Anti-Human Immunodeficiency Virus Hematopoietic Progenitor Cell-Delivered Ribozyme in a Phase I Study: Myeloid and Lymphoid Reconstitution in Human Immunodeficiency Virus Type-1–Infected Patients

Amado, Rafael G.; Mitsuyasu, Ronald T.; Rosenblatt, Joseph D.; Ngok, Frances K.; Bakker, Andreas; Cole, Steve W.; Chorn, Nathalie; Lin, Lii Shin; Bristol, Gregory; Boyd, Maureen P.; Macpherson, Janet L.; Fanning, Gregory; Todd, Alison V.; Ely, Julie A.; Zack, Jerome A.; Symonds, Geoff

doi:10.1089/104303404322886101

Cited by 127 publications

(104 citation statements)

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“…This result is unexpected under the assumption that the OZ1-transduced HSCs successfully engrafted, differentiated and expanded into the T-cell lineage, and maintained some level of anti-HIV protection over untreated CD4+ T cells. Similar Phase I trials-including reports from the same authors 4 -have confirmed successful engraftment, differentiation and expansion of autologous HSCs transduced with anti-HIV retroviral vectors. 2 Therefore, although the HSCs may have failed to engraft under the conditions of the trial, it is also possible that the anti-HIV ribozyme failed to protect the OZ1 cells from HIV-1 infection and replication.…”

mentioning

confidence: 59%

Stem cells, ribozymes and HIV

Burnett

Rossi

2009

Gene Ther

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mentioning

confidence: 59%

Stem cells, ribozymes and HIV

Burnett

Rossi

2009

Gene Ther

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“…If these manipulated cells were intended to be used to therapeutically target the T lineage, our results suggest that they need only be differentiated as far as hematopoietic progenitor cells in vitro and that the thymus would then complete the differentiation program to CD4 ϩ and CD8 ϩ T cells in vivo. This type of approach might lead to improved therapeutic strategies to treat genetic hematopoietic disorders, such as X-linked SCID (19) or infectious diseases such as acquired immunodeficiency syndrome (20).…”

Section: Discussionmentioning

confidence: 99%

T lineage differentiation from human embryonic stem cells

Galić

Kitchen

Kacena³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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133

109

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Harnessing the ability of genetically manipulated human embryonic stem cells (hESC) to differentiate into appropriate lineages could revolutionize medical practice. These cells have the theoretical potential to develop into all mature cell types; however, the actual ability to develop into all hematopoietic lineages has not been demonstrated. Using sequential in vitro coculture on murine bone marrow stromal cells, and engraftment into human thymic tissues in immunodeficient mice, we demonstrate that hESC can differentiate through the T lymphoid lineage. Stable transgene expression was maintained at high levels throughout differentiation, suggesting that genetically manipulated hESC hold potential to treat several T cell disorders.SCID-hu mouse ͉ T cell development ͉ gene therapy ͉ immune reconstitution ͉ hematopoiesis H uman embryonic stem cells (hESC) show promise to revolutionize treatment strategies for many diseases because of their potential to differentiate into all tissues and cell types in the body. However, signals required for proper directed differentiation of these cells are not well defined. Regarding hematopoietic differentiation, these cells have been directed toward myeloid and erythroid lineages by exposure to murine bone marrow stromal cells (1) or by induced formation of embryoid bodies in the presence of various cytokines (2), both conditions resulting in differentiation into CD34 ϩ hematopoietic progenitor cells capable of forming hematopoietic colonies in vitro. Similarly, B lineage differentiation has been achieved by sequential exposure of hESC to two different murine bone marrow stromal cell lines, OP9 and MS-5 (3). Recently, functional dendritic cells (4), natural killer cells (5), and macrophages (6) were derived from hESC. Although T cells were successfully derived from murine embryonic stem (ES) cells (7), the differentiation toward the T lymphoid lineage from hESC has not been reported. Herein we use a combination of in vitro exposure to the OP9 stromal cell line, followed by implantation of the newly differentiated precursors into human thymic tissues growing in immunodeficient mice, to induce T lymphoid differentiation of these cells in vivo. Costimulation of the resulting T lineage cells by CD3 and CD28 resulted in expression of activation markers, indicating that these cells are functional. Furthermore, a lentiviral vector expressing EGFP under the control of the elongation factor 1␣ (EF1␣) promoter, introduced at the hESC stage, continued to express the reporter gene at high frequency throughout thymopoiesis. Our results suggest that genetically manipulated hESC may hold promise for treatment of disorders of the T cell lineage. ResultsTo obtain genetically marked ES cells, the hESC line H1 (8, 9) was transduced with the pSIN18.cPPT.hEF1␣.EGFP.WPRE lentiviral vector, which allows constitutive expression of the EGFP reporter gene under the control of the EF1␣ promoter in hESC (9). To obtain colonies expressing EGFP at high frequency, Ϸ20 passages of manually isolating GFP ϩ cells...

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“…But in contrast to references 75 and 76, no selective advantage of the HIV-resistant CD4 + cells was observed. However, a companion study testing this vector in CD34 + cells did observe a selective survival advantage for CD4 + cells derived from CD34 + cells 78 .…”

Section: Early Genetic Antivirals In T Cellsmentioning

confidence: 99%

“…The results of clinical trials for HIV-1 using HS cells have been modest 14,78,119,120 . The numbers of peripheral blood cells containing the introduced gene have been low or undetectable in most subjects after the first few months, indicating low engraftment of genemodified HS cells.…”

Section: Hs Cell Therapiesmentioning

confidence: 99%

Genetic therapies against HIV

2007

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Highly active antiretroviral therapy prolongs the life of HIV-infected individuals, but it requires lifelong treatment and results in cumulative toxicities and viral-escape mutants. Gene therapy offers the promise of preventing progressive HIV infection by sustained interference with viral replication in the absence of chronic chemotherapy. Gene-targeting strategies are being developed with RNA-based agents, such as ribozymes, antisense, RNA aptamers and small interfering RNA, and protein-based agents, such as the mutant HIV Rev protein M10, fusion inhibitors and zincfinger nucleases. Recent advances in T-cell-based strategies include gene-modified HIV-resistant T cells, lentiviral gene delivery, CD8 + T cells, T bodies and engineered T-cell receptors. HIVresistant hematopoietic stem cells have the potential to protect all cell types susceptible to HIV infection. The emergence of viral resistance can be addressed by therapies that use combinations of genetic agents and that inhibit both viral and host targets. Many of these strategies are being tested in ongoing and planned clinical trials.Controlling HIV infection continues to be a major challenge in both underdeveloped and developed nations. Although the drug cocktails used in highly active antiretroviral therapy (HAART) have markedly changed the profile of progression to AIDS in HIV-infected individuals, they are not without significant problems and drawbacks. Pharmacokinetic differences between individuals result in many drug-related toxicities, leading to problems of nonadherence, although the increase in side effects is due in part to the improved lifespan brought by the very success of antiretroviral therapies. There is a need for personalized dosing regimens and combinations and for continued therapeutic monitoring of the drugs themselves. Drug failures for those on HAART continue to occur as a consequence of viral resistance and other complications arising from a lifelong regimen of chemotherapy. In addition, treatment guidelines traditionally have not recommended initiating therapy in the Correspondence should be addressed to J.J.R. (jrossi@coh.org).

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Anti-Human Immunodeficiency Virus Hematopoietic Progenitor Cell-Delivered Ribozyme in a Phase I Study: Myeloid and Lymphoid Reconstitution in Human Immunodeficiency Virus Type-1–Infected Patients

Cited by 127 publications

References 36 publications

Stem cells, ribozymes and HIV

Stem cells, ribozymes and HIV

T lineage differentiation from human embryonic stem cells

Genetic therapies against HIV

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