Hematopoietic-Stem-Cell-Based Gene Therapy for HIV Disease

Kiem, Hans Peter; Jerome, Keith R.; Deeks, Steven G.; McCune, Joseph M.

doi:10.1016/j.stem.2011.12.015

Cited by 113 publications

(116 citation statements)

References 97 publications

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“…At present, the general consensus is that 'true' self-renewing human HSCs are found within the CD34 + population and that engraftment of a suitably conditioned host with a sufficient number of such cells will result in long-term multi-lineage hematopoiesis [8,9]. UCB cells are a valuable source of HSCs for use in allogeneic transplantation.…”

Section: Prostaglandin-modulated Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Untitled

2015

JHVRV

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Allogeneic stem cell transplantation of hematopoietic stem cells (HSCs) resistant to HIV-1 (CCR5 null cells) using a regimen to improve homing, engraftment, and preferential cord chimerism of umbilical cord blood (UCB) cells homozygous for CCR5∆32 mutation (UCBΔ32/Δ32) favors utilization of prostaglandin E 2 (PGE 2 )-mediated mechanisms to facilitate allogeneic transplantation. Since PGE 2 has additional capacity to down-regulate CCR5 expression, this could enable dual effect a) Allogeneic transplantation of UCB cells heterozygous for the CCR5∆32 mutation (UCBΔ32/wt) b) Epigenetic down-regulation of residual CCR5 expression in synergy with improved engraftment.Such treatment has capacity not only to improve engraftment of (UCBΔ32/wt) cells heterozygous for the CCR5∆32 mutation but also prevent functional expression of the CCR5 chemokine receptor used by CCR5 (R5)-tropic HIV-1 to enter CD4 + T cells. Provided that PGE 2 or its more stable analogue dimethyl-PGE 2 (dmPGE 2 ) has lasting effects in HSCs this could lead to significant increase of the number of treatable patients (frequency of heterozygous CCR5wt/∆32 donors in US and Central and North of Europe is at least 10-fold higher than in the case of homozygous CCR5∆32/∆32 donors). Thus, ultimate goal is to create a functional R5-tropic HIV-1-resistant immune system through the use of optimized dmPGE 2 -modified UCB cells heterozygous for ∆32 mutation with improved homing, engraftment, and preferential cord chimerism with further emphasis on post-transplant amelioration of the graft versus host disease (GvHD) enabled via PGE 2 -mediated potentiation of regulatory T (Treg) cell-mediated suppression.

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Section: Prostaglandin-modulated Hematopoietic Stem Cell Transplantationmentioning

confidence: 99%

Untitled

2015

JHVRV

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“…2 As with GWAS arrays, SGS begins with library preparation by fragmenting genomic DNA, which are then ligated to universal oligonucleotide adaptors. These adapters facilitate the capture, or attachment, of the DNA fragments onto solid or bead-like platforms.…”

Section: Box 1 New Genomics Technology In Hctmentioning

confidence: 99%

“…1 More recently, HCT has also been shown to be efficacious in a number of cell-based therapies for non-hematological conditions. 2,3 Once a therapy of last resort for universally lethal diseases, a number of recent scientific and clinical advances, such as the introduction of molecular and sequence-based human leukocyte antigen (HLA) typing, have dramatically improved the long-term success rates of HCT. Despite this progress, the 1-year mortality rate among allogeneic HCT recipients remains a staggering 30-40%, making a potentially life-saving transplant risk-prohibitive for patients with significant comorbidities, at advanced ages, or for whom no appropriate HLA-matched donors can be identified.…”

Section: Introductionmentioning

confidence: 99%

Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation

Levine

Hákonarson

et al. 2013

Eur J Hum Genet

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Recent developments in second-generation sequencing (SGS) technologies provide an avenue for achieving rapid and accurate high-throughput analysis of human and microbial genomic diversity. SGS technologies have the potential to transform existing medical management of complex and life-threatening medical conditions by enabling clinicians to develop disease-targeted clinical care plans for each patient. In this review, we outline how innovative SGS-based approaches can improve the care of recipients of allogeneic hematopoietic cell transplantation (HCT), a life-saving procedure that carries a 1-year mortality risk of over 30%. We specifically evaluate foreseeable applications of SGS-based technology in facilitating rapid, phase-sensitive human leukocyte antigen (HLA) typing, assessment of non-HLA genomic compatibility, identifying patients at high risk for adverse drug reactions, and post-HCT monitoring for engraftment, minimal residual disease and infection. We conclude that innovative SGS approaches have the capacity to revolutionize the HCT recipient risk assessment process, support non-invasive clinical monitoring and improve patient outcomes, thereby setting the stage for a new era of genomically informed patient-centered medicine.

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“…4,5 Therefore the introduction of genes interfering with HIV infection of HSC could potentially break this cycle and potentially offer durable eradication of the virus. 6 Proof of concept for its curative potential was provided from allogeneic bone marrow transplantation studies in AIDS patients. Donor stem cells carrying a rare mutation, which conferred natural resistance to HIV infection (C-C chemokine receptor type 5 deletion 32 (CCR5-D32)), led to durable elimination of HIV in AIDS patients.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, there is great interest in developing HSC gene transfer technologies for therapeutic approaches for AIDS. 6 The preferred and the most commonly employed vector systems for HSC are those achieving genomic integration of the transgene and thus permanently modifying HSC and its progeny. Among retroviruses, these include vectors based on Moloney murine leukemia virus, lentiviruses and, rarely, foamy viruses.…”

Section: Introductionmentioning

confidence: 99%

CD34+ hematopoietic stem cells support entry and replication of poliovirus: a potential new gene introduction route

et al. 2013

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Pluripotent hematopoietic stem cells (HSC) are critical in sustaining and constantly renewing the blood and immune system. The ability to alter biological characteristics of HSC by introducing and expressing genes would have enormous therapeutic possibilities. Previous unpublished work suggested that human HSC co-express CD34 (cluster of differentiation 34; an HSC marker) and CD155 (poliovirus receptor; also called Necl-5/Tage4/PVR/CD155). In the present study, we demonstrate the co-expression of CD34 and CD155 in primary human HSC. In addition, we demonstrate that poliovirus infects and replicates in human hematopoietic progenitor cell lines. Finally, we show that poliovirus replicates in CD34 þ enriched primary HSC. CD34 þ enriched HSC co-express CD155 and support poliovirus replication. These data may help further understanding of poliovirus spread in vivo and also demonstrate that human HSC may be amenable for gene therapy via poliovirus-capsid-based vectors. They may also help elucidate the normal function of Necl-5/Tage4/PVR/CD155.

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Hematopoietic-Stem-Cell-Based Gene Therapy for HIV Disease

Cited by 113 publications

References 97 publications

Untitled

Untitled

Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation

CD34+ hematopoietic stem cells support entry and replication of poliovirus: a potential new gene introduction route

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