摘要:

AbstractAlthough individually inborn errors of metabolism are rare, collectively they contribute significantly to morbidity and mortality in the pediatric age group. There are several reasons why, out of these inborn errors of metabolism, urea cycle disorders have emerged as potentially good candidates for the development of gene therapy. Studies have initially focused on ornithine carbamoyltransferase (OCT) deficiency in part because there are mouse models of this disease and in part because this disease is particularly resistant to current therapies. Both in vivo and ex vivo approaches to gene therapy are being developed for the treatment of urea cycle disorders. Ex vivo gene therapy is appealing because of the long‐term expression that can be achieved, but there are clear limitations to this approach. In vivo gene therapy using adenoviral vectors is attractive for several reasons, including the fact that the virus can be administered by intravenous injection, the high levels of expression observed after a single injection, and the rapidity of that expression. Studies of transgene expression in the mouse models of OCT deficiency (OCTD) have been encouraging, but have also provided evidence that the immune system may be involved in mediating two limiting aspects of this technology, transient gene expression and inflammation. Although deletions in adenoviral early genes should limit adenoviral late gene expression and subsequent viral replication, there is in vitro and in vivo evidence of late gene expression after infection with adenoviruses deleted of some of the early genes. Future studies will focus on systematically defining the components of the virus that are recognized by the immune system and mutating these gene products. The development of an approach to gene therapy that safely, stably, and efficiently transduces gene expression holds the promise of revolutionizing the treatment of inborn errors of urea synthesis. © 1995 Wiley‐Liss,

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010112

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractDuchenne muscular dystrophy (DMD) is a wasting disease of muscle caused by mutations in a single gene on the X chromosome. Because no effective treatment is available, the disease inevitably is fatal by the third decade of life. Hence, the use of gene transfer technology to correct the biochemical defect (dystrophin‐deficiency) in muscle fibers of DMD patients may provide a promising therapeutic strategy. This review outlines recent progress toward understanding the molecular pathology of DMD, including identification of novel products of the DMD gene expressed in the nervous system and their involvement in neurological defects in DMD patients. We summarize germ‐line (transgenic) and somatic gene transfer studies performed on the mdx mouse model of DMD, using recombinant cDNA molecules. In light of these results, we discuss areas for future study, such as refinement of viral‐mediated gene transfer to muscle, and the prospects for gene therapy for human DMD patients. © 1995 Wiley‐L

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010113

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractGaucher disease, the result of inherited deficiency of glucocerebrosidase, is the most common lysosomal storage disease. No naturally occurring animal models are available for study of its pathophysiology or the development of new therapeutic strategies such as gene therapy. We describe an approach to gene targeting in embryonic stem cells to “knock out” glucocerebrosidase activity and generate a mouse line having the phenotype of severely affected infants with type 2 Gaucher disease. We also discuss an experiment in gene therapy using lethally irradiated mice that are reconstituted with murine fetal liver hematopoietic cells transduced with retrovirus encoding human glucocerebrosidase. Analyses of these animals show production of active human glucocerebrosidase in lysosomes of macrophages for at least 12 months after transplantation. © 1995 Wiley‐Lis

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010114

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010101

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY