- Email: [email protected]
Gene therapy to the rescue in Parkinson's disease
Research Update
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
103
Research News
Gene therapy to the rescue in Parkinson’s disease Allen S. Mandir, Valina L. Dawson and Ted M. Dawson Over a century ago, an influenza epidemic caused widespread parkinsonism; thus, it seems ironic that viral vectors might provide a new therapy for patients with Parkinson’s disease (PD). However, a recent study presents a series of elegant experiments that demonstrate the restorative and protective effects of a glial cell line-derived neurotrophic factor (GDNF), delivered by lentiviral vectors, in the brains of both old and parkinsonian primates. These techniques might hold promise for PD and other neurodegenerative disorders.
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder that primarily causes dopamine (DA)containing neurons to die and ultimately leads to slowness of movement, tremor, rigidity and problems with balance1,2. L-Dihydroxyphenylalanine (L-dopa), the precursor of DA, and DA agonists and related agents are the mainstay of treatment of PD and provide dramatic improvements early in the disease3. However, PD progresses and the efficacy of these medications over time is diminished and profound side-effects ensue. Thus, there is a great need for protective, regenerative and restorative therapy to slow or reverse the degenerative effects of PD. In a recent study4, Kordower and colleagues make a potential giant step forward by describing a gene-therapy approach for PD that restores function in a primate model of PD and rescues DAcontaining neurons from degeneration. Neurotrophic factors as a treatment of PD
Many investigations have focused on the development of neurotrophic factors for the treatment of PD; however, problems with delivery and bioavailability of neurotrophic factors have hampered efforts in this area5–7. In particular, these factors do not cross the blood–brain barrier and thus need to be administered directly to the brain, either intraparenchymally or intracerebroventricularly5–7. Although intraparenchymal or intracerebroventricular (i.c.v.)
administration of growth factors has had reasonable success in animal models of PD (Ref. 8), it has not been successful in clinical trials in PD patients9. However, following the advent of designer viruses, the capability of delivering neurotrophic factors directly to discrete areas of the brain is a reality and might provide a novel and important approach to restore function in PD (Refs 10,11). Lentiviral delivery of GDNF
Kordower and colleagues4 capitalized on the development and use of lentiviral vectors to deliver glial cell line-derived neurotrophic factor (GDNF) to neurons. GDNF is a potent and relatively selective trophic factor for CNS DA-containing neurons7,8 and lentiviruses provide sustained transgene expression and infect non-dividing cells including neurons12. In the study by Kordower et al., injections of GDNF-lentiviral vector (lenti-GDNF) were delivered into the DA-containing neurons within the substantia nigra and the DA-containing terminals within the striatum. Lenti-GDNF treatment of young rhesus macaques with a stable hemiparkinsonian state, induced by unilateral carotid injections of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), dramatically improved the functional capabilities of 75% of the surviving animals, whereas injection of the control vector expressing β-galactosidase (lenti-β-gal) had no significant effect. In addition, markers of DA function, such as imaging of fluorodopa uptake with positron emission tomography (PET) in living animals and postmortem analysis of tyrosine hydroxylase [TH (the rate limiting enzyme in the synthesis of DA)] immunoreactivity, were increased in the lenti-GDNF-treated monkeys compared with lenti-β-gal-treated animals. However, variability in the degree of TH immunoreactivity was noted in the striatum that was associated with the degree of functional recovery. The most striking finding was that all four lentiGDNF-treated parkinsonian animals showed a marked and significant increase
in the density of TH-immunoreactive neurons on the side ipsilateral to the MPTP injection, regardless of the degree of functional recovery. In aged rhesus monkeys, lenti-GDNF restored the ageassociated reductions in TH expression in the substantia nigra to levels similar to those observed in young adult animals. These findings are extremely important because they suggest that appropriate and effective delivery of GDNF can promote the survival and regeneration of DAcontaining neurons (Fig. 1). This is particularly relevant to the degenerative processes of PD because GDNF could restore function to ‘sick’ DA-containing neurons and protect the remaining functional neurons from degenerative cell death. Thus, lentiviral delivery of GDNF might offer an exciting new therapy for the restoration of function in PD. Clinical application of lentiviruses
Several important caveats need to be considered before this approach could be widely used in PD patients. Questions regarding the safety of lentiviruses need be addressed before human studies are undertaken because one animal from both the lenti-β-gal and lenti-GDNF groups died within one week after administration of the virus. Although no definitive cause of death was identified, necropsies revealed mild necrosis from multifocal random hepatocellular coagulation in both animals4. It is important to mention that no ill effects were observed on necropsy in the remaining surviving animals, nor were ill effects observed in other primate lentiviral studies. It is also not clear if lentiviral gene expression will last throughout the lifetime of a PD patient. Current therapies for PD allow patients to live normal life spans. In the study by Kordower et al., a benefit of at least eight months was demonstrated and even though this would have profound effects in PD patients, PD is a progressive disease and thus GDNF might need to be produced throughout the lifetime of a patient. Only 75% of the surviving animals showed functional improvements despite effective delivery and expression of GDNF;
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01638-2
Research Update
104
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
(a) Normal
(b) Parkinson’s disease or MPTP treatment Cerebral cortex Cerebral cortex
Caudate-putamen (striatum)
Caudate-putamen (striatum)
SNc SNc STN
LGP STN
LGP
MGP Thalamus
Glutamate Dopamine
MGP
SNr
Thalamus
SNr
Spinal cord Brain stem
SC RF
GABA Motor control
(c) Lenti-GDNF expression
Caudate-putamen Lenti-GDNF GDNF
New gene transcription, new protein synthesis (TH)
GDNF SNc
Lenti-GDNF
TRENDS in Pharmacological Sciences
Fig. 1. Schematic representation of the functional organization of neurons in various brain regions that are responsible for motor control in (a) normal brain function. Glutamate-mediated pathways are indicated in blue, dopamine (DA)-mediated pathways are indicated in orange and GABA-mediated pathways are indicated in pink. (b) Changes in the degree of activation of each signaling component are indicated by arrow thickness in patients with Parkinson’s disease (PD) or animals injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce experimental parkinsonism. A hallmark feature of idiopathic or experimental PD is the injury and loss of DA-containing neurons in the substantia nigra pars compacta (SNc). The loss of signal integration from this nucleus results in disregulation of the circuit leading to disruption of motor control. (c) Kordower and colleagues injected lentiviral vectors to deliver glial cell line-derived neurotrophic factor (GDNF) to the caudate-putamen and substantia nigra. Lenti-GDNF treatment results in increased expression of GDNF, which is taken up by neurons, transported to the nucleus and results in initiation of new gene transcription. Nerve terminals regenerate and DA synthesis is restored. With the restoration of tyrosine hydroxylase (TH) expression in the striatum, there was an associated improvement in functional recovery. These findings suggest that GDNF can not only promote the survival and regeneration of DA-containing neurons but can restore proper signal transduction in the basal ganglia circuit that controls movement. Abbreviations: LGP, lateral globus pallidus; MGP, medial globus pallidus; RF, parvicellular reticular formation; SC, superior colliculus; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.
thus, optimization of the timing and locations as well as the number of injections need to be clarified before human trials can begin. In rodent models of PD, GDNF injections into the substantia nigra alone http://tips.trends.com
tend to spare only DA-containing neurons, but do not restore DA concentrations in the striatum7,8. Striatal GDNF appears to be the most important for functional reinnervation to occur because in most
studies DA-containing terminals are spared and protection is conferred to DAcontaining neurons in the substantia nigra7,8. The effects of intrastriatal GDNF elicited in the substantia nigra are probably due to retrograde transport of GDNF (Refs 7,8). Thus, efforts might need to focus on the delivery of lenti-GDNF to DA-containing terminal fields, such as the striatum. Potential side-effects of GDNF also exist. In i.c.v. delivery experiments, a high dose of GDNF was associated with dyskinesias in MPTP-induced parkinsonian monkeys13, and unexplained weight loss has been encountered in monkeys receiving i.c.v. delivery of GDNF or delivery of GDNF directly to the substantia nigra. Furthermore, humans have experienced a variety of side-effects including nausea, loss of appetite, hallucinations and depression9. Thus, the ability to tightly control GDNF expression and/or activity might be required to fine-tune the actions of GDNF to optimize the therapeutic response and minimize potential side-effects. PD patients and clinicians have been anxiously awaiting the development of a proven and safe protective, regenerative and restorative therapy to slow or reverse the degenerative effects of PD, and lentiviral-mediated delivery of GDNF might fit the request. A few hurdles need to be overcome before its clinical use, but these can be readily addressed and overcome with further investigations and advances. Additionally, other vehicles might be able to deliver neurotrophic factors and neuroprotectants (e.g. engineered cells). Ultimately, the future looks bright for powerful new therapies for the treatment of PD, which might offer PD patients the protective, regenerative and restorative therapy to slow or reverse the degenerative effects of this disease. Furthermore, these approaches might be of value in other neurodegenerative diseases. References 1 Lang, A.E. and Lozano, A.M. (1998) Parkinson’s disease. First of two parts. New Engl. J. Med. 339, 1044–1053 2 Zhang, Y. et al. (2000) Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol. Dis. 7, 240–250 3 Lang, A.E. and Lozano, A.M. (1998) Parkinson’s disease. Second of two parts. New Engl. J. Med. 339, 1130–1143 4 Kordower, J.H. et al. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290, 767–773
Research Update
5 Mufson, E.J. et al. (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog. Neurobiol. 57, 451–484 6 Olson, L. (2000) Combating parkinson’s disease – step three. Science 290, 721–724 7 Walton, K.M. (1999) GDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Mol. Neurobiol. 19, 43–59 8 Grondin, R. and Gash, D.M. (1998) Glial cell linederived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson’s disease. J. Neurol. 245 (Suppl. 3), 35–42 9 Kordower, J.H. et al. (1999) Clinicopathological
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
10
11
12
13
findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann. Neurol. 46, 419–424 Bohn, M.C. (2000) Parkinson’s disease: a neurodegenerative disease particularly amenable to gene therapy. Mol. Ther. 1, 494–496 Latchman, D.S. and Coffin, R.S. (2000) Viral vectors in the treatment of Parkinson’s disease. Mov. Disord. 15, 9–17 Trono, D. (2000) Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Ther. 7, 20–23 Zhang, Z. et al. (1997) Dose response to intraventricular glial cell line-derived
105
neurotrophic factor administration in parkinsonian monkeys. J. Pharmacol. Exp. Ther. 282, 1396–1401
Allen S. Mandir Dept of Neurology Valina L. Dawson Depts of Neurology, Neuroscience & Physiology Ted M. Dawson* Depts of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 214, Baltimore, MD 21287, USA. *e-mail: [email protected]
Gene therapy to the rescue in Parkinson’s disease Response from Kordower and Aebischer Mandir and colleagues review our recent study demonstrating the ability of lentiviral (lenti)-vector-delivered glial cell line-derived neurotrophic factor (GDNF) to reverse and prevent the structural and functional correlates of nigrostriatal degeneration in nonhuman primate models of Parkinson’s disease (PD). Unlike other surgical therapies for this disease, this gene-therapy approach is directed at stopping the underlying disease process and not just at providing symptomatic benefit. This is its power. Mandir and colleagues accurately describe that lenti-GDNF: (1) resulted in robust and nontoxic transgene expression for up to eight months; (2) prevented the manifestation of motor deficits that normally occur following the intracarotid injection of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP); (3) prevented the destruction of the nigrostriatal system in MPTP-treated monkeys; and (4) induced regeneration of dopaminecontaining fibers and augmented the nigrostriatal dopamine system in aged rhesus monkeys. These findings, combined with a consensus from basic science studies illustrating the success of virally delivered GDNF in other animal models in PD (Ref. 1), contrast with the recent findings described in a PD patient who received intracerebroventricular injections of GDNF (Ref. 2). This latter treatment failed to manifest clinical benefit or nigrostriatal regeneration. This failure was probably due to the delivery method of the trophic factor because GDNF is not able to reach nigrostriatal neurons in appreciable concentrations
following intraventricular administration. Taken together, these data highlight the need for chronic intraparenchymal delivery of GDNF in a site-specific fashion. Viral delivery of GDNF allows for an easy means to do just that. Mandir and colleagues suggest that ‘optimization of the timing and locations as well as the number of injections need to be clarified before human trials can begin’. We both agree and disagree. Phase I clinical trials are safety trials and parameters related to optimized efficacy need not be in place before their initiation. Indeed, it is likely that suboptimal parameters such as lower gene dosing, and unilateral injections into fewer than anticipated sites might be purposely chosen initially. Optimizing specific parameters will be more crucial when and if Phase II studies are contemplated. Still, we strongly believe that no vector should be employed clinically in patients with PD without the ability to control gene expression. Thus, vector systems with ‘on’ or ‘off ’ switches need to be in place. Systems that employ tetracycline control should provide the adequate pharmacokinetic and safety profile needed for use of lentiviral vectors in the nervous system3. It is crucial that preclinical data not only demonstrate the ability to turn off the gene, but that this ‘off ’ switch reverses the biological effects of the trophic factor. Thus, if unexpected side-effects occur following gene delivery in patients, shutting off the gene using a controllable promoter should be able to reverse the side-effect. Although this safety feature should be in place before the initiation of
clinical trials, we are very encouraged by the fact that no preclinical gene-transfer experiments, including our own, reported serious adverse events associated with GDNF expression. The two monkeys that died in our study, and discussed by Mandir et al., apparently died from events related to MPTP toxicity and not lentiviral gene delivery. Another parameter that is crucial for PD gene therapy relates to the patient population chosen for study. Our data indicate that both regeneration and neuroprotection of nigrostriatal systems occur following lenti-GDNF. Thus, recipients with the most residual nigrostriatal system, namely those patients in which PD is less advanced, would benefit most from this procedure. The converse might also be true: patients with more advanced disease and fewer residual nigrostriatal neurons would probably receive less benefit from lentiGDNF. Whether patients who are in the early stages of the disease would be interested in, and/or deemed appropriate for, the initial clinical trials remains to be established. If experiments are initiated in patients in which the disease is more advanced, as tends to be the case with novel clinical trials, the advanced degeneration of their nigrostriatal system would diminish the likelihood that efficacy would be achieved. The potency and consistency of our results, together with the compatibility of our neuroanatomical and functional findings, suggest that such lentiviral gene therapy for PD is an exciting prospect. Indeed, gene therapy for PD is progressing
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01637-0
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
103
Research News
Gene therapy to the rescue in Parkinson’s disease Allen S. Mandir, Valina L. Dawson and Ted M. Dawson Over a century ago, an influenza epidemic caused widespread parkinsonism; thus, it seems ironic that viral vectors might provide a new therapy for patients with Parkinson’s disease (PD). However, a recent study presents a series of elegant experiments that demonstrate the restorative and protective effects of a glial cell line-derived neurotrophic factor (GDNF), delivered by lentiviral vectors, in the brains of both old and parkinsonian primates. These techniques might hold promise for PD and other neurodegenerative disorders.
Parkinson’s disease (PD) is a common progressive neurodegenerative disorder that primarily causes dopamine (DA)containing neurons to die and ultimately leads to slowness of movement, tremor, rigidity and problems with balance1,2. L-Dihydroxyphenylalanine (L-dopa), the precursor of DA, and DA agonists and related agents are the mainstay of treatment of PD and provide dramatic improvements early in the disease3. However, PD progresses and the efficacy of these medications over time is diminished and profound side-effects ensue. Thus, there is a great need for protective, regenerative and restorative therapy to slow or reverse the degenerative effects of PD. In a recent study4, Kordower and colleagues make a potential giant step forward by describing a gene-therapy approach for PD that restores function in a primate model of PD and rescues DAcontaining neurons from degeneration. Neurotrophic factors as a treatment of PD
Many investigations have focused on the development of neurotrophic factors for the treatment of PD; however, problems with delivery and bioavailability of neurotrophic factors have hampered efforts in this area5–7. In particular, these factors do not cross the blood–brain barrier and thus need to be administered directly to the brain, either intraparenchymally or intracerebroventricularly5–7. Although intraparenchymal or intracerebroventricular (i.c.v.)
administration of growth factors has had reasonable success in animal models of PD (Ref. 8), it has not been successful in clinical trials in PD patients9. However, following the advent of designer viruses, the capability of delivering neurotrophic factors directly to discrete areas of the brain is a reality and might provide a novel and important approach to restore function in PD (Refs 10,11). Lentiviral delivery of GDNF
Kordower and colleagues4 capitalized on the development and use of lentiviral vectors to deliver glial cell line-derived neurotrophic factor (GDNF) to neurons. GDNF is a potent and relatively selective trophic factor for CNS DA-containing neurons7,8 and lentiviruses provide sustained transgene expression and infect non-dividing cells including neurons12. In the study by Kordower et al., injections of GDNF-lentiviral vector (lenti-GDNF) were delivered into the DA-containing neurons within the substantia nigra and the DA-containing terminals within the striatum. Lenti-GDNF treatment of young rhesus macaques with a stable hemiparkinsonian state, induced by unilateral carotid injections of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), dramatically improved the functional capabilities of 75% of the surviving animals, whereas injection of the control vector expressing β-galactosidase (lenti-β-gal) had no significant effect. In addition, markers of DA function, such as imaging of fluorodopa uptake with positron emission tomography (PET) in living animals and postmortem analysis of tyrosine hydroxylase [TH (the rate limiting enzyme in the synthesis of DA)] immunoreactivity, were increased in the lenti-GDNF-treated monkeys compared with lenti-β-gal-treated animals. However, variability in the degree of TH immunoreactivity was noted in the striatum that was associated with the degree of functional recovery. The most striking finding was that all four lentiGDNF-treated parkinsonian animals showed a marked and significant increase
in the density of TH-immunoreactive neurons on the side ipsilateral to the MPTP injection, regardless of the degree of functional recovery. In aged rhesus monkeys, lenti-GDNF restored the ageassociated reductions in TH expression in the substantia nigra to levels similar to those observed in young adult animals. These findings are extremely important because they suggest that appropriate and effective delivery of GDNF can promote the survival and regeneration of DAcontaining neurons (Fig. 1). This is particularly relevant to the degenerative processes of PD because GDNF could restore function to ‘sick’ DA-containing neurons and protect the remaining functional neurons from degenerative cell death. Thus, lentiviral delivery of GDNF might offer an exciting new therapy for the restoration of function in PD. Clinical application of lentiviruses
Several important caveats need to be considered before this approach could be widely used in PD patients. Questions regarding the safety of lentiviruses need be addressed before human studies are undertaken because one animal from both the lenti-β-gal and lenti-GDNF groups died within one week after administration of the virus. Although no definitive cause of death was identified, necropsies revealed mild necrosis from multifocal random hepatocellular coagulation in both animals4. It is important to mention that no ill effects were observed on necropsy in the remaining surviving animals, nor were ill effects observed in other primate lentiviral studies. It is also not clear if lentiviral gene expression will last throughout the lifetime of a PD patient. Current therapies for PD allow patients to live normal life spans. In the study by Kordower et al., a benefit of at least eight months was demonstrated and even though this would have profound effects in PD patients, PD is a progressive disease and thus GDNF might need to be produced throughout the lifetime of a patient. Only 75% of the surviving animals showed functional improvements despite effective delivery and expression of GDNF;
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01638-2
Research Update
104
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
(a) Normal
(b) Parkinson’s disease or MPTP treatment Cerebral cortex Cerebral cortex
Caudate-putamen (striatum)
Caudate-putamen (striatum)
SNc SNc STN
LGP STN
LGP
MGP Thalamus
Glutamate Dopamine
MGP
SNr
Thalamus
SNr
Spinal cord Brain stem
SC RF
GABA Motor control
(c) Lenti-GDNF expression
Caudate-putamen Lenti-GDNF GDNF
New gene transcription, new protein synthesis (TH)
GDNF SNc
Lenti-GDNF
TRENDS in Pharmacological Sciences
Fig. 1. Schematic representation of the functional organization of neurons in various brain regions that are responsible for motor control in (a) normal brain function. Glutamate-mediated pathways are indicated in blue, dopamine (DA)-mediated pathways are indicated in orange and GABA-mediated pathways are indicated in pink. (b) Changes in the degree of activation of each signaling component are indicated by arrow thickness in patients with Parkinson’s disease (PD) or animals injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce experimental parkinsonism. A hallmark feature of idiopathic or experimental PD is the injury and loss of DA-containing neurons in the substantia nigra pars compacta (SNc). The loss of signal integration from this nucleus results in disregulation of the circuit leading to disruption of motor control. (c) Kordower and colleagues injected lentiviral vectors to deliver glial cell line-derived neurotrophic factor (GDNF) to the caudate-putamen and substantia nigra. Lenti-GDNF treatment results in increased expression of GDNF, which is taken up by neurons, transported to the nucleus and results in initiation of new gene transcription. Nerve terminals regenerate and DA synthesis is restored. With the restoration of tyrosine hydroxylase (TH) expression in the striatum, there was an associated improvement in functional recovery. These findings suggest that GDNF can not only promote the survival and regeneration of DA-containing neurons but can restore proper signal transduction in the basal ganglia circuit that controls movement. Abbreviations: LGP, lateral globus pallidus; MGP, medial globus pallidus; RF, parvicellular reticular formation; SC, superior colliculus; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.
thus, optimization of the timing and locations as well as the number of injections need to be clarified before human trials can begin. In rodent models of PD, GDNF injections into the substantia nigra alone http://tips.trends.com
tend to spare only DA-containing neurons, but do not restore DA concentrations in the striatum7,8. Striatal GDNF appears to be the most important for functional reinnervation to occur because in most
studies DA-containing terminals are spared and protection is conferred to DAcontaining neurons in the substantia nigra7,8. The effects of intrastriatal GDNF elicited in the substantia nigra are probably due to retrograde transport of GDNF (Refs 7,8). Thus, efforts might need to focus on the delivery of lenti-GDNF to DA-containing terminal fields, such as the striatum. Potential side-effects of GDNF also exist. In i.c.v. delivery experiments, a high dose of GDNF was associated with dyskinesias in MPTP-induced parkinsonian monkeys13, and unexplained weight loss has been encountered in monkeys receiving i.c.v. delivery of GDNF or delivery of GDNF directly to the substantia nigra. Furthermore, humans have experienced a variety of side-effects including nausea, loss of appetite, hallucinations and depression9. Thus, the ability to tightly control GDNF expression and/or activity might be required to fine-tune the actions of GDNF to optimize the therapeutic response and minimize potential side-effects. PD patients and clinicians have been anxiously awaiting the development of a proven and safe protective, regenerative and restorative therapy to slow or reverse the degenerative effects of PD, and lentiviral-mediated delivery of GDNF might fit the request. A few hurdles need to be overcome before its clinical use, but these can be readily addressed and overcome with further investigations and advances. Additionally, other vehicles might be able to deliver neurotrophic factors and neuroprotectants (e.g. engineered cells). Ultimately, the future looks bright for powerful new therapies for the treatment of PD, which might offer PD patients the protective, regenerative and restorative therapy to slow or reverse the degenerative effects of this disease. Furthermore, these approaches might be of value in other neurodegenerative diseases. References 1 Lang, A.E. and Lozano, A.M. (1998) Parkinson’s disease. First of two parts. New Engl. J. Med. 339, 1044–1053 2 Zhang, Y. et al. (2000) Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol. Dis. 7, 240–250 3 Lang, A.E. and Lozano, A.M. (1998) Parkinson’s disease. Second of two parts. New Engl. J. Med. 339, 1130–1143 4 Kordower, J.H. et al. (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290, 767–773
Research Update
5 Mufson, E.J. et al. (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog. Neurobiol. 57, 451–484 6 Olson, L. (2000) Combating parkinson’s disease – step three. Science 290, 721–724 7 Walton, K.M. (1999) GDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Mol. Neurobiol. 19, 43–59 8 Grondin, R. and Gash, D.M. (1998) Glial cell linederived neurotrophic factor (GDNF): a drug candidate for the treatment of Parkinson’s disease. J. Neurol. 245 (Suppl. 3), 35–42 9 Kordower, J.H. et al. (1999) Clinicopathological
TRENDS in Pharmacological Sciences Vol.22 No.3 March 2001
10
11
12
13
findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann. Neurol. 46, 419–424 Bohn, M.C. (2000) Parkinson’s disease: a neurodegenerative disease particularly amenable to gene therapy. Mol. Ther. 1, 494–496 Latchman, D.S. and Coffin, R.S. (2000) Viral vectors in the treatment of Parkinson’s disease. Mov. Disord. 15, 9–17 Trono, D. (2000) Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Ther. 7, 20–23 Zhang, Z. et al. (1997) Dose response to intraventricular glial cell line-derived
105
neurotrophic factor administration in parkinsonian monkeys. J. Pharmacol. Exp. Ther. 282, 1396–1401
Allen S. Mandir Dept of Neurology Valina L. Dawson Depts of Neurology, Neuroscience & Physiology Ted M. Dawson* Depts of Neurology and Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Carnegie 214, Baltimore, MD 21287, USA. *e-mail: [email protected]
Gene therapy to the rescue in Parkinson’s disease Response from Kordower and Aebischer Mandir and colleagues review our recent study demonstrating the ability of lentiviral (lenti)-vector-delivered glial cell line-derived neurotrophic factor (GDNF) to reverse and prevent the structural and functional correlates of nigrostriatal degeneration in nonhuman primate models of Parkinson’s disease (PD). Unlike other surgical therapies for this disease, this gene-therapy approach is directed at stopping the underlying disease process and not just at providing symptomatic benefit. This is its power. Mandir and colleagues accurately describe that lenti-GDNF: (1) resulted in robust and nontoxic transgene expression for up to eight months; (2) prevented the manifestation of motor deficits that normally occur following the intracarotid injection of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP); (3) prevented the destruction of the nigrostriatal system in MPTP-treated monkeys; and (4) induced regeneration of dopaminecontaining fibers and augmented the nigrostriatal dopamine system in aged rhesus monkeys. These findings, combined with a consensus from basic science studies illustrating the success of virally delivered GDNF in other animal models in PD (Ref. 1), contrast with the recent findings described in a PD patient who received intracerebroventricular injections of GDNF (Ref. 2). This latter treatment failed to manifest clinical benefit or nigrostriatal regeneration. This failure was probably due to the delivery method of the trophic factor because GDNF is not able to reach nigrostriatal neurons in appreciable concentrations
following intraventricular administration. Taken together, these data highlight the need for chronic intraparenchymal delivery of GDNF in a site-specific fashion. Viral delivery of GDNF allows for an easy means to do just that. Mandir and colleagues suggest that ‘optimization of the timing and locations as well as the number of injections need to be clarified before human trials can begin’. We both agree and disagree. Phase I clinical trials are safety trials and parameters related to optimized efficacy need not be in place before their initiation. Indeed, it is likely that suboptimal parameters such as lower gene dosing, and unilateral injections into fewer than anticipated sites might be purposely chosen initially. Optimizing specific parameters will be more crucial when and if Phase II studies are contemplated. Still, we strongly believe that no vector should be employed clinically in patients with PD without the ability to control gene expression. Thus, vector systems with ‘on’ or ‘off ’ switches need to be in place. Systems that employ tetracycline control should provide the adequate pharmacokinetic and safety profile needed for use of lentiviral vectors in the nervous system3. It is crucial that preclinical data not only demonstrate the ability to turn off the gene, but that this ‘off ’ switch reverses the biological effects of the trophic factor. Thus, if unexpected side-effects occur following gene delivery in patients, shutting off the gene using a controllable promoter should be able to reverse the side-effect. Although this safety feature should be in place before the initiation of
clinical trials, we are very encouraged by the fact that no preclinical gene-transfer experiments, including our own, reported serious adverse events associated with GDNF expression. The two monkeys that died in our study, and discussed by Mandir et al., apparently died from events related to MPTP toxicity and not lentiviral gene delivery. Another parameter that is crucial for PD gene therapy relates to the patient population chosen for study. Our data indicate that both regeneration and neuroprotection of nigrostriatal systems occur following lenti-GDNF. Thus, recipients with the most residual nigrostriatal system, namely those patients in which PD is less advanced, would benefit most from this procedure. The converse might also be true: patients with more advanced disease and fewer residual nigrostriatal neurons would probably receive less benefit from lentiGDNF. Whether patients who are in the early stages of the disease would be interested in, and/or deemed appropriate for, the initial clinical trials remains to be established. If experiments are initiated in patients in which the disease is more advanced, as tends to be the case with novel clinical trials, the advanced degeneration of their nigrostriatal system would diminish the likelihood that efficacy would be achieved. The potency and consistency of our results, together with the compatibility of our neuroanatomical and functional findings, suggest that such lentiviral gene therapy for PD is an exciting prospect. Indeed, gene therapy for PD is progressing
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0165-6147(00)01637-0