Articles Safety and tolerability of gene therapy with an adeno associated virus AAV borne GAD gene for Parkinson s disease an open label phase I trial Michael 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 During Summary Background 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 e 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 uctuations with substantial o time and age 70 years or less Patients were assessed clinically both o and on medication at baseline and after 1 3 6 and 12 months at North Shore Hospital E cacy measures included the Uni ed Parkinson s Disease Rating Scale UPDRS scales of activities of daily living ADL neuropsychological testing and PET imaging with 18F 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 Signi 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 Introduction Gene 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 de 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 e ects caused by the adeno associated virus AAV vector but after an initial promising improvement seen in patients de 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 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 www thelancet com Vol 369 June 23 2007 that are delivered systemically due to a tight vascular blood brain barrier Local gene expression might also focus therapy in speci c brain regions thereby avoiding exposure of other areas to agents that might cause undesirable e 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 neurogenetic Canavan disease was also undertaken 4 Furthermore a phase I study of intracerebral transplantation of genetically modi ed cells in patients with Alzheimer s disease ex vivo gene therapy was reported 5 However the use of modi 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 consequence is dysregulation of interacting inhibitory and Lancet 2007 369 2097 105 See Comment page 2056 Department 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 USA During 1 osu edu 2097 Articles GAD dose Age years Patient 1 Low 55 Patient 2 Low 51 Patient 3 Low 62 Patient 4 Low 53 Patient 5 Medium 62 Patient 6 Medium Patient 7 Medium Patient 8 Medium 58 Patient 9 High 67 Patient 10 High 51 Patient 11 High Patient 12 Mean Disease duration years 8 Time on levodopa years Baseline levodopa dose Baseline levodopa equivalents 2 0 250 9 8 2000 2246 13 11 1100 2018 8 8 600 656 13 12 1250 1906 63 6 5 600 873 62 6 3 1000 1267 11 9 2000 2072 11 9 650 1173 13 13 600 461 50 7 7 1600 2300 High 63 6 4 1600 1600 58 2 9 8 1083 1402 Low dose 1 1011 vg mL Medium dose 3 1011 vg mL High dose 1 1012 vg mL Mg daily 100 mg levodopa is equivalent to 10 mg bromocriptine 1 mg pergolide 1 mg pramipexole or 3 mg ropinirole Patient 1 was unable to tolerate levodopa before study entry and had been o of it for several years Table 1 Baseline
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