesting no modifications were adversely affecting stem cell health. These early studies truly are cutting edge, as Dr. Hans-Peter Kiem commented, "This was the first time that nuclease-mediated genome-edited stem cells have been shown to engraft and provide multilineage constitution of the blood and immune system. These finding have important implications for other nuclease-mediated gene editing approaches e.g. using CRISPR/Cas technology and other genetic disease like sickle cell disease or thalassemia."
These studies demonstrate the exciting future of gene therapy and gene editing to improve human health. They also emphasize how therapeutic approaches may overlap between unique diseases, and the value of expanding our focus at Fred Hutch beyond cancer.

Peterson CW,Haworth KG,Burke BP,Polacino P,Norman KK,Adair JE,Hu SL,Bartlett JS,Symonds GP,Kiem HP. (2016). Multilineage polyclonal engraftment of Cal-1 gene-modified cells and in vivo selection after SHIV infection in a nonhuman primate model of AIDS. Mol Ther Methods Clin Dev, 3, 16007.

Chinese Researchers Attempt to Edit CCR5 Out of Embryos

https://www.technologyreview.com/s/601235/chinese-researchers-experiment-with-making-hiv-proof-embryos/

Chinese fertility doctors have tried to make HIV-proof human embryos, but the experiments ended in a bust. The new report is the second time researchers in China revealed that they had a go at making genetically modified human embryos.
The controversial experiments are, in effect, feasibility studies of whether it’s possible to make super-people engineered to avoid genetic disorders or resist disease.
“It is foreseeable that a genetically modified human could be generated,” according to Yong Fan, a researcher at Guangzhou Medical University, who published the report

....

The Chinese scientists tried to make human embryos resistant to HIV by editing a gene called CCR5. It’s known that some people possess versions of this gene which makes them immune to the virus, which causes AIDS. The reason is they no longer make a protein that HIV needs to enter and hijack immune cells.
Doctors in Berlin demonstrated the effect after they gave a man sick from HIV a bone marrow transplant from a person with the protective gene mutation. The man—known since as the “Berlin patient”—was cured of HIV, too.
Using the gene-editing method called CRISPR, Fan and his team tried to change the DNA in the embryos over to the protective version of the CCR5 gene in order to show, in principle, that they could make HIV-proof people.

Blood Journal | The clinical applications of genome editing in HIV

1. Cathy X. Wang and
2. Paula M. Cannon

Abstract

HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. While conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semi-randomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now allowing more precise genetic manipulations. The possible outcomes of genome editing include gene disruption, which has been most notably applied to the CCR5 co-receptor gene, or the introduction of small mutations or larger whole gene cassette insertions at a targeted locus. Disruption of CCR5 using zinc-finger nucleases was the first-in-man application of genome editing and remains the most clinically advanced platform, with 7 completed or ongoing clinical trials in T cells and hematopoietic stem/progenitor cells (HSPCs). Here we review laboratory and clinical findings of CCR5 editing in T cells and HSPCs for HIV therapy, and summarize other promising genome editing approaches for future clinical development. In particular, recent advances in the delivery of genome editing reagents, and the demonstration of highly efficient homology-directed editing in both T cells and HSPCs, are expected to spur the development of even more sophisticated applications of this technology for HIV therapy.