Emerging and Experimental Neurosurgical Treatments for Parkinson’s Disease

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CHAPTER 84 Emerging and Experimental Neurosurgical Treatments for Parkinson’s Disease

Idiopathic Parkinson’s disease (PD) affects more than 1 million North Americans, including approximately 1% of individuals older than 65 years. PD is the second most common neurodegenerative disease after Alzheimer’s, and neurodegenerative diseases as a whole are projected to surpass cancer as the second leading cause of death in the elderly by 2040.1 With a protracted course of progressive disability and dependence on others, increased mortality, and a total estimated cost of $23 billion a year in the United States, PD represents a significant ongoing burden to society.24

PD is diagnosed on clinical grounds, with resting tremor, rigidity, bradykinesia or akinesia, and postural instability representing the cardinal features of the disease.5 Other important manifestations can include dementia, gait disturbance, autonomic dysfunction, and depression. Neuropathologically, PD is characterized by widespread degeneration of select sites within the central and peripheral nervous systems.6,7 Although this multisystem disorder affects many brain regions and neurotransmitter systems, the loss of dopaminergic neurons within the substantia nigra pars compacta (SNc) accounts for the reduction in striatal dopaminergic innervation that underlies the symptoms of akinesia and rigidity.8 Widespread accumulation of proteinaceous Lewy bodies and Lewy neurites is also observed in PD. In the central nervous system, these deposits accumulate in predictable stages with progressive involvement of brainstem, subcortical, and neocortical regions.9 However, the relationship of these deposits to the pathogenesis of PD remains unclear.5,10 Although numerous mechanisms underlying the neurodegeneration seen in PD have been proposed, none has provided a definitive explanation of its pathogenesis.

Since their introduction more than 40 years ago, dopaminergic agents have been the mainstay of treatment for the motor symptoms of PD. More than 90% of patients initially respond well to levodopa therapy, with the majority continuing to derive some benefit throughout the course of the disease.5 Unfortunately, progressive treatment resistance, coupled with the gradual development of motor fluctuations, dyskinesias, and psychiatric disturbances, limits levodopa’s long-term use.11,12 Other agents such as dopamine agonists, anticholinergics, amantadine, and monoamine oxidase inhibitors generally yield minimal benefit and may induce unpalatable side effects.12 Clinical features of advanced PD such as postural and gait dysfunction are particularly resistant to dopamine-based therapies, suggesting a greater involvement of nondopaminergic pathways in their pathophysiology.13,14 Importantly, no pharmacotherapy has been able to alter disease progression.

The shortcomings of pharmacotherapy and the growing understanding of the pathophysiologic correlates of parkinsonism have led to a resurgence in stereotactic and functional neurosurgery for PD over the past two decades. Targeted lesioning and deep brain stimulation (DBS) at the thalamus, globus pallidus, and subthalamic nucleus have proved to be valuable additions to our therapeutic armamentarium.15 At present, surgery is reserved for medically intractable cases when tremor is a major source of disability or when levodopa-responsive patients are experiencing significant “on-off” cycling between rigidity or bradykinesia and levodopa-induced dyskinesias.16 Although highly efficacious in properly selected patients, the benefits of stereotactic surgery are limited mainly to improving rigidity, tremor, “off-state” akinesia, and levodopa-induced dyskinesias. There is little or no effect on other manifestations of the disease.15 In addition, the benefit of surgery remains symptomatic in nature, without altering the natural history of the disease.

Therefore, our present therapeutic armamentarium could be improved in a number of ways. First, making DBS more effective and safer would allow more patients to be treated and to undergo surgery earlier in the disease course. Second, new treatments could address the many symptomatic features of PD that remain poorly treated or are not affected at all by current therapies. Third, disease-modifying treatments could deter disease progression. The following sections outline experimental and emerging neurosurgical treatments whose development has been geared specifically toward closing these gaps in our current treatment options and ultimately achieving the elusive goal of modifying the natural history of PD through neuroprotection or neuroregeneration. DBS-related strategies, motor cortex stimulation, growth factor delivery, gene therapy, and cellular replenishment are discussed, with reference to currently available clinical data (Fig. 84-1).

New Strategies for Deep Brain Stimulation

In properly selected patients, and when appropriate resources are available, high-frequency DBS of the subthalamic nucleus (STN) or internal globus pallidus (GPi) is the surgical treatment of choice for PD.17 Clinical outcomes and surgical techniques are now well established, with more than 30,000 patients treated worldwide.15 Armed with this baseline knowledge and experience, attempts to improve the utility of DBS in PD through early surgery and novel targets are ongoing.

Early Surgery

The observation that STN inactivation prevents nigral degeneration in rodent models of PD18,19 led investigators to consider the possibility that, in addition to its symptomatic benefits, subthalamic DBS might be neuroprotective in humans. The neuroprotective mechanism was thought to be reduced excitotoxin-induced nigral degeneration, mediated by the glutamatergic projections from the STN to the nigra.20,21 To examine this, Hilker and coworkers22 used 18F-fluorodopa (F-dopa) positron emission tomography (PET), which quantifies presynaptic dopaminergic function,2325 to study the progression of PD after high-frequency STN-DBS. Although the study did not include controls, the annual striatal reduction in F-dopa uptake in 30 STN-DBS–treated patients with advanced PD was roughly 10% to 12%, which is consistent with previously reported rates in PD.26 This evidence, along with clinical experience, suggests that the neuroprotective effects seen in animal models cannot be readily confirmed in humans.

It remains uncertain whether a neuroprotective effect of high-frequency STN-DBS might be observed if patients were treated early in the course of their disease. Patients with advanced PD may no longer harbor the capacity to alter the course of degeneration, whereas the striatum of patients in the early stages of the disease might be more apt to gain a survival benefit from a reduction in STN-mediated glutamatergic input. In March 2006, a phase I trial of early surgery in PD began under the supervision of Dr. Charles at Vanderbilt University.27 The hypothesis of this study is that STN-DBS slows disease progression in subjects with early PD. In this single-center study, which is expected to be completed in 2010, eligible patients who have received dopaminergic therapy for less than 4 years are randomized to surgery plus medical therapy versus medical therapy alone. Motor outcomes are assessed in a single-blind fashion. A multicenter phase III trial is planned if safety and tolerability criteria are met.

Another line of investigation suggests that early surgery in patients suffering from motor fluctuations or dyskinesias may promote the maintenance of quality of life and social functioning.28 The mean time from PD diagnosis to surgery is more than 10 years; however, dopamine-related motor fluctuations and dyskinesias may arise much sooner and typically contribute to a progressive decline in social and occupational function.29 Early reports suggest that patients with a disease duration of less than 10 years who have undergone operation can maintain a baseline involvement in their work and personal lives postoperatively.28 Schüpbach and associates30 performed a matched-pairs study of 20 PD patients with a mean symptom duration of 7 years, comparing functional outcomes in patients receiving DBS versus best medical therapy. Eighteen months postoperatively, the surgical patients experienced a 24% improvement in disease-specific quality of life versus 0% in the nonsurgical patients. The principal investigator of this study, Dr. Agid, is now leading a multicenter, randomized, open-label, phase III trial (EARLYSTIM Study) examining quality of life outcomes in patients with STN-DBS versus medical therapy, with 2-year follow-up data expected in 2010.27 This promises to offer further insight into the potential benefits of early surgery.

A New Target: The Pedunculopontine Nucleus

Postural and gait dysfunction leading to falls is the leading cause of emergency room visits and is a significant cost generator in the care of PD patients.3133 In addition, the fear of falling results in depression and a loss of independence.34 Postural and gait dysfunction is particularly resistant to current dopaminergic and surgical therapies, suggesting a greater involvement of nondopaminergic pathways and brain loci other than the pallidal and subthalamic nuclei in their pathophysiology.13,14,3541

The pedunculopontine nucleus (PPN) is part of a brainstem locomotive center that also processes sensory and behavioral information. Running roughly between the SNc and locus caeruleus, the PPN primarily connects with basal ganglia structures and the spinal cord.42,43 Midfrequency electrical or glutamatergic stimulation of the PPN leads to increased activity of its neuronal population and produces controlled locomotion on a treadmill in decerebrate animals.44,45 Other neurotransmitters, including γ-aminobutyric acid (GABA) and acetylcholine, decrease PPN activity and inhibit locomotion.42 It has been theorized that the PPN regulates tone and locomotion by modulating lower brainstem nuclei.46,47 These nuclei, in turn, activate central pattern generators in the spinal cord, which generate the motor patterns governing locomotion and limb tone.4750 Given the evidence for the PPN’s role in the initiation and maintenance of gait and the stability of postural tone, as well as its pharmacologic and electrophysiologic properties that appear to be reliant on cholinergic and other nondopaminergic neurotransmitters, pathologic function related to this structure could theoretically play a significant role in the gait and postural manifestations of PD.42

Although direct evidence linking PPN dysfunction to PD-related postural and gait disturbances is lacking, there are several hints at a pathophysiologic connection. The PPN in anesthetized rats with hydroxydopamine (6-OHDA) nigral lesions is characterized by abnormally enhanced activity compared with controls.51 Furthermore, some of the electrophysiologic changes recorded in the basal ganglia structures of these PD-model animals could be reversed by PPN lesions.52,53 Matsumura and Kojima54 observed a smaller degree of nigral degeneration and fewer parkinsonian symptoms if monkeys with 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) lesions were given PPN lesions. Similarly, Nandi and colleagues55 showed that microinjections of the GABAergic antagonist bicuculline into the PPN improve parkinsonian symptoms in MPTP primates. Electrophysiologic changes have been matched to metabolic alterations in the PPN of parkinsonian rodents and nonhuman primates.56,57 More important, studies of human pathology demonstrate that a significant proportion of the large cholinergic PPN neurons degenerate in PD.5860 These individual lines of evidence collectively invoke the possibility that PD-related degeneration of nondopaminergic PPN neurons leads to electrophysiologic and metabolic disturbances that culminate in the dysregulation of PPN-mediated gait and postural functions. Therefore, medical or surgical interventions that modulate PPN activity in PD patients might normalize gait initiation and maintenance and postural stability.

Following this hypothesis, DBS of the PPN is being evaluated as a therapeutic modality in PD patients with significant gait disturbance (Fig. 84-2).6163 Initial subjects have included PD patients with refractory and functionally significant impairment of gait initiation (debilitating freezing) and postural stability (associated with an unacceptable risk of falling). Those suffering from comorbidities that might adversely affect gait and posture, including dementia, primary affective disorders, and marked sensory impairments, are considered poor candidates for PPN stimulation.6467

Initial reports of PPN-DBS in PD patients documented the technical aspects and electrophysiologic findings of the procedure, as well as short-term indicators of clinical outcome.61,62 A more recent study provided greater insight into the clinical outcome of six patients who underwent simultaneous bilateral PPN- and STN-DBS.63 Six months after surgery, Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores in the “off-medication–on-stimulation” condition were improved by an average of 33% with PPN-DBS alone. This was less than the improvement obtained from STN-DBS alone (54%) or simultaneous STN- and PPN-DBS (56%) in these same patients. Improvements specifically in axial symptoms (e.g., rising from a chair, posture, gait, postural stability) were similar with PPN-only, STN-only, and simultaneous PPN- and STN-DBS (60% to 70%). In patients taking medication, Stefani and colleagues63 found a greater improvement in UPDRS motor scores with combined STN and PPN stimulation compared with stimulation at either target alone. Moreover, STN-only stimulation did not improve axial symptoms in patients who were taking medication. If only axial symptoms were taken into account in the on-medication condition, both PPN-only DBS and simultaneous PPN- and STN-DBS led to a 50% to 60% improvement versus no stimulation. Importantly, no major complications were described. The only minor side effect reported was paresthesias associated with high-frequency PPN stimulation, likely resulting from the target’s proximity to the medial lemniscus.63 In summary, reports suggest the possibility of a therapeutic response to low-frequency PPN stimulation, but larger controlled studies are needed to verify these results and define its potential role in the treatment of PD.

Motor Cortex Stimulation

The concept of therapeutic modulation of cortical activity in movement disorders arose following James Parkinson’s description of the temporary abolishment of a tremor following a cortical stroke in 1824.68 Reports in the mid-1900s described improvements in posttraumatic and parkinsonian tremors following motor cortex or corticospinal tract lesioning.69,70 More recently (1979), Woolsey and colleagues71 observed immediate and temporary improvements in rigidity and tremor in PD patients undergoing intraoperative motor cortex stimulation (MCS) for the purpose of brain mapping, and several reports have described a simultaneous improvement of tremor in patients undergoing MCS for the treatment of pain.7274

Further support for the attempt to modulate cortical activity in PD patients comes from evidence linking the disease to regional cortical dysfunction. Functional neuroimaging and electroencephalography in PD patients demonstrate hypoactivity in the supplementary motor area and dorsolateral prefrontal cortex.7584 Interestingly, MPTP monkeys receiving chronic MCS (cMCS) exhibited a reversal of hypoactivity in the supplementary motor area and an improvement in akinesia.85 Changes in motor cortical activity are also observed in PD patients, with reduced activity early in the disease and increased activity in advanced disease.78,79,86,87 Although this variation remains poorly understood, hyperactivity may reflect compensatory cortical reorganization resulting from an increasingly deficient subcortical motor system, and it has been theorized to promote the development of levodopa-induced dyskinesias.88

Based on the observation of abnormal motor cortex activity in PD and clinical reports suggesting an acute benefit from MCS, a rationale emerged for investigating the use of cMCS in PD. Both theoretical predictions and experimental results suggested that cMCS might exert orthodromic or antidromic effects on subcortical elements of corticobasal ganglia loops (Fig. 84-3).85,8991 STN-DBS in PD patients evokes short-latency responses, improves movement-related asynchrony, restores intracortical inhibition, and decreases resting activity in the human motor cortex.9298 Similarly, the motor cortices can affect basal ganglia activities. Microelectrode recordings in MPTP monkeys receiving cMCS show substantial normalization of the mean firing rate and less abnormal synchronized oscillatory activity of GPi and STN neurons.85 In humans with PD, MCS using a single pulse of transcranial magnetic stimulation (TMS) evokes short-latency excitation, followed by long-lasting inhibition, of neurons located in the dorsolateral sensorimotor area of the STN.91 PET studies also demonstrate that MCS using 10-Hz TMS induces focal dopamine release within the ipsilateral dorsal striatum.89,90

Attempts to deliver cMCS to PD patients has been driven by the search for less invasive alternatives to DBS. In particular, a therapeutic void exists for patients with disabling motor symptoms who are deemed ineligible for DBS surgery based on their age (typically, older than 70 years) or other surgical risk factors. To date, cMCS has been attempted in PD patients using TMS as well as surgically implanted epidural or subdural stimulating electrodes.

Epidural and Subdural Electrodes

Internalized epidural and subdural electrodes provide titratable systems with relatively precise target specificity, allowing focal stimulation while avoiding the greater risk of intraparenchymal placement. Since 2000, five reports have described 19 patients with advanced PD who were treated with epidural or subdural cMCS (Table 84-1).99103 Although these publications collectively suggest a trend toward varying degrees of improvement across all clinically relevant motor domains, the modest benefits reported remain unconvincing. One poorly understood finding is the relatively consistent occurrence of bilateral improvement in symptoms despite unilateral cMCS, a phenomenon that is generally not observed with DBS. Further evidence indicates that cMCS in PD patients produces no alteration in movement-related regional cerebral blood flow as measured by PET scans, casting further doubt on its potential utility in PD.104 An additional report investigated the use of subdural cMCS for multiple system atrophy with predominant parkinsonism, a rapidly progressive neurodegenerative disease that shares some motor features with PD but for which treatments are generally ineffective.105 In the five patients studied, neither low- nor high-frequency stimulation had any benefit. Larger studies in appropriate patients may better define the efficacy and potential indications for epidural and subdural cMCS in PD. At the time of this writing, additional small phase I-II randomized, controlled, and crossover clinical trials investigating cMCS in PD are ongoing in France and Italy, with expected completion in the next couple of years.27

Transcranial Magnetic Stimulation

TMS is a noninvasive technique that induces changes in cortical activity through electromagnetic induction (see Fig. 84-3). Repetitive TMS (rTMS) delivered to the motor cortex at 5 to 25 Hz improves motor performance in PD patients.106111 A recent systematic review of noninvasive neurostimulation in PD pooled the results from eight double-blind, sham-controlled studies of rTMS involving patients with a mean age and disease duration of 63 and 7 years, respectively. The standardized mean difference in pre- and posttreatment UPDRS scores was a modest 0.60 (95% confidence interval, 0.24 to 0.96), with no significant heterogeneity. Moreover, the longevity of this modest effect is uncertain, given the less than 2 months of follow-up.112 Frequencies of approximately 1 Hz applied to the supplementary motor area worsened motor performance but improved levodopa-induced dyskinesias.113,114 One interesting study demonstrated a concomitant increase in motor performance and relief of depression with rTMS applied to the dorsolateral prefrontal cortex, raising the possibility that modulating cortical activity might address the often debilitating comorbid depression that is often observed in patients with advancing PD.115 Other studies have failed to demonstrate any motor benefits with stimulation at the dorsolateral prefrontal cortex.116118 Despite the appeal of its minimal invasiveness, the modest demonstrated efficacy of TMS and the practical issues involved in using it over a long period may ultimately limit its clinical utility.

Intraparenchymal Growth Factor Delivery

Glial cell line–derived neurotrophic factor (GDNF) is a neurotrophin protein that belongs to the transforming growth factor-β superfamily.119 Along with other cell types, dopaminergic neurons respond to GDNF through cell signaling pathways and react with enhanced growth, survival, differentiation, and regeneration.119 The cerebral administration of GDNF through viral vector delivery, intracerebroventricular infusion, or putaminal injection in rodent and nonhuman primate models of PD imparts neuroprotective and neuroregenerative effects.120124 In addition, 6-OHDA rodents and MPTP primates demonstrate motor performance improvements following GDNF therapy.122,124127

Based on these findings and the need to develop disease-modifying therapies for PD, studies have been undertaken to determine whether GDNF benefits PD patients. Cloning of the human GDNF gene led to the production of a human recombinant peptide (r-metHuGDNF, liatermin; Amgen, Thousand Oaks, CA) available for human administration. To circumvent the blood-brain barrier, targeted surgical delivery has been employed. The first randomized, controlled trial in PD patients to be published involved monthly bolus injections into the frontal horn of the lateral ventricle through an implanted cannula connected to an access port.128 Blinded outcomes in 50 patients at 8 months failed to demonstrate an improvement in UPDRS scores over a range of GDNF doses, and fairly frequent adverse effects were noted. Although these results were discouraging, an independent postmortem study of a PD patient who had received intraventricular GDNF suggested that this route of administration did not deliver GDNF to the dopamine-deficient putamen.129 Further, it appears that correct location is more important than dose when examining the efficacy of GDNF delivery in primate PD models.130

A smaller single-center, open-label trial of five PD patients receiving continuous intraputaminal infusion reported a 32% mean improvement in off-medication UPDRS motor scores at 6 months follow-up.131 There was also a significant increase in putaminal F-dopa uptake on PET imaging near the catheter tip. Most important, this route of administration was well tolerated. Slevin and colleagues132 reported similar results, documenting a mean 30% improvement in the off-medication UPDRS motor scores 6 months after the start of therapy in an open-label trial of 10 PD patients. However, in a randomized, controlled, blinded trial of intraputaminal GDNF infusion in 34 patients with idiopathic PD, no significant difference was noted in the UPDRS scores of patients receiving active GDNF and those receiving placebo.133 The fact that greater F-dopa uptake was noted on the PET scans of treated patients suggests a biologic effect that did not translate into a clinical response.

Despite the failure of intraparenchymal GDNF therapy in clinical trials, hope remains that the exciting responses of animal models of PD to growth factor delivery will eventually be translated into therapies. More basic research is required to better understand the mechanisms behind this animal-human discrepancy. Hints are beginning to emerge, including evidence that the neuroprotective action of GDNF may rely on other factors, such as transforming growth factor-β, and that drug delivery may need to be optimized to ensure ideal exposure of the targeted tissue.134,135 Indeed, the targeted surgical delivery of compounds that promote neuronal health, survival, and regeneration may one day be a reality as new data come to light.

Gene Therapy

Gene therapies for PD have long been sought as a means of providing targeted symptomatic, neuroprotective, and neuroregenerative therapy. Potential benefits include the ability to produce biologically active molecules within the brain and thus circumvent the blood-brain barrier, focus therapy in specific brain regions and thereby avoid side effects related to the exposure of other areas, and address potential underlying causes of the disorder directly. Although gene therapy has yielded encouraging preclinical results for a number of disorders, safety and technical concerns have hampered its successful translation into clinical use.136,137 Nonetheless, three gene therapy strategies have made considerable progress toward becoming viable therapies, all of which employ stereotactic delivery to specific brain targets and adeno-associated virus (AAV) vectors to mediate gene transfer. These strategies are increasing striatal dopamine production, reducing STN output, and expressing an ectopic growth factor in the striatum.

Augmenting Striatal Dopamine Production

This strategy aims to increase dopamine production in neurons and glia within the striatum by ectopically expressing the enzyme aromatic L-amino-acid decarboxylase (AADC), which catalyzes the conversion of levodopa to dopamine (Fig. 84-4). In essence, this is an extension of current pharmacologic interventions with dopaminergic drugs. Bankiewicz and associates138 theorized that declining levels of AADC not only contribute to the disease by reducing dopamine production but also lead to a backlog of exogenous levodopa, which may promote the development of levodopa-induced dyskinesias.

Convection-enhanced delivery of AAV-AADC to the striatum increases that nucleus’s capacity to decarboxylate exogenous levodopa in animal models of PD. Efficient and long-term expression of the transgene in the striatum restores local dopamine production and promotes behavioral recovery in 6-OHDA rats and MPTP monkeys treated with levodopa.138142 PET data suggest that these same monkeys exhibit persistent AADC activity for at least 6 years after transfection.138,140 Similar studies using the simultaneous transduction of tyrosine hydroxylase and AADC showed a significant increase in intracellular dopamine in the striatum, producing better behavioral recovery than with the transduction of either enzyme alone; however, this multipronged approach adds complexity to the delivery.143145

A human phase I study of AAV-AADC gene therapy for idiopathic PD is now under way.146 A noteworthy inclusion criterion is the presence of intractable motor fluctuations. Patients receive three escalating doses through bilateral stereotactic infusions into the postcommissural putamen, delivered in two 50-µL volumes spaced approximately 6 mm apart. The key outcome measures are an improvement in 18F-fluorometatyrosine PET signal at 1 and 6 months, indicating the presence of the AADC transgene, and an improvement in standard clinical rating scales. Preliminary data in five patients who received the lowest dose demonstrated increases in PET signal, suggesting successful AADC transgene expression.146 Future results, particularly from the higher dose groups, should shed light on the potential safety and efficacy of this approach.

Altering Pathologic Subthalamic Nucleus Output

The second approach to gene therapy for PD under active investigation aims to modify STN output through ectopic expression of glutamic acid decarboxylase (GAD), which catalyzes the production of GABA. The theory behind the therapy is that the local production of GAD transforms the STN projection neurons, which are naturally glutamatergic and excitatory, into inhibitory GABAergic neurons (Fig. 84-5), thereby reducing the excessive stimulatory effects of the STN on the GPi, which are thought to contribute to many parkinsonian symptoms. This follows the theory that STN-DBS generates its positive effects in PD by similarly reducing STN excitatory output.147

Before considering a clinical application of this concept, AAV-GAD was injected into the STN of 6-OHDA rats.148 These animals demonstrated activity-dependent GABA release from STN nerve terminals, increased survival of dopaminergic neurons, and marked behavioral recovery. Moreover, GAD transduction of the STN appeared to protect SNc dopaminergic neurons by preventing the lesion induced by 6-OHDA. A recently published study in MPTP monkeys given AAV-GAD injections found more modest improvements (about 20%) in motor behavior, although statistically significant gross motor skill and tremor improvements were noted at 1 year.149

A human phase I clinical trial of AAV-GAD gene therapy is well under way, with interim data already published.150 Twelve PD patients with reduced efficacy or tolerance of levodopa underwent unilateral stereotactic STN injections of one of three vector doses based on magnetic resonance imaging targeting. Outcome measures include changes in brain metabolism on PET scans and standard clinical rating scales. No study-related significant adverse events or withdrawals occurred, and no new antivector or anti-GAD peripheral antibodies were detected. At 1 year of follow-up, modest but significant improvements were noted in UPDRS scores, along with a trend toward superior activities of daily living scores. Further, fluorodeoxyglucose (FDG) PET demonstrated reduced thalamic metabolism in the operated hemisphere and increased local metabolism in the ipsilateral supplementary motor area, the latter being highly correlated with UPDRS score improvement.150,151 These promising clinical findings and supportive imaging studies, along with a favorable safety profile, suggest that AAV-GAD gene therapy may be beneficial in PD. Although future data from this trial will help confirm this early impression, a subsequent phase II trial will be required to judge whether the magnitude of effect is clinically meaningful.

Growth Factor Gene Therapy

Unlike the other two strategies, which are directed at controlling PD symptoms, the goal of this therapy is to prevent ongoing degeneration of dopamine neurons by ectopically expressing the growth factor neurturin throughout the striatum. Growth factors (particularly GDNF) attenuate the loss of nigrostriatal dopaminergic neurons and restore function of the nigrostriatal pathway in animal models of PD.119,152 Accordingly, targeted delivery of a gene that promotes growth factor production in the human SNc might achieve clinically meaningful neuroprotection or neurorestoration in PD patients. Owing to intellectual property issues, clinical gene therapy with GDNF is impossible at this time; however, work is proceeding with a related neurotrophin, neurturin. Neurturin is a naturally occurring structural and functional GDNF analogue and has already been used in patients.153155

Lentivirus- and AAV-mediated GDNF gene therapy and striatal neurturin infusion have shown protective effects against the loss of dopaminergic nigral neurons and the motor consequences of MPTP intoxication in primates and 6-OHDA lesioning in rats.122,156,157 However, it was uncertain whether benefits would also be realized when nigral degeneration was quite advanced at the time of disease diagnosis. Kordower and colleagues158 performed AAV-neurturin gene therapy in MPTP monkeys and showed that neurturin expression is associated with substantial histologic and clinical neuroprotection. Importantly, these monkeys received the vector infusion following MPTP administration at a time when nigral destruction was under way. AAV-neurturin also improved motor function in aged monkeys, restoring failing nigrostrial function.159

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