Another Player in Gene Therapy for Parkinson Disease

Michael G. Kaplitt


Abstract and Introduction


Gene therapies have entered clinical trials for several neurological disorders, most notably Parkinson disease. A study in a nonhuman primate model of Parkinson disease has reported motor deficit improvements following the use of a lentiviral vector to restore extracellular dopamine levels. A clinical trial is now underway to evaluate the effectiveness of this approach in humans.


Gene therapy has made a resurgence over the past decade as a potential means of treatment for a variety of diseases. In the case of neurological disorders, the majority of clinical gene therapy studies have focused on Parkinson disease (PD). This disease is a particularly attractive gene therapy target because surgical infusion is currently required for viral vector delivery into the brain, and PD is the only neurodegenerative disorder routinely treated with neurosurgery. Furthermore, several animal models of PD that accurately reflect the human disorder are available to test new therapies. In general, these models mimic the loss of dopaminergic neurons and the resultant abnormal basal ganglia function found in the human disease. Jarraya and colleagues have now used a nonhuman primate model of PD to test a novel gene therapy, which involves delivering multiple genes in one viral vector into the putamen to restore dopamine levels.[1] The positive outcomes generated from this study provide optimism for the effectiveness of this approach in humans.

To date, three different gene therapy approaches for PD have been tested in humans. These therapies all used the adeno-associated virus (AAV) vector as the gene delivery agent. In the first approach, the glutamic acid decarboxylase gene was transferred into the subthalamic nucleus—the currently preferred target for traditional deep brain stimulation surgery—in an attempt to restore normal physiological functioning to the basal ganglia circuitry.[2] Significant clinical and radiographical improvements were observed in patients after treatment in this phase I study, and a randomized, blinded phase II study is currently in progress, with results expected later this year. The second gene therapy approach expressed neurturin, a growth factor similar to glial-derived neurotrophic factor, in the putamen. This phase I trial aimed to improve PD symptoms by promoting sprouting from the remaining dopaminergic neurons and to slow disease progression by reducing cell death.[3] Notable improvements in a variety of clinical ratings over time were reported in patients in this study. Neurturin treatment failed, however, to meet the primary end point in a phase II trial (as announced by the trial's sponsors). A second phase II trial has been proposed. Most recently, the aromatic L-amino acid decarboxylase (AADC) gene was transferred into the putamen, with the aim of increasing conversion of levodopa to dopamine where the neurotransmitter is locally needed.[4] This phase I study reported clinical and radiographical improvements in patients following treatment.

Instead of single gene transfer via an AAV vector, Jarraya and colleagues used a lentiviral vector that included all three genes necessary for dopamine synthesis—tyrosine hydroxylase (TH), AADC and guanosine 5′-triphosphate cyclohydrolase 1 (GCH1). Lentiviral vectors belong to a distinct class of retroviral vectors that are capable of transferring genes into nondividing cells. The lentivirus family includes HIV; however, Jarraya et al. employed a vector derived from the equine infectious anemia virus that has been proven to be safe in many animal studies. The vector lenti-TH-AADC-GCH1 was injected into the putamen of macaques in which parkinsonism had been induced by systemic administration of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In animals that received the vector, a marked improvement was observed in symptoms typically observed in human PD, including tremor and slow movements. These effects were reported to be stable for 1 year. One animal, however, was maintained beyond this period and still exhibited improvements 4 years later.

By using a lentiviral vector, Jarraya et al. were able to deliver all three genes in a single vehicle—a potential technical advantage over the use of other vectors. Indeed, the smaller size of AAV meant that multiple vectors were required to deliver the three dopamine synthesis genes in an earlier nonhuman primate PD study, although similarly promising results were obtained.[5] In humans, while some unique benefits might be derived from the lentiviral approach, both the safety profile of lentivirus and the long-term consequences of lentiviral integration into the host genome remain to be demonstrated.

Numerous reports have demonstrated that many treatments can improve symptoms in the nonhuman primate MPTP model, in particular cell transplantation or gene therapies that increase putaminal dopamine transmission. The study by Jarraya and colleagues is notable because the researchers have made an unusually comprehensive attempt to replicate the conditions that might be found in patients, including relevant medication doses, timing and adverse effects. Chronic levodopa treatment is associated with several adverse effects, notably abnormal involuntary movements (dyskinesias). The injection of lenti-TH-AADC-GCH1 did not induce dyskinesias, even though such movements were observed in levodopa-treated control macaques. Furthermore, dopaminergic medication failed to induce dyskinesias in the lenti-TH-AADC-GCH1-injected animals, and administration of gene therapy to macaques with existing levodopa-induced dyskinesias reduced this adverse effect by 60%. The researchers believe that the absence of dyskinesias in lenti-TH-AADC-GCH1-treated animals might be due to continuous production and release of dopamine, as opposed to intermittent dopamine spikes associated with periodic intake of oral levodopa. In support of this view, gene therapy using AADC alone, which requires ongoing periodic oral levodopa therapy, has been associated with an increase in dyskinesias in a nonhuman primate model of PD.[6]

On the basis of the results from the study by Jarraya et al. and other data, a phase I–II clinical trial of intraputaminal delivery of lenti-TH-AADC-GCH1 for PD has been initiated. Translation of such promising results in animals into a successful clinical trial can be difficult, as demonstrated by the history of other promising biological therapies for PD. Fetal cell transplantation was long thought to be a potentially important therapy for PD, and strong data in animal models of PD encouraged this view. In humans, however, fetal cell transplants were efficacious in only a subset of patients with PD, and some individuals developed substantial off-drug dyskinesias.[7,8] Interestingly, PET scans in some of the patients who received fetal cell transplants confirmed that the cells survived and produced dopamine.[8,9] Given the Jarraya et al. hypothesis that continuous dopamine production might reduce the likelihood of developing dyskinesias, why these patients experienced such involuntary movements is unclear. One possible explanation is that variation in dopmamine production and release exists between exogenous fetal neurons and endogenous intrinsic neurons. Alternatively, differences between the nonhuman primate and human putamen could explain the inconsistent responses to fetal cell transplantation and gene therapies directed at this brain region.

The successful translation of positive results from nonhuman primate studies into effective clinical treatments has so far proved elusive for a variety of new surgical therapies for PD, including gene and cell therapies. Nonetheless, the number of promising gene therapy studies in progress is encouraging. Indeed, Jarraya et al. have provided compelling preclinical evidence to suggest that their ongoing human trial might help to further advance the field of PD gene therapy.


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