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Phase I/II Clinical Trials Using Gene-Modified Adult Hematopoietic Stem Cells for HIV: Lessons Learnt.

Mitsuyasu RT, Zack JA, Macpherson JL, Symonds GP - Stem Cells Int (2011)

Bottom Line: Gene therapy for individuals infected with HIV has the potential to provide a once-only treatment that will act to reduce viral load, preserve the immune system, and mitigate cumulative toxicities associated with highly active antiretroviral therapy (HAART).The authors have been involved in two clinical trials (phase I and phase II) using gene-modified adult hematopoietic stem cells (HSCs), and these are discussed as prototypic trials within the general field of HSC gene therapy trials for HIV.They point to the requirement for (i) the ability to transduce and infuse as many as possible gene-containing HSC and/or (ii) high engraftment and in vivo expansion of these cells, (iii) potentially increased efficacy of the anti-HIV agent(s) and (iv) automation of the cell processing procedure.

View Article: PubMed Central - PubMed

Affiliation: Center for Clinical AIDS Research and Education (CARE Center), University of California-Los Angeles, Los Angeles, CA 90035, USA.

ABSTRACT
Gene therapy for individuals infected with HIV has the potential to provide a once-only treatment that will act to reduce viral load, preserve the immune system, and mitigate cumulative toxicities associated with highly active antiretroviral therapy (HAART). The authors have been involved in two clinical trials (phase I and phase II) using gene-modified adult hematopoietic stem cells (HSCs), and these are discussed as prototypic trials within the general field of HSC gene therapy trials for HIV. Taken as a group these trials have shown (i) the safety of both the procedure and the anti-HIV agents themselves and (ii) the feasibility of the approach. They point to the requirement for (i) the ability to transduce and infuse as many as possible gene-containing HSC and/or (ii) high engraftment and in vivo expansion of these cells, (iii) potentially increased efficacy of the anti-HIV agent(s) and (iv) automation of the cell processing procedure.

No MeSH data available.


Related in: MedlinePlus

The figure shows the concept of introducing an anti-HIV gene (in this case a ribozyme) into hematopoietic stem cells. As these cells mature and differentiate into T lymphocytes and myeloid cells, the anti-HIV gene is expressed in these cells potentially providing an anti-HIV effect in cells susceptible to HIV.
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Related In: Results  -  Collection


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fig1: The figure shows the concept of introducing an anti-HIV gene (in this case a ribozyme) into hematopoietic stem cells. As these cells mature and differentiate into T lymphocytes and myeloid cells, the anti-HIV gene is expressed in these cells potentially providing an anti-HIV effect in cells susceptible to HIV.

Mentions: The gene therapy vector OZ1 (also termed RRz2 in publications) comprises a Moloney murine leukemia virus-based, replication-incompetent gamma retroviral vector (LNL6) containing a gene that encodes a ribozyme targeting the overlapping vpr and tat reading frames of HIV-1 [4, 32, 36–39]. OZ1 has been shown to inhibit the replication of laboratory and clinical isolates of HIV-1 in vitro [36–39]. Resistance mutations in the region of HIV-1 targeted by OZ1 were not observed in long-term cell culture [10, 27, 37, 39]. The concept tested in the two clinical trials conducted by the present investigators and colleagues (phase I and phase II) was that, OZ1-transduced CD34+ HSC would engraft, divide, and differentiate in vivo to produce a pool of mature myeloid and lymphoid cells protected from productive HIV-1 replication and, in the case of the phase II trial, that this protection could be measured by differences in plasma HIV-1 RNA levels in the absence of antiretroviral therapy [32]. This concept is shown pictorially in Figure 1. In both these prototypic trials, autologous CD34+ HSC were transduced and administered without the subject undergoing myeloablation or any form of bone marrow conditioning.


Phase I/II Clinical Trials Using Gene-Modified Adult Hematopoietic Stem Cells for HIV: Lessons Learnt.

Mitsuyasu RT, Zack JA, Macpherson JL, Symonds GP - Stem Cells Int (2011)

The figure shows the concept of introducing an anti-HIV gene (in this case a ribozyme) into hematopoietic stem cells. As these cells mature and differentiate into T lymphocytes and myeloid cells, the anti-HIV gene is expressed in these cells potentially providing an anti-HIV effect in cells susceptible to HIV.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3116533&req=5

fig1: The figure shows the concept of introducing an anti-HIV gene (in this case a ribozyme) into hematopoietic stem cells. As these cells mature and differentiate into T lymphocytes and myeloid cells, the anti-HIV gene is expressed in these cells potentially providing an anti-HIV effect in cells susceptible to HIV.
Mentions: The gene therapy vector OZ1 (also termed RRz2 in publications) comprises a Moloney murine leukemia virus-based, replication-incompetent gamma retroviral vector (LNL6) containing a gene that encodes a ribozyme targeting the overlapping vpr and tat reading frames of HIV-1 [4, 32, 36–39]. OZ1 has been shown to inhibit the replication of laboratory and clinical isolates of HIV-1 in vitro [36–39]. Resistance mutations in the region of HIV-1 targeted by OZ1 were not observed in long-term cell culture [10, 27, 37, 39]. The concept tested in the two clinical trials conducted by the present investigators and colleagues (phase I and phase II) was that, OZ1-transduced CD34+ HSC would engraft, divide, and differentiate in vivo to produce a pool of mature myeloid and lymphoid cells protected from productive HIV-1 replication and, in the case of the phase II trial, that this protection could be measured by differences in plasma HIV-1 RNA levels in the absence of antiretroviral therapy [32]. This concept is shown pictorially in Figure 1. In both these prototypic trials, autologous CD34+ HSC were transduced and administered without the subject undergoing myeloablation or any form of bone marrow conditioning.

Bottom Line: Gene therapy for individuals infected with HIV has the potential to provide a once-only treatment that will act to reduce viral load, preserve the immune system, and mitigate cumulative toxicities associated with highly active antiretroviral therapy (HAART).The authors have been involved in two clinical trials (phase I and phase II) using gene-modified adult hematopoietic stem cells (HSCs), and these are discussed as prototypic trials within the general field of HSC gene therapy trials for HIV.They point to the requirement for (i) the ability to transduce and infuse as many as possible gene-containing HSC and/or (ii) high engraftment and in vivo expansion of these cells, (iii) potentially increased efficacy of the anti-HIV agent(s) and (iv) automation of the cell processing procedure.

View Article: PubMed Central - PubMed

Affiliation: Center for Clinical AIDS Research and Education (CARE Center), University of California-Los Angeles, Los Angeles, CA 90035, USA.

ABSTRACT
Gene therapy for individuals infected with HIV has the potential to provide a once-only treatment that will act to reduce viral load, preserve the immune system, and mitigate cumulative toxicities associated with highly active antiretroviral therapy (HAART). The authors have been involved in two clinical trials (phase I and phase II) using gene-modified adult hematopoietic stem cells (HSCs), and these are discussed as prototypic trials within the general field of HSC gene therapy trials for HIV. Taken as a group these trials have shown (i) the safety of both the procedure and the anti-HIV agents themselves and (ii) the feasibility of the approach. They point to the requirement for (i) the ability to transduce and infuse as many as possible gene-containing HSC and/or (ii) high engraftment and in vivo expansion of these cells, (iii) potentially increased efficacy of the anti-HIV agent(s) and (iv) automation of the cell processing procedure.

No MeSH data available.


Related in: MedlinePlus