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Logo of neurologyNeurologyAmerican Academy of Neurology
 
Neurology. 2013 April 30; 80(18): 1698–1701.
PMCID: PMC3716474

Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients

Raymond T. Bartus, PhD,corresponding author

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. 1) Non-paid Section Editor for Neurobiology of Aging 2) Non-paid Editorial Board member for Brain Research; Drug Delivery and Translational Research

Patents:

  1. Several patents related to use of AAV-NRTN for neurodegenerative diseases, including PD. However, all rights assigned to Ceregene, Inc.

Publishing Royalties:

  1. Several patents related to AAV-NRTN as therapy for neurodgenerative diseases, including PD, but all rights assigned to Ceregene.

Employment, Commercial Entity:

  1. Chief Scientific Officer and Exec Vice President of Ceregene, Inc. a for-profit company that has been developing CERE-120 for PD and CERE-110 for AD for past 11+ years

Consultancies:

  1. Officer for Ceregene, a non-profitable, for-profit company that has been developing CERE-120 for PD and CERE- 110 for AD for past 11+ years

Speakers' Bureaus:

  1. NONE

Other activities:

  1. As Officer of Ceregene, have been awared stock options

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. received salary from Ceregene, a commerical entity, as listed earlier

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. Adjunct Professor, Tufts University Medical School

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. Yes, stock optinos from Ceregene, as stated above

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. Expert witness for legal litigation involving biotech industry.
Tiffany L. Baumann, BS,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Receives salary and stock options as employee at Ceregene since 2004. Current position = Director of Clinical Operations & Manager of Regulatory Affairs

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Joao Siffert, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. 1) Avanir Pharmaceuticals, SVP, R&D and Chief Scientific Officer (August, 2011 - Present) 2) Ceregene, Inc., VP, Chief Medical Officer (9/2007-8/2011)

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Full time employee of Avanir Pharmaceuticals (see above)

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. The Michael J Fox Foundation for PD Research (J. Siffert, PI; grant awarded to Avanir Pharmaceuticals, Inc.)

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. 1) 5 thousand stock options from Ceregene 2) Stock options and stocks from Avanir Pharmaceuticals

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Christopher D. Herzog, PhD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. Received salary and stock options as an employee of Ceregene, Inc.

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Ron Alterman, MD,

Scientific Advisory Boards:

  1. Medtronic, Inc. Codman, Inc.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Ceregene, Inc.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Nicholas Boulis, MD,

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for travel or speaker honoraria:

  1. 1. NeuralStem paid for a trip to Mexico so that i could evaluate the surgical facilities available to support an ALS stem cell transplantation trial.

Editorial Boards:

  1. NONE

Patents:

  1. 1. I received a 170,000 dollar payment as part of payment for my share of IntElect Medical after its sale to Boston Scientific. 2. NeuralStem licensed 2 patents from the Cleveland Clinic that i own a share of. I received an $80,000 this in 2011.

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. 1. i work for Emory University and Emory Healthcare. 2. I received income for reviewing a lawsuit against medtronic and a pain surgeon.

Consultancies:

  1. 1. I served as a consultant for Ceregene receiving $9999/year. This relationship ended in 2012. 2. I receive $9999 from NeuralStem/year.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License fee payments, Technology or Inventions:

  1. 1. see above reference to payment for Cleveland Clinic Patents by NeuralStem.

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. 1. Case review for law firm defending medtronic about a sacral stimulation case.
Dennis A. Turner, MD,

Scientific Advisory Boards:

  1. Ceregene advisory position for study plan reviews

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Medtronics Neurological Consultant for Alnylam/Medtronics planned siRNA study for Huntington's Disase

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NIH Grants R01AG037599 (PI) 2010-2014,R21NS066115 (PI) 2010-2013, and RO1NS079312 (Coll Inv) 2012-1016; VA Merit Review funding (PI) 1982-2012

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Mark Stacy, MD,

Scientific Advisory Boards:

  1. Scientific Advisory Committee: Allergan

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Editorial Board: Journal of Clinical Investigation

Patents:

  1. NONE

Publishing Royalties:

  1. 1) Handbook of Dystonia, Informa Press, 2012.

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. Johnson & Johnson, Merz Pharmaceuticals, Osmotica, Neuronova, Pfizer, ProStrakan, Psychogenics, SKLSI.

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. Ceregene, EMD Serono, Merck, Neuraltus, Novartis, Parkinson Study Group.

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Michael J. Fox Foundation

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
Anthony E. Lang, MD,

Scientific Advisory Boards:

  1. Dr. Lang has served as an advisor for Abbott, Allon Therapeutics, Biovail, Boerhinger-Ingelheim, Cephalon, Ceregene, Eisai, Medtronic, Lundbeck A/S, NeuroMolecular, Novartis, Merck Serono, Solvay, and Teva, and received grants from Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, Ontario Problem Gambling Research Centre, Parkinson's Disease Foundation.

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. Schapira A, Lang AE, Fahn S. Movement Disorders 4. Saunders, Elsevier, Philadelphia, PA 2009. Olanow CW, Stocchi F, Lang AE. The Non-motor and Non- Dopaminergic Features of Parkinson's Disease. Wiley- Blackwell, UK. 2011. Weiner WJ, Shulman LM, Lang AE. Parkinson's Disease: A Complete Guide for Patients and Families. The Johns Hopkins University Press, Baltimore. 2001

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. Canadian Institutes of Health Research,

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, Ontario Problem Gambling Research Centre, Parkinson's Disease Foundation, and

Stock/Stock Options/Board of Directors Compensation:

  1. Ceregene

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. Welding rod companies
Andres M. Lozano, MD,

Scientific Advisory Boards:

  1. Johnson and Johnson (Corporate Office of Science and Technology) Codman Ceregene Neurologix Functional Neuroscience

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. Canadian Journal of Neurological Science (Associate Editor 2001-2006) Brain Stimulation (Deputy Editor) Journal of Neurosurgery Neurosurgery Movement Disorders World Neurosurgery Neurological Research Stereotactic and Functional Neurosurgery Operative Neurosurgery NeuroRx Surgical Neurology Parkinsonism and Related Disorders Neurobiology of disease (Guest Editor) Neurosurgical focus (Guest Editor)

Patents:

  1. 1) Lozano AM and Mayberg HS. Methods of treating depression, mood disorders and anxiety using neuromodulation, 2010, US patent No. 7,653,433. 2) Lozano AM and Mayberg HS. Methods of treating depression, mood disorders and anxiety using neuromodulation, 2008, US patent No. 7,346,395. 3) Velasco F, Jimenez F, Velasco M and Lozano AM. Method of treating mood disorders and/or anxiety disorders by brain stimulation. 2007, US patent No. 7,313, 442. 4) Lozano AM. Brain Stimulation lead used for lesioning. 2007, US patent No. 7,285,118. 5) Lozano AM and Rise M. Method of treating movement disorders by electrical stimulation and/or drug infusion of the pendunculopontine nucleus. 2002, US patent No. 6,356,784.

Publishing Royalties:

  1. 1) Tarsy D, Vitek JL, Lozano AM (Eds). Surgical Treatment of Parkinson's Disease and Other Movement Disorders. 2002 Humana Press. 2) Lozano AM, Tasker RR, Gildenberg P (Eds). Textbook of Stereotactic and Functional Neurosurgery (2nd edition). 195 Chapters and 3285 pages, Springer. Published May 2009

Employment, Commercial Entity:

  1. Board of Functional Neuromodulation Inc.

Consultancies:

  1. Medtronic St-Jude Boston Scientific Amgen Eli Lilly Bristol Myers Elekta Bayer Schering-Plough QIC Functional Neuroscience

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. Ceregene

License fee payments, Technology or Inventions:

  1. Functional Neuroscience

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE
and C. Warren Olanow, MD

Scientific Advisory Boards:

  1. NONE

Gifts:

  1. NONE

Funding for Travel or Speaker Honoraria:

  1. NONE

Editorial Boards:

  1. NONE

Patents:

  1. NONE

Publishing Royalties:

  1. NONE

Employment, Commercial Entity:

  1. NONE

Consultancies:

  1. NONE

Speakers' Bureaus:

  1. NONE

Other Activities:

  1. NONE

Clinical Procedures or Imaging Studies:

  1. NONE

Research Support, Commercial Entities:

  1. NONE

Research Support, Government Entities:

  1. NONE

Research Support, Academic Entities:

  1. NONE

Research Support, Foundations and Societies:

  1. NONE

Stock/Stock Options/Board of Directors Compensation:

  1. NONE

License Fee Payments, Technology or Inventions:

  1. NONE

Royalty Payments, Technology or Inventions:

  1. NONE

Stock/Stock Options, Research Sponsor:

  1. NONE

Stock/Stock Options, Medical Equipment & Materials:

  1. NONE

Legal Proceedings:

  1. NONE

Abstract

Objective:

In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).

Methods:

After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen.

Results:

Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery.

Conclusions:

Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated.

Classification of evidence:

This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.

Abundant preclinical research argues that neurotrophic factors offer promising therapies for Parkinson disease (PD).1 Clinical trials have generally been disappointing, likely because of difficulties delivering sustained bioactive protein throughout the targeted brain region. Gene transfer can potentially solve these problems.1 A double-blind study testing putaminal gene delivery of the neurotrophic factor neurturin (NRTN) failed to meet its primary endpoint at 12 months but showed benefit for the predefined primary endpoint at 18 months and for several secondary endpoints at 12 and 18 months (no measure similarly favored sham).1,2 Postmortem studies suggest that serious deficiencies in axonal transport in PD limited NRTN transport to the substantia nigra pars compacta (SNc), thereby impairing the ability of putaminal delivery to activate repair genes in SNc neurons, thereby reducing and delaying clinical benefit.3 We therefore initiated a study testing NRTN gene delivery to both SNc and putamen. However, a number of safety concerns have been raised regarding stereotactically targeting the SNc and expressing neurotrophic factors in the substantia nigra (SN) and surrounding structures.46 Based on safety associated with targeting the SNc and neighboring regions in patients with PD with deep brain stimulation7 and fetal tissue transplant,8 and the lack of serious side effects observed following NRTN gene delivery to the SNc in preclinical studies,9 we began a clinical trial in patients with advanced PD. In the present article, we present the 24-month results of an open-label safety study of 6 patients who underwent bilateral NRTN gene delivery (CERE-120) to the putamen and SNc.

METHODS

Standard protocol approvals, registrations, and patient consents.

This study is registered with ClinicalTrials.gov, number NCT00985517, was approved by the US Food and Drug Administration, and was publicly discussed and reviewed by the Recombinant DNA Advisory Committee of the NIH. The study protocol and patient consent forms were approved by institutional ethics and biological safety committees at each institution. Each patient signed informed consent before entry into the trial.

Subjects.

Inclusion/exclusion criteria were similar to prior AAV2-NRTN clinical trials, involving subjects diagnosed with idiopathic PD according to UK Brain Bank criteria.2,10

Dosing and assessment.

To assess the feasibility and safety of targeting the SN plus putamen with AAV2-NRTN in PD, 2 dose cohorts were tested (3 subjects each) with a 1-month interval between each surgery and a 5-week hiatus between the low-dose and high-dose cohorts. An independent data monitoring committee (DMC) reviewed the entire CERE-120 safety profile after each surgery. In the first cohort, patients received a total dose of CERE-120 of 4.0 × 1011 vector genomes (vg) to the SN, and 5.4 ×1011 vg to the putamen (the same putaminal dose used in the prior phase IIa CERE-120 trial).2 The SN dose was determined based on between-species “dose scaling,” designed to adequately cover the SN without risk of substantial spread to non-SN structures.9 The second dose cohort received the same dose to the SN and a nearly 4-fold higher dose to the putamen, for a total dose of 24.0 × 1011 vg, in a volume of 360 μL. The infusion rate was increased from 2 μL/min to 3 μL/min for the putamen (but remained 2 μL/min for the SN), using an automated infusion pump (World Precision Instruments, Sarasota, FL).

Following surgery, subjects were evaluated for safety and tolerability at week 2, month 1, month 3, and every 3 months thereafter for the next 2 years, as well as on number of motor and quality-of-life measurements assessed at baseline and at visits starting at month 6. This design, wherein each subject served as his or her own control (and comparisons in performance were made on protocol-prescribed, objective measures between pretreatment baseline scores and a series of post-treatment scores), was intended to provide Class IV evidence regarding the feasibility and safety of administering CERE-120 to the SN and putamen in patients with moderately advanced PD.

Stereotactic targeting and surgery.

Targeting and stereotactic surgery were performed in a similar manner to past gene transfer of NRTN studies for PD.2,10 All subjects were administered CERE-120 bilaterally, using a single burr hole per hemisphere. To help ensure uniformity of dosing across subjects and clinical sites, and to reduce the risk of mistargeted protein, a consensus with respect to targets and trajectories was required between the operating neurosurgeon and an independent neurosurgical reviewer.

Two CERE-120 bolus infusions were delivered to the SN via one trajectory in each hemisphere; doses were separated by 2–4 mm (figure). CERE-120 was then delivered to the putamen via 3 trajectories per hemisphere. The 3 putaminal target sites were evenly spaced across the anterior-posterior extent of the putamen. If an extremely narrow area at the posterior end of the putamen occurred, this “tail” was excluded for purposes of selecting target locations. In each subject, 2 of the 3 target locations were positioned posterior to the anterior commissure. All 3 targets were positioned in the ventral half of the putamen, approximately two-thirds of the way down from the dorsalmost edge, but at least 4 mm from the inferior boundary, and all were relatively centered in the medial-lateral dimension.

Figure
Artist's rendition of the dosing scheme employed to bilaterally target the substantia nigra and putamen with AAV2-NRTN (CERE-120)

Postsurgical MRIs were reviewed by a central neuroradiologist (Daniel Lefton, Beth Israel Medical Center, New York, NY) to confirm adherence to targeting guidelines and to identify any safety issues. In many instances a clear signal from the needle track could be seen on the postsurgical MRI confirming appropriate trajectories to the putamen or SN, though it was never possible to identify with certainty the location of the tip of the injection cannula. In no case was any evidence for any mistargeted trajectories observed, nor did any individual differences in size or shape of putamen negatively impact the ability to target it.

RESULTS

Six subjects underwent the procedure and were followed for 2 years. Demographic information is provided in table 1. No serious adverse events (SAEs) were reported. The most common adverse events were incision site pain (n = 4), dyskinesias (n = 4), headache (n = 4), and abnormal dreams (n = 4); these were transient, considered clinically insignificant, and unrelated to AAV2-NRTN treatment. Dyskinesias reported in this study were not increased in severity, occurred no more frequently than in the earlier putaminal-only phase I CERE-120 study, and were all transient.10 No patient experienced off-medication dyskinesia. No clinically significant changes were detected on physical or neurologic examination or vital signs. Specifically, there was no clinically significant weight loss associated with the procedure (table 2) and no subject experienced psychosis or clinically significant alteration in mental status. Laboratory tests of serum revealed no abnormalities and no increase in AAV antibodies, detectable NRTN antibodies, or CERE-120 vg. MRIs of the brain at day 1 and months 1, 12, and 24 postoperatively revealed no clinically significant abnormalities related to either the surgical procedure or CERE-120. An independent DMC had access to all data and had no safety concerns. The Unified Parkinson's Disease Rating Scale, motor-off, suggested a decrease from 38.2 (±2.6 SEM) to 33.2 (±3.5) and 32.7 (±3.6) at 12 and 24 months, respectively, and a decrease in off-time on self-report home diary measures from 5.4 (±0.8) hours at baseline to 4.3 (±1.5) and 3.1 (±0.7) at 12 and 24 months, respectively. Parkinson's Disease Questionnaire-39: Activities of Daily Living scores appeared stable (25 ± 2.6 and 25 ± 6.1 at baseline and 24 months, respectively).

Table 1
Characteristics of patientsa
Table 2
Body weight (kg)

DISCUSSION

We report here the long-term (2-year) safety results from 6 subjects with PD who were treated with AAV2-NRTN (a gene-transfer viral vector encoding the neurotrophic factor NRTN) delivered to both the SNc and putamen. In this phase I study, CERE-120 delivered into both the SNc and putamen was well-tolerated, with no safety or serum laboratory complications identified over the course of 2 years of follow-up. No SAEs were reported in any subject; all adverse events were expected for an advanced PD patient population undergoing a neurosurgical procedure, and none was clinically significant or enduring. Specifically, no problems were encountered with respect to stereotactically targeting the SNc, expression of a trophic factor in the SNc, or possible spread to adjacent sites like the ventral tegmental area or hypothalamus. More specifically, we did not observe weight loss, which has been reported as a potential concern for targeting the SN with neurotrophic factors, based on certain preclinical studies,5,6,11 though others suggested that outcome is likely due to mistargeting protein extending into the ventricles or hypothalamus.9 We also did not observe any evidence of psychiatric symptoms such as addiction or psychosis that theoretically might result from trophic enhancement of the ventral tegmental area.4 Thus, these data provide support for the feasibility and safety of targeting both the SN and putamen with AAV2-NRTN in subjects with moderately advanced PD.

This open-label study was designed to generate preliminary safety and tolerability information. Based on the data generated in this study, a multicenter, double-blind, sham surgery–controlled trial has been launched to assess the effect of combined intraputaminal and SNc gene delivery of NRTN on key motor and quality-of-life measurements in 51 patients with moderately advanced PD. Consistent with the 2-year safety results reported here, no serious, unexpected safety issues have been encountered after more than a year of follow-up after dosing in any of the subjects in this ongoing phase IIb study.12

ACKNOWLEDGMENT

The authors thank Daniel Lefton and David Barba for help and advice regarding stereotactically targeting the SNc; Eugene Johnson, Jeffrey Kordower, Floyd Bloom, Rusty Gage, Karl Kieburtz, Ray Watts, Barry Hoffer, Paul Larson, Herbert Meltzer, and Carol Tamminga for comments and advice during due diligence of assessing the risks vs benefits; Stewart Factor, Michele Tagliati, and Catherine Cho, who served as PIs for 2 sites and enrolled and assessed 2 of the 6 subjects in this phase I trial; the trial coordinators at each site who provided operational support; Jeffrey Ostrove for support throughout this study; Amanda Sánchez Losada for administrative assistance in helping to prepare this manuscript, including formatting of tables and references; and the Michael J. Fox Foundation for Parkinson's Research for assistance in the form of a LEAPS award to R.T.B. and J.S.

GLOSSARY:

DMC
data monitoring committee
NRTN
neurturin
PD
Parkinson disease
SAE
serious adverse event
SN
substantia nigra
SNc
substantia nigra pars compacta
vg
vector genomes

AUTHOR CONTRIBUTIONS

R.T. Bartus contributed to the design and concept of the study, analysis and interpretation of the data, and drafting and revising the manuscript for intellectual content. He also wrote the initial draft, along with C.W.O. T.L. Baumann contributed to the design and concept of the study, analysis and interpretation of the data, and drafting and revising the manuscript for intellectual content. J. Siffert contributed to the design and concept of the study, analysis and interpretation of the data, and drafting and revising the manuscript for intellectual content. C.D. Herzog contributed to the design of parts of the study, interpretation of the data, and revisions to the manuscript for intellectual content. R. Alterman contributed to the design of the surgical component of the study, analysis and interpretation of the data, and revising the manuscript for intellectual content. N. Boulis contributed to the design and concept of the surgical component of the study, interpretation of the data, and revisions to the manuscript for intellectual content. D.A. Turner contributed to the design of the surgical component of the study, interpretation of the data, and revisions to the manuscript for intellectual content. M. Stacy contributed to the design of the study, interpretation of the data, and drafting and revising the manuscript for intellectual content. A.E. Lang contributed to the design and concept of the study, interpretation of the data, and drafting and revising the manuscript for intellectual content. A.M. Lozano contributed to the design and concept of the surgical component of the study, analysis and interpretation of the data, and revisions to the manuscript for intellectual content. C.W. Olanow contributed to the design and concept of the study, analysis and interpretation of the data, and drafting and revising the manuscript for intellectual content. He also wrote the initial draft, along with R.T.B. He has accepted responsibility to be guarantor for this manuscript.

STUDY FUNDING

This study was funded by Ceregene, Inc., with partial funding received from the Michael J. Fox Foundation for Parkinson's Research via a competitive LEAPS award to R.T.B. and J.S.

DISCLOSURE

R.T. Bartus is an employee of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives salary, benefits, and stock options. He is receiving grant support from the MJFF. T.L. Baumann is an employee of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives salary, benefits, and stock options. J. Siffert is a former employee of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and had previously received salary and benefits and still has stock options. He is currently employed at Avanir Pharmaceuticals, Inc., and also received grant support from the MJFF. C.D. Herzog is an employee of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives salary, benefits, and stock options. R. Alterman was an investigator for this trial and a paid consultant prior to its launch. N. Boulis has been a consultant to Ceregene and currently consults for NeuralStem. D.A. Turner is a consultant for Medtronics and has grants from NIH, the Defense Department, and the VA. M. Stacy was an investigator for this trial and is a consultant for Allergan, Chelsea, GE, GlaxoSmithKline, Merck, Merz, Neuronova, Novartis, Noven, Osmotica, SK Life Sciences, TEVA, and UCB. He has received grant support from IMPAX, MJFF, NIH, Novartis, and the Parkinson's Study Group. A.E. Lang is a member of the Scientific Advisory Board of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives financial remuneration and stock options. He is also a paid advisor to Boehringer-Ingelheim, Cephalon, Eisai, Medtronic, Lundbeck A/S, NeuroMolecular, Novartis, Solvay, Taro, and Teva. Grants: Canadian Institutes of Health Research, Dystonia Medical Research Foundation, Michael J. Fox Foundation, National Parkinson Foundation, Ontario Problem Gambling Research Centre, and Parkinson's Disease Foundation. Andres M. Lozano is a member of the Scientific Advisory Board of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives financial remuneration and stock options. He is also a member of the advisory boards for Johnson & Johnson (Corporate Office of Science and Technology), Codman, Brainstorm Cell Therapeutics, Neurophage, Aleva, and Alcyone Life Sciences. He is a cofounder and Chair of the SAB for Functional Neuromodulation and a consultant for Medtronic, St-Jude, Boston Scientific, Amgen, Ely Lilly, Bristol Myers, Elekta, Bayer, Schering-Plough, QIG, Focused Ultrasound Foundation, Neuronova, and Neurospace. C.W. Olanow is a member of the Scientific Advisory Board of Ceregene, which is developing AAV2-NRTN for Parkinson's disease, and receives financial remuneration and stock options. He also is a paid consultant for Novartis, Orion, Teva Pharmaceuticals, Lundbeck, Merck-Serono, and Abbott. Go to Neurology.org for full disclosures.

REFERENCES

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