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Zinc Fingers 'Cure' Therapy
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Here is link to the oral presentations including the one on zinc fingers by Pablo Tebas:
http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20481&&dp=player.jsp&e=16643&mediaType=podiumVideo
CROI ABSTRACT
Induction of Acquired CCR5 Deficiency with Zinc Finger Nuclease-modified Autologous CD4 T Cells (SB-728-T) Correlates with Increases in CD4 Count and Effects on Viral Load in HIV-infected Subjects
CROI March 5-8 2012 Seattle, WA
C June1, Pablo Tebas*1, D Stein2, R Mitsuyasu3, J Lalezari4, S Wang5, G Lee5, B Levine1, W Tang5, and D Ando5
1Univ of Pennsylvania, Philadelphia, US; 2Albert Einstein Coll of Med, Bronx, NY, US; 3Univ of California, Los Angeles, US; 4Quest Clin Res, San Francisco, CA, US; and 5Sangamo BioSci, Richmond, CA, US
Background: CCR5 is an important co-receptor for HIV entry and zinc finger nuclease (ZFN)-mediated modification of this receptor in CD4 T cells may render a survival advantage in HIV infection. We have previously reported preliminary data from 2 Phase 1 studies of SB-728-T. Here, we report additional data relating to safety, increases in CD4, persistence and trafficking of SB-728-T, and effect on HIV.
Methods: In the Penn study, 6 immunologic responders (IR) with CD4 ³450 cells/μL and 6 immunologic non-responders (INR) with CD4 ≤500 cells/μL were infused with 1010 cells. At week 4, IR underwent a 12-week HAART treatment interruption (TI). In the CA study, 9 INR (CD4 200 to 500 cells/μL) were enrolled into 3 cohorts that received 1x, 2x or 3x1010 cells. The median duration of follow up for both studies was 232 days (range 56 to 561).
Results: The mean CD4 and SB-728-T count increased by 1533/μL (range 216 to 3025) and 83/μL, respectively, on D7 in IR and by 820/μL (range 133 to 4467) and 19/μL, respectively, in INR from the 2 studies. Increases in CD4 over time correlated with SB-728-T engraftment (Γ = 0.78, p <0.0001). SB-728-T was detected in the gut mucosa of all 18 subjects biopsied (median 6%). During TI, HIV-RNA dropped ~0.8 to 2.1 log from their peak levels in 3 subjects. In one CCR5 Δ32 heterozygous subject with a viral set point of 165K copies/mL, viral load peaked at 6247 during week 6 of TI and was undetectable by week 12. In the CA study, peripheral blood mononuclear cell HIV proviral DNA was evaluated using a new Digital Droplet qPCR method. Samples with previously undetectable levels using traditional qPCR now showed measurable proviral DNA. Three of 6 subjects with >11 months follow up had an ~1-log decrease over time. CD4 T cell interferon gamma (IFN-γ) ELISpots to HIV gag peptides performed at baseline showed stratification into a high and low (360 vs 130 SFC/106) ELISpot group. One subject with high baseline IFN-γ ELISpot developed a high antibody response to env and gag in response to viremia along with >1-log drop from peak in HIV RNA during TI. SB-728-T infusions were well tolerated with only mild reversible infusion-related adverse events.
Conclusions: SB-728-T infusion increases CD4 counts that persist over time. SB-728-T expands rapidly and home to the gut. Preliminary data suggest that SB-728-T may decrease proviral DNA. In one subject with the highest level of CCR5 modification, viral load was controlled (< limit of detection) without HAART. These data suggest that in addition to the previously documented increases in CD4 cell, SB-728-T may also suppress HIV replication.
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March 8, 2012 announcement from Sangamo company
Sangamo Presents New Clinical Data at CROI 2012 Demonstrating Persistent Positive Effects of ZFN Therapeutic® for "Functional Cure" of HIV/AIDS
Data Highlight Positive Effects of SB-728-T on Immune System and Viral Load Reduction and Further Validate Strategy of Ongoing Phase 2 Trials
RICHMOND, Calif., March 8, 2012 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that new data from its program to develop a 'functional cure' for HIV/AIDS were described in two presentations at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), held in Seattle from March 5 to March 8, 2012.
"These data differentiate SB-728-T from other novel therapies as a feasible approach to controlling HIV/AIDS," said Ronald Mitsuyasu, M.D., Professor of Medicine, David Geffen School of Medicine at UCLA and a principal investigator in Sangamo's SB-728-T studies. "The results suggest that SB-728-T has a positive effect on immune health of HIV-infected patients and this effect is persistent for over a year in some subjects. Most importantly, SB-728-T treatment provides HIV-resistant T-cells that are capable of mounting an immune response to an inflammatory event in lymphoid tissues and has yielded encouraging effects on HIV viral load when antiretroviral drugs are withdrawn during a treatment interruption."
"These data add to our understanding of the positive viral load changes in SB-728-T-treated subjects, and suggest that an early cytokine burst may initiate the dramatic and prolonged increase in CD4 counts observed following SB-728-T treatment," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "They also confirm that SB-728-T meets key requirements for our strategy for a 'functional cure' for HIV, by demonstrating durable engraftment and prolonged trafficking and dynamic immunological responsiveness in the gut mucosa. Together, these data further validate our strategy for the continued development of this ZFP Therapeutic as a 'functional cure' for HIV in two ongoing Phase 2 clinical trials designed to extend the observation of a statistically significant correlation between levels of bi-allelic modification of CD4 T cells and viral load reductions during treatment interruptions in HIV infection. The first study builds on the approximate doubling of bi-allelic engraftment that can be achieved in CCR5 delta-32 heterozygotes and seeks to confirm the occurrence of aviremia during treatment interruption as observed in one such patient in our Phase 1 program. The other clinical trial will examine the ability of a lymphopenic preconditioning regimen to enhance bi-allelic engraftment, and reduce viral load during treatment interruption, in non-CCR5-mutated HIV subjects."
Clinical Trial Data Summary
Abstract # 155 "Induction of Acquired CCR5 Deficiency with Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) Correlates with Increases in CD4 Count and Effects on Viral Load (VL) in HIV-infected Subjects" -Thursday, March 8, 2012
21 HIV-infected subjects were enrolled in Phase 1 clinical studies at the University of Pennsylvania and in California (SB-728-902) and received a single dose of SB-728-T (5 to 30 billion cells). All subjects were taking highly active antiretroviral therapy (HAART) and had stably controlled undetectable levels of HIV in their blood. Subjects were classified into two groups based on their CD4+ T-cell counts: one group of 15 subjects, with CD4+ T-cell counts below 500 cells/ ul designated Immune Non-Responders (INR), and a second group of six subjects with CD4+ T-cell counts of greater than 450 cells/ ul designated Immune Responders (IR). One month after SB-728-T treatment, six subjects in the INR group enrolled in the University of Pennsylvania study underwent a 12-week treatment interruption (TI) of their HAART.
The studies 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. In addition, viral DNA and changes in viral load (VL), as measured by HIV-RNA, were measured during the TI in the six INR subjects.
These studies demonstrated:
· During the TI, the viral load, as measured by HIV-RNA levels, initially increased as expected in all six subjects. Subsequently, a 0.8 to > 2.0-log reduction in VL from peak achieved during the TI was observed in 3 of 6 subjects with the highest estimated circulating levels of cells with biallelic modification of their CCR5 gene. In one subject (Subject 205) VL decreased to undetectable levels such that the subject was aviremic at the end of the TI period. This subject entered the study carrying the natural CCR5 delta-32 mutation on one copy of his CCR5 gene resulting in an estimated percentage of biallelically-disrupted CCR5 genes that was twice that of subjects entering the study with wild-type CCR5 genes.
· Control of HIV-RNA (suppression of VL) correlates significantly (p < 0.05) with calculated levels of circulating CD4+ T-cells that have undergone biallelic modification (i.e. modification of both copies) of the CCR5 gene.
· The level of circulating viral DNA, a measure of the viral reservoir, exhibited a limited increase in five of six subjects over this period and was elevated in only one subject whose SB-728-T engraftment was the lowest of the group.
· Confirmation and extension of previous observations of unprecedented improvements in overall CD4+ T-cell counts and CD4+ to CD8+ T-cell ratios, a measure of immune health, for over a year post administration of SB-728-T.
· Elevated levels of certain T-cell cytokines (IL-2, IL-7 and IL-15) in the blood in the first few days post SB-728-T infusion which may have a role in the dramatic post-infusion expansion of CD4+T-cells. The magnitude of this increase was marked in Subject 205, who had an undetectable VL at the end of the TI.
· Durable engraftment and persistence of ZFN-CCR5-modified cells (SB-728-T) in the peripheral blood for over a year (range: 90-738 days).
· Ability of SB-728-T to traffic to the gut mucosa, an important reservoir of active HIV infection.
· SB-728-T treatment continues to be safe and well tolerated with only mild, reversible symptoms typical of infusion reactions.
Abstract #433 "A Single Infusion of Zinc Finger Nuclease CCR5 Modified Autologous CD4 T Cells (SB-728-T) Increases CD4 Counts and Leads to Decrease in HIV Proviral Load in an Aviremic HIV-infected Subject" Wednesday, March 7, 2012
In one INR subject (01-104) who received a single dose of SB-728-T (10 billion cells) an inflammatory event unrelated to SB-728-T infusion was observed in the gut mucosa by histology and surface marker staining of mucosal inflammatory cells from 3 to 6 months after infusion. Subsequently, a greater than 1 log increase in SB-728-T was observed locally in the gut, preceding resolution of the inflammation.
This study demonstrated:
· That SB-728-T is functionally active and capable of participating in an immunologic response and has the potential to maintain or restore health in the gastrointestinal tract.
· An associated increase in total CD4+ T-cells and percent of ZFN-CCR5-modified CD4+ T-cells in the gut mucosa in response to the inflammation event.
· Analysis of individual T-cell clones confirmed that this significant increase in SB-728 was specific to the gut mucosa and indicative of a precise response by these cells to local gut inflammation.
· HIV-DNA levels in both the gut mucosa and the periphery decreased from peak levels by about 1 log, coinciding with the timeline of significant increases in SB-728-T at the site of inflammation suggesting a possible SB-728-T antiviral effect.
"The data presented at CROI further support our fundamental rationale for SB-728-T and, importantly, the design of our ongoing Phase 2 clinical trials which will enable us to quickly maximize the impact of SB-728-T on viral load and the overall immune system of HIV-infected individuals," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "Our ZFP technology provides a novel platform for the creation of transformational ZFP Therapeutics and we are focused on using it to develop curative therapies for HIV and multiple monogenic and rare diseases."
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. It has ongoing Phase 2 and Phase 1/2 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, hemoglobinopathies such as sickle cell anemia and beta-thalassemia, and a program in Parkinson's disease. 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 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
ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.
SOURCE Sangamo BioSciences, Inc.
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