Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trialIntroductionMethodsPatientsProceduresViral vectorStatistical analysisRole of the funding sourceResultsClinical outcomeDiscussionAcknowledgmentsReferencesArticleswww.thelancet.com Vol 369 June 23, 2007 2097Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trialMichael G Kaplitt, Andrew Feigin, Chengke Tang, Helen L Fitzsimons, Paul Mattis, Patricia A Lawlor, Ross J Bland, Deborah Young, Kristin Strybing, David Eidelberg, Matthew J DuringSummaryBackground Dopaminergic neuronal loss in Parkinson’s disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential effi cacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson’s disease. Methods We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinson’s disease (mean age 58∙2, SD=5∙7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fl uctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Effi cacy measures included the Unifi ed Parkinson’s Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fl uorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143. Findings All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Signifi cant improvements in motor UPDRS scores (p=0∙0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area.Interpretation AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinson’s disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases. IntroductionGene therapy has yielded encouraging preclinical results for various disorders; however, safety and technical concerns have restricted successful translation into clinical therapy. In 1999, the death of a patient with ornithine transcarbamylase defi ciency in a gene therapy trial with adenovirus led to a temporary suspension of gene therapy trials,1 but technological advances and regulatory changes have renewed interest in the approach. Nonetheless, challenges remain. A recent study in patients with haemophilia B showed no clear toxic eff ects caused by the adeno-associated virus (AAV) vector, but after an initial promising improvement seen in patients defi cient in the factor IX protein, anti-AAV immunity developed, which might have caused nearly complete loss of the therapeutic gene from transduced liver cells.2 The lack of similar fi ndings in animals further emphasises the importance of testing in human beings; however, safety concerns call for careful design of appropriate dose-ranging clinical trials.The brain is an attractive organ for gene therapy, because production of biologically active molecules within the brain might circumvent poor penetration of compounds that are delivered systemically due to a tight vascular blood–brain barrier. Local gene expression might also focus therapy in specifi c brain regions, thereby avoiding exposure of other areas to agents that might cause undesirable eff ects. Several attempts have been made to use gene therapy for malignant tumours, including those in the brain, but the main aim of these studies was to destroy target cancer cells.3 A trial aimed at correcting the genetic defect in the rare and lethal paediatric neuro-genetic Canavan disease was also undertaken.4 Further-more, a phase I study of intracerebral transplantation of genetically-modifi ed cells in patients with Alzheimer’s disease (“ex-vivo” gene therapy) was reported.5 However, the use of modifi ed viruses (vectors) to introduce genetic material into endogenous neurons directly (so-called “in-vivo” gene therapy) has not been previously attempted for any adult neurodegenerative disorder.Parkinson’s disease is associated with degeneration of many brainstem, limbic, and midbrain neurons, but its hallmark is the loss of dopaminergic neurons of the substantia nigra, which leads to alterations in the activity of brain networks that control movement.6,7 The con-sequence is dysregulation of interacting inhibitory and Lancet 2007; 369: 2097–105See Comment page 2056Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA (M G Kaplitt MDPhD, K S Strybing MSc, M J During MDDSc); Center for Neurosciences, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA (A Feigin MD, C Tang MD, P Mattis PhD, D Eidelberg MD); Departments of Neurology and Medicine, New York University School of Medicine, New York, NY, USA (A Feigin MD, D Eidelberg MD); Neurologix, Ft Lee, NJ, USA (H L Fitzsimons PhD, R J Bland PhD); and Department of Molecular Medicine, University of Auckland, Auckland, New Zealand (P A Lawlor PhD, D Young PhD, M J During MDDSc)Correspondence to: Matthew J During, The Ohio State University School of Medicine, 912 BRT, 460 West 12th Avenue, Columbus, OH 43210, [email protected] www.thelancet.com Vol 369 June 23, 2007excitatory pathways, leading to a movement disorder that is characterised by diffi culty initiating movements, muscular rigidity, and tremor.8,9 Pharmacological facilitation of dopaminergic neurotransmission benefi ts most patients initially, but those
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