Garlick J A, Fenjves E S
Department of Oral Biology and Pathology, State University of New York at Stony Brook 11794-8702, USA.
Crit Rev Oral Biol Med. 1996;7(3):204-21. doi: 10.1177/10454411960070030101.
Gene therapy has moved beyond the pre-clinical stage to the treatment of a variety of inherited and acquired diseases. For such therapy to be successful, genes must be efficiently delivered to target cells and gene products must be expressed for prolonged periods of time without toxic effects to the host. This may be achieved by means of an in vivo strategy where genes are transferred directly into a host cell, or by means of an ex vivo approach through which cells are removed, cultured, targeted for gene delivery, and grafted back to the host. Several obstacles continue to delay safe and effective clinical application of gene therapy in a variety of target cells. The limited survival of transplanted cells, transient expression of transferred genes, and difficulties in targeting stem cells are technical issues requiring further investigation. Epidermal and oral keratinocytes are potential vehicles for gene therapy. Several features of these tissues can be utilized to achieve delivery of therapeutic gene products for local or systemic delivery. These qualities include: (1) the presence of stem cells; (2) the cell-, strata-, and site-specific regulation of keratinocyte gene expression; (3) tissue accessibility; and (4) secretory capacity. Such features can be exploited by the use of gene therapy strategies to facilitate: (1) identification, enrichment, and targeting of stem cells to ensure the continued presence of the transferred gene; (2) high-level and persistent transgene expression using keratinocyte-specific promoters; (3) tissue access needed for culture and grafting for ex vivo therapy and direct in vivo gene transfer; (4) secretion of transgene product for local or systemic delivery; and (5) monitoring of genetically modified tissue and removal if treatment termination is required. Optimal gene therapy strategies are being tested in a variety of tissues to treat dominant and recessive genetic disorders as well as acquired diseases such as neoplasia and infectious disease. This experience provides a basis for the application of such clinical studies to a spectrum of diseases effecting epidermal and oral keratinocytes. Gene therapy is in an early stage yet holds great promise for its ultimate clinical application.
基因治疗已从临床前阶段发展到用于治疗多种遗传性和后天性疾病。要使这种治疗取得成功，基因必须有效地传递到靶细胞，并且基因产物必须长时间表达而对宿主无毒性作用。这可以通过体内策略来实现，即将基因直接转移到宿主细胞中，或者通过体外方法来实现，即细胞被取出、培养、进行基因传递靶向，然后再移植回宿主。几个障碍继续延缓基因治疗在各种靶细胞中的安全有效临床应用。移植细胞的有限存活、转移基因的瞬时表达以及靶向干细胞的困难是需要进一步研究的技术问题。表皮和口腔角质形成细胞是基因治疗的潜在载体。这些组织的几个特征可用于实现治疗性基因产物的局部或全身递送。这些特性包括：（1）干细胞的存在；（2）角质形成细胞基因表达的细胞、层和位点特异性调节；（3）组织可及性；（4）分泌能力。通过使用基因治疗策略可以利用这些特征来促进：（1）干细胞的鉴定、富集和靶向，以确保转移基因的持续存在；（2）使用角质形成细胞特异性启动子进行高水平和持续的转基因表达；（3）体外治疗和直接体内基因转移所需的培养和移植的组织可及性；（4）转基因产物的分泌以进行局部或全身递送；（5）对基因改造组织的监测以及在需要终止治疗时进行清除。正在各种组织中测试最佳基因治疗策略，以治疗显性和隐性遗传疾病以及诸如肿瘤和传染病等后天性疾病。这一经验为将此类临床研究应用于影响表皮和口腔角质形成细胞的一系列疾病提供了基础。基因治疗尚处于早期阶段，但对其最终临床应用具有巨大潜力。
