AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial - 06/08/11

Doi : 10.1016/S1474-4422(11)70039-4

Peter A LeWitt, ProfMD ^a, Ali R Rezai, ProfMD ^b, Maureen A Leehey, ProfMD ^c, Steven G Ojemann, MD ^c, Alice W Flaherty, MD ^d, Emad N Eskandar, MD ^d, Sandra K Kostyk, MD ^b, Karen Thomas, DO ^b, Atom Sarkar, MD ^b, Mustafa S Siddiqui, MD ^e, Stephen B Tatter, ProfMD ^e, Jason M Schwalb, MD ^f, Kathleen L Poston, MD ^g, Jaimie M Henderson, MD ^g, Roger M Kurlan, ProfMD ^h, Irene H Richard, MD ^h, Lori Van Meter, MS ⁱ, Christine V Sapan, PhD ^j, Matthew J During, ProfMD ^b,^{^{‡
These authors contributed equally}}, Michael G Kaplitt, MD ^k,^{^{‡
These authors contributed equally}}, Andrew Feigin, DrMD ^l,^⁎

^a Wayne State University School of Medicine, Parkinson’s Disease and Movement Disorders Program, Henry Ford West Bloomfield Hospital, MI, USA

^b Ohio State University College of Medicine, Columbus, OH, USA

^c University of Colorado School of Medicine, Aurora, CO, USA

^d Massachusetts General Hospital, Boston, MA, USA

^e Wake Forest University School of Medicine, Winston-Salem, NC, USA

^f Henry Ford Health System, West Bloomfield Charter Township, MI, USA

^g Stanford University School of Medicine, Stanford, CA, USA

^h University of Rochester School of Medicine, Rochester, NY, USA

ⁱ PharmaNet Development Group, Princeton, NJ, USA

^j Neurologix Inc, Fort Lee, NJ, USA

^k Weill Cornell Medical College, New York, NY, USA

^l The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY, USA

^* Correspondence to: Dr Andrew Feigin, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA

Summary

Background

Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson’s disease.

Methods

Patients aged 30–75 years who had progressive levodopa-responsive Parkinson’s disease and an overnight off-medication unified Parkinson’s disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890.

Findings

Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two).

Interpretation

The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson’s disease and shows the promise for gene therapy for neurological disorders.

Funding

Neurologix.

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Plan

Introduction

Methods

Patients

Randomisation and masking

Procedures

Statistical analysis

Role of the funding source

Results

Discussion

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Vol 10 - N° 4

P. 309-319 - avril 2011 Retour au numéro

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AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial - 06/08/11

Summary

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