- Email: [email protected]
Clinical gene therapy back in the race
Literature
The
MOLECULAR MEDICINE TODAY, SEPTEMBER 2000 (VOL. 6)
Caspases and neurodegenerative diseases Caspases are cysteine proteases that have a central role in programmed cell death (PCD). Activation of these proteolytic enzymes has been demonstrated in several neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), and Huntington’s (HD) disease. In addition, in vitro studies have shown that huntingtin (htt), which is implicated in HD, is cleaved by caspases, although it is not yet clear which caspases or other proteases are involved in this process in vivo. Two such candidates have been put forward by Wellington et al.1, who have used site-directed mutagenesis of htt to show that this protein is a substrate for caspases 3 and 6 in vitro and that the htt cleavage further activates caspase-3. In this work, they have shown that upon induction of PCD by tamoxifen, htt is cleaved and that mutagenising the predicted caspase sites on htt blocks this cleavage. This inhibition in turn reduced the cytotoxic effects of N-terminal htt fragments, possibly by inhibiting further activation of caspase-3. Moreover, their data indicate a reduction in the formation of aggregates in the cell lines that contained caspase resistant htt. The extent and importance of caspase cleavage of htt and some other pathogenic polyglutamine proteins in the onset and progression of neurodegenerative diseases remain to be verified in vivo. 1 Wellington, C.L. et al. (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells, J. Biol. Chem. 275, 19831–19838 Majid Hafezparast PhD [email protected]
338
Clinical gene therapy back in the race Gene therapy of human diseases has a rather short history of less than 15 years. Despite this, there is immense interest in gene therapy among scientists, clinicians and the general public because of the great potential of this field. Among the great variety of gene therapeutic approaches, one of the most promising is the transfer of genetic material into hematopoietic stem cells, because it has potential benefit for a wide range of infectious and inherited diseases. However, the first results of clinical gene therapy approaches were rather disappointing, which was, in part, owing to a low transduction efficiency of pluripotent stem cells in the early trials. To improve this major obstacle for stemcell gene therapy approaches, Abonour et al.1 have used a chimeric molecule (CH296), which colocalises vector and target cells, thus improving gene transfer efficiency. The impact of this improvement was investigated in a clinical phase I trial for the treatment of patients with recurrent germ cell tumours. In this study, the authors demonstrated the highest level of gene transfer into clonogenic progenitor cells seen so far and, more impor-
tantly, achieved a long-term effect (over 1 year). Moreover, there was some evidence of in vivo selection during chemotherapy, as the transduced cells bear a multidrug resistance 1 gene that renders them resistant to ‘doseintensive’ chemotherapy. Together with another report on the successful treatment of two patients with severe combined immunodeficiency-X1 (Ref. 2) using the same gene transfer technology, these data highlight how important methodological improvements are for the success of clinical gene therapy trials. 1 Abonour, R. et al. (2000) Efficient retrovirus-mediated transfer of multidrug resistance 1 gene into autologous human long-term repopu-lating hematopoetic stem cells. Nat. Med. 6, 652–658 2 Cavazzana-Calva, M. et al. (2000) Gene therapy of human severe combined immuno-deficiency (SCID)-X1 disease. Science 288, 669–672 Dieter Klein Dr Med. Vet. [email protected]
Neurological articles of interest in other Trends journals
•
Pathogenetic role of autoantibodies in neurological diseases, by Juan J. Archelos and Hans-Peter Hartung (2000), Trends in Neurosciences 23, 279–330
•
Neuronal migration disorders: from genetic diseases to developmental mechanisms, by Joseph G. Gleeson and Christopher A. Walsh (2000), Trends in Neurosciences 23, 331–381
Forthcoming neurodegenerative articles in Molecular Medicine Today
• •
Secretases as targets for the treatment of Alzheimer’s disease, by Martin Citron Protein aggregation in Huntington’s and Parkinson’s disease: implications for therapy, by Erich Wanker
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
The
MOLECULAR MEDICINE TODAY, SEPTEMBER 2000 (VOL. 6)
Caspases and neurodegenerative diseases Caspases are cysteine proteases that have a central role in programmed cell death (PCD). Activation of these proteolytic enzymes has been demonstrated in several neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer’s (AD), and Huntington’s (HD) disease. In addition, in vitro studies have shown that huntingtin (htt), which is implicated in HD, is cleaved by caspases, although it is not yet clear which caspases or other proteases are involved in this process in vivo. Two such candidates have been put forward by Wellington et al.1, who have used site-directed mutagenesis of htt to show that this protein is a substrate for caspases 3 and 6 in vitro and that the htt cleavage further activates caspase-3. In this work, they have shown that upon induction of PCD by tamoxifen, htt is cleaved and that mutagenising the predicted caspase sites on htt blocks this cleavage. This inhibition in turn reduced the cytotoxic effects of N-terminal htt fragments, possibly by inhibiting further activation of caspase-3. Moreover, their data indicate a reduction in the formation of aggregates in the cell lines that contained caspase resistant htt. The extent and importance of caspase cleavage of htt and some other pathogenic polyglutamine proteins in the onset and progression of neurodegenerative diseases remain to be verified in vivo. 1 Wellington, C.L. et al. (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells, J. Biol. Chem. 275, 19831–19838 Majid Hafezparast PhD [email protected]
338
Clinical gene therapy back in the race Gene therapy of human diseases has a rather short history of less than 15 years. Despite this, there is immense interest in gene therapy among scientists, clinicians and the general public because of the great potential of this field. Among the great variety of gene therapeutic approaches, one of the most promising is the transfer of genetic material into hematopoietic stem cells, because it has potential benefit for a wide range of infectious and inherited diseases. However, the first results of clinical gene therapy approaches were rather disappointing, which was, in part, owing to a low transduction efficiency of pluripotent stem cells in the early trials. To improve this major obstacle for stemcell gene therapy approaches, Abonour et al.1 have used a chimeric molecule (CH296), which colocalises vector and target cells, thus improving gene transfer efficiency. The impact of this improvement was investigated in a clinical phase I trial for the treatment of patients with recurrent germ cell tumours. In this study, the authors demonstrated the highest level of gene transfer into clonogenic progenitor cells seen so far and, more impor-
tantly, achieved a long-term effect (over 1 year). Moreover, there was some evidence of in vivo selection during chemotherapy, as the transduced cells bear a multidrug resistance 1 gene that renders them resistant to ‘doseintensive’ chemotherapy. Together with another report on the successful treatment of two patients with severe combined immunodeficiency-X1 (Ref. 2) using the same gene transfer technology, these data highlight how important methodological improvements are for the success of clinical gene therapy trials. 1 Abonour, R. et al. (2000) Efficient retrovirus-mediated transfer of multidrug resistance 1 gene into autologous human long-term repopu-lating hematopoetic stem cells. Nat. Med. 6, 652–658 2 Cavazzana-Calva, M. et al. (2000) Gene therapy of human severe combined immuno-deficiency (SCID)-X1 disease. Science 288, 669–672 Dieter Klein Dr Med. Vet. [email protected]
Neurological articles of interest in other Trends journals
•
Pathogenetic role of autoantibodies in neurological diseases, by Juan J. Archelos and Hans-Peter Hartung (2000), Trends in Neurosciences 23, 279–330
•
Neuronal migration disorders: from genetic diseases to developmental mechanisms, by Joseph G. Gleeson and Christopher A. Walsh (2000), Trends in Neurosciences 23, 331–381
Forthcoming neurodegenerative articles in Molecular Medicine Today
• •
Secretases as targets for the treatment of Alzheimer’s disease, by Martin Citron Protein aggregation in Huntington’s and Parkinson’s disease: implications for therapy, by Erich Wanker
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.