Loss of transgene expression in vivo can be slowed, but not eliminated, by sequestering cells

Gg, Krueger; Jorgensen, Cynthia M.; Morgan, J.; Liimatta, Andrew P.; Petersen, MJ

doi:10.1016/s0923-1811(98)83822-x

Cited by 2 publications

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“…This difference persisted out to 12 weeks; however, after 4 weeks the differences were no longer statistically significant. This experiment suggests that sequestering GMFb can prolong transgene expression in vivo, although it does not result in permanent expression (30).…”

Section: Analysis Of the Loss Of Transgene Expression In Vivomentioning

confidence: 80%

Biologic Aspects of Expression of Stably Integrated Transgenes in Cells of the Skin In Vitro and In Vivo

Krueger

Morgan

Petersen

1999

Proc Assoc American Phys

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The observation that transgenes can be stably integrated into the genome of fibroblasts using recombinant retroviruses enhanced interest in using these cells as a vector for gene therapy. This enthusiasm has lessened during the past 8 years, not because skin has lost the features that make it attractive for gene therapy, but rather because stable transgene expression in vivo has not been achieved. All investigators who have used genetically modified fibroblasts to study in vivo aspects of gene therapy have shown a decrease in transgene expression with time. This contrasts with transgene expression in similarly transduced fibroblasts in vitro, where expression is not lost or is lost very slowly. We have initiated an approach to bring further understanding to the biology of transgene expression by fibroblasts carrying stably integrated transgenes in an in vivo setting. Experiments described permit the following conclusions. Expression by and survival of genetically modified fibroblasts a) requires a persistent matrix scaffold in in vivo settings; b) is prolonged if the matrix is allowed to mature in vitro; c) is enhanced if the matrix is partially sequestered behind a coating of normal fibroblasts; and d) can be substantively prolonged in vivo by immortalizing the cells. These observations support the notion that prolonged expression of transgenes by fibroblasts can be achieved in vivo and that gene therapy utilizing fibroblasts and other cells of the skin has clinical utility.

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Section: Analysis Of the Loss Of Transgene Expression In Vivomentioning

confidence: 80%

Biologic Aspects of Expression of Stably Integrated Transgenes in Cells of the Skin In Vitro and In Vivo

Krueger

Morgan

Petersen

1999

Proc Assoc American Phys

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Fibroblasts and Dermal Gene Therapy: A Minireview

Krueger

2000

Human Gene Therapy

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This review highlights our current understanding of the biology of, survival of, and transgene expression by genetically modified fibroblasts (GMFb) carrying stably integrated transgenes in vivo. Experimental data demonstrate that three elements will enhance expression by and survival of GMFb in vivo: a matrix scaffolding to take the place of the existing dermis, the presence of elements of the extracellular matrix in the construct used to move GMFb to the in vivo setting, and the utilization of immortalized fibroblasts to carry the transgenes. Although moving GMFb to an in vivo setting is an invasive procedure, there are a number of clinical settings where GMFb appear to be the suitable cell for gene therapy.

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Loss of transgene expression in vivo can be slowed, but not eliminated, by sequestering cells

Cited by 2 publications

References 0 publications

Biologic Aspects of Expression of Stably Integrated Transgenes in Cells of the Skin In Vitro and In Vivo

Biologic Aspects of Expression of Stably Integrated Transgenes in Cells of the Skin In Vitro and In Vivo

Fibroblasts and Dermal Gene Therapy: A Minireview

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