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Genetic correction of stem cells in the treatment of inherited diseases and focus on xeroderma pigmentosum.

Rouanet S, Warrick E, Gache Y, Scarzello S, Avril MF, Bernerd F, Magnaldo T - Int J Mol Sci (2013)

Bottom Line: Most patients die from the consequences of budding hundreds of skin cancers in the absence of photoprotection.We have developed a safe procedure of genetic correction of epidermal stem cells isolated from XP patients.Preclinical and safety assessments indicate successful correction of XP epidermal stem cells in the long term and their capacity to regenerate a normal skin with full capacities of DNA repair.

View Article: PubMed Central - PubMed

Affiliation: Genetics and Physiopathology of Epithelial Cancers, INSERM U 1081-CNRS UMR 7284-UNS, Institute for Research on Cancer and Aging, Nice, Medical school, 28 Avenue de Valombrose, 06107 Nice Cedex 2, France. tmagnaldo@unice.fr.

ABSTRACT
Somatic stem cells ensure tissue renewal along life and healing of injuries. Their safe isolation, genetic manipulation ex vivo and reinfusion in patients suffering from life threatening immune deficiencies (for example, severe combined immunodeficiency (SCID)) have demonstrated the efficacy of ex vivo gene therapy. Similarly, adult epidermal stem cells have the capacity to renew epidermis, the fully differentiated, protective envelope of our body. Stable skin replacement of severely burned patients have proven life saving. Xeroderma pigmentosum (XP) is a devastating disease due to severe defects in the repair of mutagenic DNA lesions introduced upon exposure to solar radiations. Most patients die from the consequences of budding hundreds of skin cancers in the absence of photoprotection. We have developed a safe procedure of genetic correction of epidermal stem cells isolated from XP patients. Preclinical and safety assessments indicate successful correction of XP epidermal stem cells in the long term and their capacity to regenerate a normal skin with full capacities of DNA repair.

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Related in: MedlinePlus

Schematic representation of human epidermis. Cell layers and corresponding abbreviations are indicated. Note that the basal epidermal layer, also called stratum germinativum, contains stem cells endowed with potential of full thickness epidermal regeneration. Conversely, the suprabasal compartment does not normally shelter proliferative cells but is characterized by a sequential program of genetic expression as attested by stepwise expression of markers, as indicated. BMZ, basement membrane zone; Epi, epidermis; Der, dermis; K, keratinocytes; Fb, fibroblasts; Kx, keratin X; Lor, Loricrin; Tsg, membrane bound transglutaminase.
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f1-ijms-14-20019: Schematic representation of human epidermis. Cell layers and corresponding abbreviations are indicated. Note that the basal epidermal layer, also called stratum germinativum, contains stem cells endowed with potential of full thickness epidermal regeneration. Conversely, the suprabasal compartment does not normally shelter proliferative cells but is characterized by a sequential program of genetic expression as attested by stepwise expression of markers, as indicated. BMZ, basement membrane zone; Epi, epidermis; Der, dermis; K, keratinocytes; Fb, fibroblasts; Kx, keratin X; Lor, Loricrin; Tsg, membrane bound transglutaminase.

Mentions: Schematically, three types of disease are thought appropriate candidates for corrective gene transfer using epidermal keratinocytes: (1) systemic diseases such as hemorrhagic deficiencies [54], insulino-dependent diabete [55] and leptin-dependent obesity [56]. In these cases, although skin or epidermis do not necessarily express overt phenotypic traits of the disease, modified epidermal stem cells may serve as a reservoir for stable delivery of diffusible substances in the blood stream; (2) diseases with main expression of traits in skin (genodermatoses) resulting from defects in proteins such as keratins, loricrin, epidermal transglutaminase, cell envelope precursors, integrins, collagens, or protease inhibitors; (3) diseases due to alteration of ubiquitously expressed genes with special impact in skin. These include gene products involved in essential processes of the control of cell growth (P63, ectodermal dysplasia), transcriptional regulation (NEMO/IKKγ, incontinenta pigmenti; PATCHED, nevoid basal cell carcinoma or Goltz-Gorlin’s syndrome), telomeric (congenital dyskeratosis), and non-telomeric genome maintenance (xeroderma pigmentosum). Figure 1 is a schematic representation of a section of human skin. Table 2 combines representative examples of those diseases.


Genetic correction of stem cells in the treatment of inherited diseases and focus on xeroderma pigmentosum.

Rouanet S, Warrick E, Gache Y, Scarzello S, Avril MF, Bernerd F, Magnaldo T - Int J Mol Sci (2013)

Schematic representation of human epidermis. Cell layers and corresponding abbreviations are indicated. Note that the basal epidermal layer, also called stratum germinativum, contains stem cells endowed with potential of full thickness epidermal regeneration. Conversely, the suprabasal compartment does not normally shelter proliferative cells but is characterized by a sequential program of genetic expression as attested by stepwise expression of markers, as indicated. BMZ, basement membrane zone; Epi, epidermis; Der, dermis; K, keratinocytes; Fb, fibroblasts; Kx, keratin X; Lor, Loricrin; Tsg, membrane bound transglutaminase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821600&req=5

f1-ijms-14-20019: Schematic representation of human epidermis. Cell layers and corresponding abbreviations are indicated. Note that the basal epidermal layer, also called stratum germinativum, contains stem cells endowed with potential of full thickness epidermal regeneration. Conversely, the suprabasal compartment does not normally shelter proliferative cells but is characterized by a sequential program of genetic expression as attested by stepwise expression of markers, as indicated. BMZ, basement membrane zone; Epi, epidermis; Der, dermis; K, keratinocytes; Fb, fibroblasts; Kx, keratin X; Lor, Loricrin; Tsg, membrane bound transglutaminase.
Mentions: Schematically, three types of disease are thought appropriate candidates for corrective gene transfer using epidermal keratinocytes: (1) systemic diseases such as hemorrhagic deficiencies [54], insulino-dependent diabete [55] and leptin-dependent obesity [56]. In these cases, although skin or epidermis do not necessarily express overt phenotypic traits of the disease, modified epidermal stem cells may serve as a reservoir for stable delivery of diffusible substances in the blood stream; (2) diseases with main expression of traits in skin (genodermatoses) resulting from defects in proteins such as keratins, loricrin, epidermal transglutaminase, cell envelope precursors, integrins, collagens, or protease inhibitors; (3) diseases due to alteration of ubiquitously expressed genes with special impact in skin. These include gene products involved in essential processes of the control of cell growth (P63, ectodermal dysplasia), transcriptional regulation (NEMO/IKKγ, incontinenta pigmenti; PATCHED, nevoid basal cell carcinoma or Goltz-Gorlin’s syndrome), telomeric (congenital dyskeratosis), and non-telomeric genome maintenance (xeroderma pigmentosum). Figure 1 is a schematic representation of a section of human skin. Table 2 combines representative examples of those diseases.

Bottom Line: Most patients die from the consequences of budding hundreds of skin cancers in the absence of photoprotection.We have developed a safe procedure of genetic correction of epidermal stem cells isolated from XP patients.Preclinical and safety assessments indicate successful correction of XP epidermal stem cells in the long term and their capacity to regenerate a normal skin with full capacities of DNA repair.

View Article: PubMed Central - PubMed

Affiliation: Genetics and Physiopathology of Epithelial Cancers, INSERM U 1081-CNRS UMR 7284-UNS, Institute for Research on Cancer and Aging, Nice, Medical school, 28 Avenue de Valombrose, 06107 Nice Cedex 2, France. tmagnaldo@unice.fr.

ABSTRACT
Somatic stem cells ensure tissue renewal along life and healing of injuries. Their safe isolation, genetic manipulation ex vivo and reinfusion in patients suffering from life threatening immune deficiencies (for example, severe combined immunodeficiency (SCID)) have demonstrated the efficacy of ex vivo gene therapy. Similarly, adult epidermal stem cells have the capacity to renew epidermis, the fully differentiated, protective envelope of our body. Stable skin replacement of severely burned patients have proven life saving. Xeroderma pigmentosum (XP) is a devastating disease due to severe defects in the repair of mutagenic DNA lesions introduced upon exposure to solar radiations. Most patients die from the consequences of budding hundreds of skin cancers in the absence of photoprotection. We have developed a safe procedure of genetic correction of epidermal stem cells isolated from XP patients. Preclinical and safety assessments indicate successful correction of XP epidermal stem cells in the long term and their capacity to regenerate a normal skin with full capacities of DNA repair.

Show MeSH
Related in: MedlinePlus