Gene therapy for autosomal dominant disorders of keratin.
Dominant mutations that interfere with the assembly of keratin filaments cause painful and disfiguring epidermal diseases like pachyonychia congenita and epidermolysis bullosa simplex. Genetic therapies for such diseases must either suppress the production of the toxic proteins or correct the genetic defect in the chromosome. Because epidermal skin cells may be genetically modified in tissue culture or in situ, gene correction is a legitimate goal for keratin diseases. In addition, recent innovations, such as RNA interference in animals, make an RNA knockdown approach plausible in the near future. Although agents of RNA reduction (small interfering RNA, ribozymes, triplex oligonucleotides, or antisense DNA) can be delivered as nucleotides, the impermeability of the skin to large charged molecules presents a serious impediment. Using viral vectors to deliver genes for selective inhibitors of gene expression presents an attractive alternative for long-term treatment of genetic disease in the skin.
Lewin
Alfred S
AS
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida 32610-0266, USA. lewin@ufl.edu
Glazer
Peter M
PM
Milstone
Leonard M
LM
D000818:Animals; D007644:Darier Disease / Q000235:genetics / Q000628:therapy; D000229:Dependovirus / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000628:therapy*; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics / Q000628:therapy; D020868:Gene Silencing; D018390:Gene Targeting; D005799:Genes, Dominant; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007633:Keratins / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000628:therapy*; D051379:Mice; D009154:Mutation; D009264:Nails, Malformed / Q000235:genetics / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use; D034622:RNA Interference; D016337:RNA, Catalytic / Q000235:genetics / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use
D016376:Oligonucleotides, Antisense; D016337:RNA, Catalytic; D034741:RNA, Small Interfering; D007633:Keratins