ISSN:1080-4013    

DOI:10.1002/mrdd.1410010102

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010103

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractIt is likely that gene therapy will be of most benefit in the single gene disorders that cause severe mental retardation. Reviews published in this issue focus on a number of these disorders in which vector development and preclinical trials or in vivo and ex vivo gene therapy are already in progress for urea cycle disorders, Lesch‐Nyhan disease, Gaucher disease, and phenylketonuria. On the other hand it is unlikely that gene therapy will hold much promise for the treatment of mild mental retardation which accounts for more than 80% of all cases of mental retardation. Here there is a strong environmental influence and early intervention and educational programs carry significant benefit. © 1995 Wiley‐Liss,

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010104

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractThis article discusses resources in ethics for investigators who will pursue gene therapy for disorders that cause mental retardation: literature on the ethical principles that ought to guide clinical research, norms and practices of human experimentation, paradigm cases for human gene therapy, and professional integrity. I review major ethical considerations in the process of planning and conducting experiments, including benefits to subjects, the safety of subjects, voluntary informed assent of soem children and the permission of parents of children with retardation, as well as concerns for fairness in the selection of subjects. From a perspective of social justice, I criticize the potential of proposals for interventions to enhance mental abilities and argue for restraint and long‐range openness toward human germ‐line therapy to prevent genetic disorders. Depending on technical developments, gene therapy may provide humans with great benefits, including the prevention of the mental retardation caused by some genetic disorders. It is the responsibility of scientists and public review bodies to implement and monitor guidelines and safeguards so that human gene therapy can be fully tested and its benefits fairly distributed to those whose need and opportunity to benefit are greatest. © 1995 Wiley‐Lis

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010105

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractMost of the approved clinical trials of human gene therapy are based on vectors derived form retroviruses. For some retroviruses, such as murine leukemia virus, the life cylcel and means of gene regulation are well understood, and provirus sequences have been cloned. Cell lines that allow the generation of high‐titer retroviral vectors without helper virus contamination have been established. Vectors generated from such cell lines are infectious and can efficiently deliver the gene of interest into the target cells. Because virus‐specific genes are deleted from these vectors, further spread of the vectors is prevented. Retrovirus‐mediated gene transfer has been tested in human clinical trials for the treatment of the inherited deficiency of adenosine deaminase and the inherited deficiency of low‐density lipoprotein receptor. Preliminary results from both trials demonstrate the feasiblility and potential efficacy of using gene therapy to treat human diseases. © 1995 Wiley

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010106

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe development of methods for human gene therapy will require efficient and stable introduction of foreign gene into somatic cells. A number of gene transfer technologies are being developed that have the potential for therapeutic application to illnesses such as cancer, genetic diseases, and infectious diseases [Mulligan, 1993]. Viruses have been used in many early gene therapy model studies. Indeed, recombinant adenoviruses are one of the most promising gene transfer systems currently available. Adenovirus vectors are used in about 10% of all the gene therapy protocols approved by the recombinant advisory committee. This review focuses on the development of adenovirus vectors, their use in clinical settings, and current obstacles to prolonged gene expression. © 1995 Wiley‐Liss, I

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010107

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractPotential new approaches to central nervous system (CNS) dysfunction have been created by the convergence of neural progenitor and stem cell biology with gene therapy and repair. Neural progenitors can be maintained in a proliferative state in vitro through retroviral transduction of an immortalizing gene. The immobilized progenitors then appear to behave much like normal CNS stem cells and hence have been termed stem‐like cells. The ability to transplant clonally related neural progenitors that self‐renew in culture but, after transplantation to the brain, differentiate appropriately into neurons and gila, may not only facilitate developmental inquiries, but also circumvent the limitations of primary fetal tissue for neural grafting. These cells are homogenous, abundant, and well‐characterized. They may express therapeutic gene products intrinsically or be readily engineered ex vivo to do so their ability to integrate efficiently into germinal zones and to migrate make possible transplant techniques that ensure widespread engraftment. Exploiting the inherent properties of neural progenitors, which allow them to become integral members of normal structures throughout the host brain, may allow foreign gene products to be delivered in a sustained, direct, and perhaps regulated fashion without disturbing other neurobiological processes. Transplants of such stem‐like cells may make possible new strategies for gene therapy and repair of the CNS, including the replacement of degenerated cells, the engineering of donor cells to be resistant to toxins, the delivery of missing metabolic or other gene products, to the over‐expression of molecules, and the substitution of alternate metabolic pathways. These approaches appear to be successful in various mouse models of neurodegeneration. Such observation may also provide a paradigm for the therapeutic use of stem cells from other organ systems. © 1995 Wiley

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010108

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractGene therapy for inborn errors of metabolism that cause mental retardation remains a major challenge to gene therapists. In general, such disorders can be divided into two categories: those in which the primary site of pathology resides outside of the central nervous system (CNS), leading to the accumulation of toxic compounds that cross the blood‐brain barrier and cause neurologic dysfunction, and those in which the primary site of pathology resides within the neurons of the CNS. We focus on the strategies and prospects for treating the latter group of diseases, which require delivery of therapeutic genes or gene products to the CNS. Both ex vivo and in vivo approaches can be used. Among the ex vivo strategies, transplanted, genetically corrected hematopoietic stem cells obtained from a patient can enter the CNS and establish microglia within the brain that then secrete therapeutic proteins. Alternatively, neural cells such as oligodendrocytes or astrocytes can be obtained by brain biopsy, genetically corrected in the laboratory using viral or nonviral vectors, then autologously transplanted back into patients for migration and secretion of the therapeutic gene products. Among the in vivo delivery techniques, direct stereotaxic injection of therapeutic gene constructs can be used to correct a metabolic abnormality in a specific region. Intracarotid injection of therapeutic genes coupled with transient disruption of the blood brain barrier could also be used to obtain global delivery. Various approaches to the treatment of inborn errors of metabolism with mental retardation can be envisioned. We discuss each of the major gene delivery systems and related therapeutic strategies. © 1995 Wiley‐Liss,

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010109

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractAs a model disease for the development of suitable gene transfer techniques and their physiological and neurological testing, Lesch‐Nyhan syndrome (LNS) provides important advantages, including the availability of a well‐characterized genetic defect and candidate metabolic targets, as well as a relevant animal model and appropriate gene transfer vectors. On the other hand, the serious gap between the level of characterization of the underlying genetic defects and the resulting neuropathological effects is one of several major impediments to the development of gene therapy. However, the dopamine defect that occurs in LNS may be much more amenable to genetic manipulation than is the deficiency of hypoxanthine guanine phosphoribosyltransferase. A genetic approach to the correction of this intermediate biochemical aberration, which probably is responsible for at least some neurological signs and symptoms of LNS, may be within reach of even the currently imperfect tools of gene therapy. Exploration of this possibility, along with other studies, is likely to lead, slowly but surely, to definition of the conditions under which the genetic and neurophysiological aberrations of LNS will be susceptible to a degree of correction that is not possible by drug therapy alone. © 1995 Wiley‐Lis

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010110

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY

摘要:

AbstractClassical phenylketonuria (PKU; Mckusick MIM Cat 261600) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (phenylalanine 4‐monooxygenase; PAH; EC 1.14.16.1). The hyperphenylalinemia and mental retardation typical of this disease can be greatly reduced or prevented though the institution, early in life, of a low‐phenylalanine diet. However, the effectiveness of dietary therapy is often limited by poor compliance, especially by adolescents or young adults. This can lead to declines in neuropsychological function. The potential of somatic gene therapy for the treatment of PKU is therefore worth exploring. We discuss three different vector systems. Recombinant retroviral vectors and DNA/protein complexes can efficiently transduce PAH‐ deficient hepatocytes in vitro, but their present application is limited by their low transduction efficiency in vivo. In contrast, infusing a recombinant adenoviral vector expressing the human PAH cDNA into the portal circulation of PAH‐deficient mice restores 10%‐80% of normal hepatic PAH activity and completely normalizes serum phenylalanine levels. At present, this effect is transient and readministration has no further effect. However, this result suggests that PKU and other monogenic hepatic deficiencies can be completely corrected by somatic gene therapy when more persistent vectors are developed. © 1995 Wiley

ISSN:1080-4013    

DOI:10.1002/mrdd.1410010111

出版商:John Wiley&Sons, Inc.    

年代:1995

数据来源: WILEY