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: 28.05). 03/2009; 15(3):285-92. DOI: 10.1038/nm.1932
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Janet Macpherson, Aug 14, 2015
1 Follower
  • Source
    • "In stem cells, the key HIV regulatory protein Rev has been targeted using dominant mutant or trans-dominant forms of Rev (Bonyhadi et al., 1997; Kang et al., 2002; Podsakoff et al., 2005; Su et al., 1997). HIV Tat and its overlapping genes have also been targeted in stem cells using hammerhead ribozymes, catalytically active RNA structures that target critical gene regions (Amado et al., 2004; Mitsuyasu et al., 2009). TAR decoys have been used to inhibit viral replication in stem cells by binding and sequestering the viral transactivator TAT (Banerjea et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although combination antiretroviral therapy can dramatically reduce the circulating viral load in those infected with HIV, replication-competent virus persists. To eliminate the need for indefinite treatment, there is growing interest in creating a functional HIV-resistant immune system through the use of gene-modified hematopoietic stem cells (HSCs). Proof of concept for this approach has been provided in the instance of an HIV-infected adult transplanted with allogeneic stem cells from a donor lacking the HIV coreceptor, CCR5. Here, we review this and other strategies for HSC-based gene therapy for HIV disease.
    Cell stem cell 02/2012; 10(2):137-47. DOI:10.1016/j.stem.2011.12.015 · 22.15 Impact Factor
  • Source
    • "Many ribozyme-based strategies for treatment of HIV-1 infection have been developed and show promising antiviral activity in vitro (Hotchkiss et al., 2004; Sarver et al., 1990; Zhou et al., 1994). Three ribozymes directed against HIV-1 tat/vrp (Amado et al., 2004; Macpherson et al., 2005; Mitsuyasu et al., 2009), HIV-1 rev/tat (Michienzi et al., 2003) and the viral U5 leader region (Wong-Staal et al., 1998) have already been tested in separate clinical trials. The gene transfer was proven to be safe in all studies, but none showed significant antiviral efficacy. "
    Recent Translational Research in HIV/AIDS, 11/2011; , ISBN: 978-953-307-719-2
  • Source
    • "Mitsuyasu and colleagues recently reported the first phase II clinical trial of an anti-HIV gene therapy. This trial involved 74 subjects enrolled in randomized, double-blind and placebo-controlled groups in a multi-centre trial (Mitsuyasu et al., 2009). A murine gamma retroviral vector was used to transduce a tat/vpr specific ribozyme into granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood CD34+ cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self-renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately eradicate HIV from patients by a single or minimal treatment. Recent progress in the development of new technologies and clinical trials sets the stage for the current generation of gene therapy approaches to combat HIV infection. In this review, we will discuss two major approaches that are currently underway in the development of stem cell-based gene therapy to target HIV: one that focuses on the protection of cells from productive infection with HIV, and the other that focuses on targeting immune cells to directly combat HIV infection.
    Virology 03/2011; 411(2):260-72. DOI:10.1016/j.virol.2010.12.039 · 3.28 Impact Factor
Show more