Keratinocyte gene therapy

Vogel, Jonathan

doi:10.1001/archderm.129.11.1478

Cited by 14 publications

(12 citation statements)

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“…Keratinocyte gene therapy appears to be a promising treatment goal for improving management of intractable genetic, neoplastic and inflammatory skin diseases. [1][2][3] Several advantages have been proposed in using keratinocytes cells as targets for gene therapy. First, their ease of accessibility.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, keratinocytes could be used also as bioreactor targets for gene therapy in the treatment of systemic diseases caused by insufficient amounts of circulating proteins: the appropriate genes would be introduced into keratinocytes, the gene products synthesized and secreted into the circulation. 1,2,6 Injection of naked DNA into the skin Successful keratinocyte gene therapy requires the development of highly efficient gene transfer methods into epidermal keratinocytes. Several viral and nonviral methods have been reported for in vivo gene transfer into keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

“…As keratinocytes are known to synthesize many cytokines that modulate keratinocyte functions, keratinocyte gene therapy using cytokine genes has a great potential for the treatment of certain intractable skin diseases. Furthermore, keratinocytes could be used also as bioreactor targets for gene therapy in the treatment of systemic diseases caused by insufficient amounts of circulating proteins: the appropriate genes would be introduced into keratinocytes, the gene products synthesized and secreted into the circulation 1,2,6 …”

Section: Introductionmentioning

confidence: 99%

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Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy

Sawamura

Akiyama

Shimizu

2002

Clinical and Experimental Dermatology

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Intradermally injected DNA diffuses into the epidermis and can then enter keratinocytes and become expressed by these cells. Using this method, plasmids containing cytokine genes that have been introduced into keratinocytes can induce a level of cytokine expression sufficient to provide biological effects in the treated skin. Furthermore, transgenic cytokines released from the transduced keratinocytes can also enter the circulation and have downstream effects on other target organs. Thus far, naked DNA injection appears to be a safe, simple, and relatively efficient method that enables genes to be expressed in transplanted human skin on immunosuppressed animals. In humans, keratinocyte gene therapy using the cytokine gene DNA injection method has the potential to become a powerful therapeutic tool for dermatologists in the management of certain inflammatory and other dermatoses.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy

Sawamura

Akiyama

Shimizu

2002

Clinical and Experimental Dermatology

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“…The epidermis has many features making it a tempting target for somatic gene therapy. For reviews, see (1)(2)(3)(4). The high accessibility, useful cell culture systems and efficient protein production/ secretion are some of the characteristics that have 298 been highlighted.…”

Section: Introductionmentioning

confidence: 99%

Transgene expression in human epidermal keratinocytes: cell cycle arrest of productively transfected cells

Jensen

Petersen

Lund

et al. 2000

Experimental Dermatology

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We have analysed the consequences of liposome mediated gene transfer into human primary epidermal keratinocytes and compared non-Epstein-Barr Virus (EBV) and EBV based expression vectors that carry the genes encoding human Growth Hormone (hGH) or Enhanced Green Fluorescent Protein (EGFP). Different kinetics between the non-EBV and EBV based vectors were revealed upon subcultivation of hGH transfected keratinocytes. The keratinocytes transfected with non-EBV based vector showed a rapid reduction in hGH production. Although the EBV based vector resulted in more stable expression, this was also reduced over time. Chromatin inactivation by deacetylation was investigated by treatment with sodium butyrate and found not to be the reason for the decreasing expression. Keratinocytes divided into subpopulations enriched for either stem cells or transit amplifying cells, based on beta1-integrin expression and function, do not differ significantly with respect to susceptibility to productive transfection. However, when the keratinocytes were transfected with the EGFP gene and sorted live by FACS into EGFP negative and positive populations, only the negative cells were capable of forming significant numbers of colonies. This is consistent with the observation that the ability to incorporate BrdU was dramatically reduced in the EGFP expressing population within 24-48 h post transfection indicating an almost complete cell cycle arrest. p53 levels were unaffected by the procedures, and the keratinocyte cell line HaCat, mutated in both p53 alleles, also shows a marked reduction in clonogenic potency upon transfection. There was a slight increase of TUNEL positive apoptotic nuclei in the positive population at early time points. However, the apoptotic index was still very low. When we measured the frequency of involucrin expressing cells, we found an increase in the productively transfected population over time indicating an initiation of terminal differentiation. In contrast to the transfected cultures, keratinocytes that were transduced using a retroviral vector showed no decrease in colony forming efficiency. In conclusion we find that transgene expressing cells from transfected cultures of epidermal keratinocytes undergo cell cycle arrest and initiate terminal differentiation by mechanisms which are independent of p53 levels.

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“…The use of stratum-specific promoters to drive the expression properly both in terms of level and location has been proposed. 56,57 Gene promoters of structural proteins normally expressed in large amounts and in a stratum-specific manner such as keratins would be excellent candidates for this purpose. A great deal of knowledge about keratin and other epidermal gene promoters has been accumulated during the past years, mostly through the use of transgenic mice.…”

Section: The Problem Of Gene Expression Modulation: How To Be In the mentioning

confidence: 99%

Recent advances in gene therapy with skin cells

2002

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Somatic gene therapy remains a promising therapeutic approach for both inherited and acquired disorders. Among the tissues amenable to gene therapy, the skin, and particularly the epidermal cells, present several features advantageous for genetic manipulation and monitoring of therapeutic effects. Candidate diseases for cutaneous gene therapy not only involve skin defects but also systemic abnormalities. The robust basic and pre-clinical data gathered during the last few years have allowed the imminent launching of keratinocyte-based gene therapy with applications to patients.

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Keratinocyte gene therapy

Cited by 14 publications

References 0 publications

Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy

Direct injection of naked DNA and cytokine transgene expression: implications for keratinocyte gene therapy

Transgene expression in human epidermal keratinocytes: cell cycle arrest of productively transfected cells

Recent advances in gene therapy with skin cells

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