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Parkin gene therapy could treat Parkinson's disease
Newsdesk
rats age 60 days, 25 days before expected disease onset. Disease onset in rats given VEGF was 10 days later than in control rats implanted with minipumps delivering artificial CSF. Rats given VEGF were also more active on a rotating-rod test of motor function and survived longer than those in the control group. Similarly, when VEGF (0·2 mg/kg daily) was given to SOD1G93A/HWr rats, again 25 days before expected disease onset, motor skills and survival time were improved and disease onset was delayed compared with the control group (Nat Neurosci 2004; 8: 85–92). Despite the fast progression of disease in SOD1G93A/HWr rats, survival was also
prolonged when treatment was started at the time of disease onset. However, rats were less likely to develop a more severe form of the disease when VEGF was given before disease onset than when treatment was delayed. By use of stereological analysis, Carmeliet and co-workers also showed that motor-neuron degeneration was delayed in SOD1G93A/HWr rats treated with VEGF compared with the control group. Carmeliet told The Lancet Neurology, “our data show that intracerebroventricular delivery of VEGF is particularly effective in slowing degeneration of bulbar and cervical motor neurons”, and explained
“stronger effects on bulbar motor neurons may enable patients to communicate for a longer time with their family members”. However, cautions Jeffrey Rothstein (Johns Hopkins University, Baltimore, USA), to date these models have not been predictive of success in humans: “This is an animal model of the familial form of ALS, which occurs in only 1–2% of patients”. Serge Przedborski (Columbia University, USA) is also cautious to speculate about human response but both neurologists suggest that the work may have far-reaching implications.
Gillian Carmichael
Parkin gene therapy could treat Parkinson’s disease Rats engineered to overexpress human synuclein lose nigral neurons and have reduced striatal tyrosine hydroxylase (TH) activity. However, these abnormalities can be corrected by injecting a viral vector containing the parkin gene into the substantia nigra of these rats, according to new research by Patrick Aebischer (Swiss Federal Institute of Technology, EPFL, Lausanne, Switzerland) and colleagues.
JJ Hauw, ISM/Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
synuclein is a component of Lewy bodies found in Parkinson’s disease
82
“These findings raise the possibility that parkin gene therapy could treat the subset of patients with Parkinson’s disease (PD) who have mutations in the -synuclein gene”, comments Mark Tuszynski, who was not involved in the study. “Further, if indeed parkin overexpression broadly corrects anatomical degeneration in the substantia nigra and striatum, this might be a potential therapy for any form of PD.” Parkin is thought to have a role in dopamine neuron survival because loss of parkin’s E3 ligase activity leads to dopaminergic neuronal degeneration in early onset autosomal recessive juvenile parkinsonism. To test the hypothesis that parkin has neuroprotective properties, Aebischer’s team developed a lentiviral vector that was capable of delivering the parkin gene. They then stereotaxically injected the viral vector into the substantia nigra of adult rats that overexpress synuclein. 6 weeks later they used immunocytochemistry to evaluate the expression of TH, synuclein, and parkin in the substantia nigra (Proc Natl Acad Sci USA 2004; 101: 17510–15). The researchers showed that animals that overexpressed parkin had
reduced -synuclein-induced pathology compared with normal control animals; the TH-positive cell bodies in the substantia nigra were preserved as were TH-positive nerve terminals in the striatum. However, rats injected with the viral vector had a large number of hyperphosphorylated -synuclein inclusions. “The obvious next step is to identify and test small molecules that induce parkin expression”, says Aebischer. “A gene therapy approach may also be considered as a significant number of dopaminergic nigral cells can be infected with viral vectors through a single nigral injection.” Tuszynski thinks the gene therapy approach is promising, but would like to know whether parkin gene therapy can correct motor abnormalities in animal models of PD. “These data were not reported in the paper”, he says, “and would be an important prerequisite to potential human trials”. He also wonders whether this approach would work in a neurotoxin models of PD, such as the MPTP or 6-hydroxy-dopamine lesion models.
James Butcher http://neurology.thelancet.com Vol 4 February 2005
rats age 60 days, 25 days before expected disease onset. Disease onset in rats given VEGF was 10 days later than in control rats implanted with minipumps delivering artificial CSF. Rats given VEGF were also more active on a rotating-rod test of motor function and survived longer than those in the control group. Similarly, when VEGF (0·2 mg/kg daily) was given to SOD1G93A/HWr rats, again 25 days before expected disease onset, motor skills and survival time were improved and disease onset was delayed compared with the control group (Nat Neurosci 2004; 8: 85–92). Despite the fast progression of disease in SOD1G93A/HWr rats, survival was also
prolonged when treatment was started at the time of disease onset. However, rats were less likely to develop a more severe form of the disease when VEGF was given before disease onset than when treatment was delayed. By use of stereological analysis, Carmeliet and co-workers also showed that motor-neuron degeneration was delayed in SOD1G93A/HWr rats treated with VEGF compared with the control group. Carmeliet told The Lancet Neurology, “our data show that intracerebroventricular delivery of VEGF is particularly effective in slowing degeneration of bulbar and cervical motor neurons”, and explained
“stronger effects on bulbar motor neurons may enable patients to communicate for a longer time with their family members”. However, cautions Jeffrey Rothstein (Johns Hopkins University, Baltimore, USA), to date these models have not been predictive of success in humans: “This is an animal model of the familial form of ALS, which occurs in only 1–2% of patients”. Serge Przedborski (Columbia University, USA) is also cautious to speculate about human response but both neurologists suggest that the work may have far-reaching implications.
Gillian Carmichael
Parkin gene therapy could treat Parkinson’s disease Rats engineered to overexpress human synuclein lose nigral neurons and have reduced striatal tyrosine hydroxylase (TH) activity. However, these abnormalities can be corrected by injecting a viral vector containing the parkin gene into the substantia nigra of these rats, according to new research by Patrick Aebischer (Swiss Federal Institute of Technology, EPFL, Lausanne, Switzerland) and colleagues.
JJ Hauw, ISM/Science Photo Library
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
synuclein is a component of Lewy bodies found in Parkinson’s disease
82
“These findings raise the possibility that parkin gene therapy could treat the subset of patients with Parkinson’s disease (PD) who have mutations in the -synuclein gene”, comments Mark Tuszynski, who was not involved in the study. “Further, if indeed parkin overexpression broadly corrects anatomical degeneration in the substantia nigra and striatum, this might be a potential therapy for any form of PD.” Parkin is thought to have a role in dopamine neuron survival because loss of parkin’s E3 ligase activity leads to dopaminergic neuronal degeneration in early onset autosomal recessive juvenile parkinsonism. To test the hypothesis that parkin has neuroprotective properties, Aebischer’s team developed a lentiviral vector that was capable of delivering the parkin gene. They then stereotaxically injected the viral vector into the substantia nigra of adult rats that overexpress synuclein. 6 weeks later they used immunocytochemistry to evaluate the expression of TH, synuclein, and parkin in the substantia nigra (Proc Natl Acad Sci USA 2004; 101: 17510–15). The researchers showed that animals that overexpressed parkin had
reduced -synuclein-induced pathology compared with normal control animals; the TH-positive cell bodies in the substantia nigra were preserved as were TH-positive nerve terminals in the striatum. However, rats injected with the viral vector had a large number of hyperphosphorylated -synuclein inclusions. “The obvious next step is to identify and test small molecules that induce parkin expression”, says Aebischer. “A gene therapy approach may also be considered as a significant number of dopaminergic nigral cells can be infected with viral vectors through a single nigral injection.” Tuszynski thinks the gene therapy approach is promising, but would like to know whether parkin gene therapy can correct motor abnormalities in animal models of PD. “These data were not reported in the paper”, he says, “and would be an important prerequisite to potential human trials”. He also wonders whether this approach would work in a neurotoxin models of PD, such as the MPTP or 6-hydroxy-dopamine lesion models.
James Butcher http://neurology.thelancet.com Vol 4 February 2005