Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34 + cells

Center for Clinical AIDS Research and Education, University of California-Los Angeles, 9911 West Pico Boulevard, Suite 980, Los Angeles, California 90035, USA.
Nature medicine (Impact Factor: 27.36). 03/2009; 15(3):285-92. DOI: 10.1038/nm.1932
Source: PubMed


Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

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Available from: Janet Macpherson
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    • "Rzs targeting HIV-1 RNA were among the first gene therapy agents tested in a clinical setting,36 and the only agent tested in a phase II vector controlled trial.37 While no toxicity has been observed in this study, the moderate effect reported emphasizes the need to find more inhibitory molecules for use in gene therapy. "
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    ABSTRACT: Antisense-based molecules targeting HIV-1 RNA have the potential to be used as part of gene or drug therapy to treat HIV-1 infection. In this study, HIV-1 RNA was screened to identify more conserved and accessible target sites for ribozymes based on the hepatitis delta virus motif. Using a quantitative screen for effects on HIV-1 production, we identified a ribozyme targeting a highly conserved site in the Gag coding sequence with improved inhibitory potential compared to our previously described candidates targeting the overlapping Tat/Rev coding sequence. We also demonstrate that this target site is highly accessible to short hairpin directed RNA interference, suggesting that it may be available for the binding of antisense RNAs with different modes of action. We provide evidence that this target site is structurally conserved in diverse viral strains and that it is sufficiently different from the human transcriptome to limit off-target effects from antisense therapies. We also show that the modified hepatitis delta virus ribozyme is more sensitive to a mismatch in its target site compared to the short hairpin RNA. Overall, our results validate the potential of a new target site in HIV-1 RNA to be used for the development of antisense therapies.
    Full-text · Article · Jul 2014 · Molecular Therapy
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    • "Nevertheless, in one HIV-infected individual, allogeneic hematopoietic stem cell transplantation (ASCT) with a CCR5 delta32/delta32 donor resulted in the first definitive cure of HIV-1 infection [6]. This cure has generated enthusiasm for further investigation of potentially curative interventions for HIV-1, including allogeneic stem cell transplantation [7], [8] and autologous transplantation with genetically modified CD4+ T cells [9] or stem cells [10], [11]. Along these lines, the National Heart, Lung and Blood Institute (NHLBI) recently identified the possible role of hematopoietic stem cells in curative approaches for HIV-1 infection as an essential question that needs to be addressed [12]. "
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    ABSTRACT: The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median pre-chemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. NCT00001137.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Autologous HSCT, if successful, would restore and maintain CD4 levels after a single treatment, and this has motivated the search for a method using genetically-modified HSPC (HSPC-GT). Two landmark studies of this type have been discussed, namely those of Mitsuyasu et al [22••] and DiGiusto et al [25••] (Table 1). These studies established feasibility, but showed that new methods were needed if levels of gene modification likely to have an anti-HIV-1 effect were to be attained. "
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    ABSTRACT: Despite the success of antiretroviral therapy in suppressing HIV-1 replication and extending the life of HIV-1 infected individuals, this regimen is associated with risks for non-AIDS morbidity and mortality, requires life commitment, and has a high cost. In this context, gene therapy approaches that have the potential to cure HIV-1 infection present a clear option for eradication of the virus in the next decades. Gene therapy must overcome concerns related to its applicability to HIV-1 infection, the safety of cytotoxic conditioning required for cell-based approaches, clinical trial design, selection of gene-modified cells, and the restrictive cost of manufacturing and technology. These concerns are discussed herein in the context of the most relevant gene therapy studies conducted so far in HIV/AIDS.
    Full-text · Article · Jan 2014 · Current HIV/AIDS Reports
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