Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

Wolkowicz, Roland; Nolan, Garry P.

doi:10.1038/sj.gt.3302488

Cited by 44 publications

(30 citation statements)

References 95 publications

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“…36,37 Our previous findings using a neomycin PM1 cell line selected for high levels of CCR5 intrabody transgene integration demonstrated a 7-day survival advantage after R5-tropic viral exposure. 16,25 To further investigate if CCR5 intrabody expression provides both survival and cell expansion, we established assays to determine if small numbers of PM1 CAD-R5-transduced cells have a selective survival and growth advantage during an ongoing HIV-1 infection.…”

Section: Enrichment Of the Pm1 Cd4 + T-cell Line Expressing The Ccr5 mentioning

confidence: 99%

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

et al. 2006

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CCR5 is the chemokine co-receptor for R5-tropic human immunodeficiency virus type 1 (HIV-1) isolates most often associated with primary infection. We have developed an HIV-1 self-inactivating vector, CAD-R5, containing a CCR5 single-chain antibody (intrabody) gene, which when expressed in T-cell lines and primary CD4 + T cells disrupts CCR5 cell surface expression and provides protection from R5-tropic isolate exposure. Furthermore, CAD-R5 intrabody expression in primary CD4 + T cells supports significant growth and enrichment over time during HIV-1-pulsed dendritic cell-T-cell interactions. These results indicate that CCR5 intrabody-expressing CD4 + T cells are refractory against this highly efficient primary route of infection. CD34 + cells transduced with the CAD-R5 vector gave rise to CD4 + and CD8 + thymocytes in non-obese diabetic (NOD)/ severely combined-immunodeficient (SCID)-human thymus/ liver (hu thy/liv) mice, suggesting that CCR5 intrabody expression can be maintained throughout differentiation without obvious cellular effects. CD4 + T cells isolated from NOD/SCID-hu thy/liv mice were resistant to R5-tropic HIV-1 challenge demonstrating the maintenance of protection. Our findings demonstrate delivery of anti-HIV-1 activity through CCR5 intrabodies in primary CD4 + T cells and CD34 + cell-derived T-cell progeny. Thus, gene delivery strategies that provide a selective survival and growth advantage for T effector cells may provide a therapeutic benefit for HIV-1-infected individuals who have failed conventional therapies.

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Section: Enrichment Of the Pm1 Cd4 + T-cell Line Expressing The Ccr5 mentioning

confidence: 99%

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

et al. 2006

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“…As such their combination with other therapies may be preferred so as to prevent the emergence of resistant strains and help achieve a synergistic effect against viral infection. 41,73 RNA aptamers NS Que-Gewirth and BA Sullenger each. Specific combinations may be tailored to enable each of these inhibitors to target distinct phases of the viral cell cycle, reduce the possibility of viral escape mutants and possibly obtain a synergized level of inhibition.…”

Section: Aptamers For Intracellular Targets Are Being Developedmentioning

confidence: 99%

“…Aptamers are regarded as highly viable drug candidates because they present little of the notorious side effects associated with the current available treatments. 36,[40][41][42][43] In addition, whereas gene therapies involving ribozymes and/or Figure 2 Aptamer activity can be reversed by an antidote. Two aptamer-antidote designs have been described.…”

Section: Aptamers For Intracellular Targets Are Being Developedmentioning

confidence: 99%

Gene therapy progress and prospects: RNA aptamers

2007

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Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody-and small-moleculebased therapeutics owing to their stability, low toxicity, low immunogenicity and improved safety. With the recent approval of the first aptamer drug Macugen by the US FDA, there is great impetus to develop therapeutic aptamers that can target a wide array of disease states. The recent demonstration that aptamer activity can be reversed by the administration of a simple antidote greatly enhances the potential value of aptamers as therapeutic agents.

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“…It is therefore attractive to consider hematopoietic stem cell transduction with lentiviral vectors as a gene therapy approach for shRNA delivery. 4,6 Engraftment of autologous transduced hematopoietic stem cells will eventually result in the steady production of HIV-1-resistant immune cells that may lead to (partial) reconstitution of the immune system.…”

mentioning

confidence: 99%

“…4,6 Efficient and durable inhibition of HIV-1 replication can be achieved when an RNAi inducer directed against the virus is stably expressed as a short hairpin RNA (shRNA) in T-cell lines. [7][8][9][10] Several target cells for HIV infection are found in the immune system, in particular CD4 + T lymphocytes, monocytes, macrophages and dendritic cells.…”

mentioning

confidence: 99%