Kaplitt, MG, Feigin, A, Tang, C, Fitzsimons, HL, Mattis, P, Lawlor, PA et al.. 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. Lancet 369: 2097-2105

Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY, USA.
The Lancet (Impact Factor: 45.22). 07/2007; 369(9579):2097-105. DOI: 10.1016/S0140-6736(07)60982-9
Source: PubMed


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 efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinson's disease.
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 fluctuations 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. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the registry, number NCT00195143.
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. Significant 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.
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.


Available from: Helen L Fitzsimons
Articles Vol 369 June 23, 2007
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
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 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
F-fl uorodeoxyglucose. The trial is registered
with the 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
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 defi ciency in a gene therapy
trial with adenovirus led to a temporary suspension of
gene therapy trials,
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.
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.
A trial aimed at correcting the
genetic defect in the rare and lethal paediatric neuro-
genetic Canavan disease was also undertaken.
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.
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.
The con-
sequence 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
Page 1
2098 Vol 369 June 23, 2007
excitatory pathways, leading to a movement disorder that
is characterised by diffi culty initiating movements,
muscular rigidity, and tremor.
facilitation of dopaminergic neurotransmission benefi ts
most patients initially, but those with advanced Parkinson’s
disease often develop unacceptable drug-related com-
plications such as dyskinesia and motor fl uctuations.
Once these complications have begun, interventions that
directly increase dopaminergic neuro transmission might
simply worsen dyskinesia and other dopamine-related
complications such as hallucinations. Hence, we explored
non-dopaminergic strategies that might provide
substantial benefi t without these side-eff ects. On the basis
of the hypothesis that re-establishment of normal brain
activity within motor circuits might reverse motor defi cits
of Parkinson’s disease, we developed a gene therapy
approach to deliver the glutamic acid decarboxylase (GAD)
gene directly into neurons of the human subthalamic
nucleus with an AAV vector. GAD catalyses synthesis of
GABA, the major inhibitory neurotransmitter in the brain;
in patients with Parkinson’s disease, activity of the
subthalamic nucleus is increased mainly because of
reduced GABAergic input from the globus pallidus.
Studies in human beings have shown that reduction of
activity of the subthalamic nucleus by electrical
stimulation, lesioning, or GABA infusion could ameliorate
signs of advanced Parkinson’s disease,
whereas studies
in animals indicate that AAV-GAD seems to improve brain
function and signs of the disease without toxic eff ects.
Our aim was to assess the safety and tolerability of
AAV-GAD gene therapy for patients with Parkinson’s
disease over a period of one year, using a single-arm,
open label, dose-escalation design. Here, we report the
clinical results of the completed 1 year follow-up in all
study patients.
12 patients (11 men and 1 woman; age 58∙2±5∙7 years) with
idiopathic Parkinson’s disease were enrolled in the study.
Entry criteria included: age between 25 and 70 years,
disease duration of at least 5 years, Hoehn and Yahr stage 3
or more,
score of 30 or more on the motor section
(part III) of the Unifi ed Parkinson’s Disease Rating Scale
(UPDRS) in the off medication state,
motor complications
of therapy with levodopa, and a stable antiparkinsonian
medication regimen for at least 3 months before the
baseline visit. Exclusion criteria included substantial
cognitive dysfunction on neuropsychological testing, medi-
cal contraindication to surgery, secondary or atypical
parkin son ism, and substantial psychiatric illness. Table 1
shows baseline demographic data.
Baseline neuropsychological assessment revealed an
estimated intelligence quotient of 111∙2 (SD=10∙2), no
evidence of dementia (dementia rating scale=137∙5,
SD=3∙1), and minor signs of depression (Beck depression
inventory=8∙0, SD=4∙0). The study was reviewed by the
advisory committee of the US National Institutes of
Health on recombinant DNA, and was approved by the
US Food and Drug Administration (FDA), and the
institutional review boards and institutional biosafety
committees at Weill Cornell Medical College and the
North Shore-Long Island Jewish Health System. The trial
was monitored by a medically qualifi ed monitor, an
external monitoring board for data and safety, and the
monitoring board for data and safety of Weill Cornell
Medical College. Informed consent for the study was
separately obtained at both participating institutions. The
trial is registered with the registry with
the number NCT00195143.
Patients underwent clinical screening within 1 month
before surgery, at baseline (within 1 week of surgery),
and 1, 3, 6, and 12 months after surgery. Participants were
contacted by telephone between the time of surgery and
the 1 month visit to inquire about adverse events.
Additionally, adverse events were assessed at every visit.
Part III (motor section) of the UPDRS was done at
baseline, and at 1, 3, 6, and 12 months in the
practically defi ned off state 12 h after withdrawal of all
antiparkinsonian medications, and in the on state 1 h
after administration of the usual morning dose of
medication. We also rated patients for dyskinesia
according to part IV of the UPDRS (complications of
Activities of daily living were rated at each
timepoint according to the Schwab and England scale.
Neuropsychological tests were completed before surgery
and after 12 months, according to a model that we
previously used to assess the eff ects of deep brain
stimulation of the subthalamic nucleus.
drug dosages were assessed at every visit and expressed
as levodopa equivalents.
Eff orts were made to restrict
GAD dose Age
Time on
Patient 1 Low 55 8 2 0‡ 250
Patient 2 Low 51 9 8 2000 2246
Patient 3 Low 62 13 11 1100 2018
Patient 4 Low 53 8 8 600 656
Patient 5 Medium 62 13 12 1250 1906
Patient 6 Medium 63 6 5 600 873
Patient 7 Medium 62 6 3 1000 1267
Patient 8 Medium 58 11 9 2000 2072
Patient 9 High 67 11 9 650 1173
Patient 10 High 51 13 13 600 461
Patient 11 High 50 7 7 1600 2300
Patient 12 High 63 6 4 1600 1600
Mean .. 58·2 9 8 1083 1402
Low dose=1×10
vg/mL. Medium dose=3×10
vg/mL. High dose=1×10
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 off of it for several years.
Table 1: Baseline demographic data
Page 2
Articles Vol 369 June 23, 2007
changes in medication dose throughout the course of the
study, but changes were allowed if medically required.
PET studies with ¹⁸F-fl uorodeoxyglucose were done
before gene therapy and repeated 12 months after surgery.
The details of these studies have been provided
All antiparkinsonian drugs were withheld
for at least 12 h before the imaging sessions. Images
from patients who had AAV-GAD infusion in the
subthalamic nucleus on the right side were reversed so
that all operated hemispheres appeared on the left.
Changes in regional metabolism associated with
AAV-GAD infusion in the subthalamic nucleus were
detected on a voxel basis by comparing the scans at
12 months to those at baseline with statistical parametric
mapping (SMP99, Wellcome Department of Cognitive
Neurology, Institute of Neurology, London, UK). We also
identifi ed brain regions in which changes in metabolic
activity after gene therapy correlated with clinical
outcome. The results were regarded as signifi cant if
p<0∙001, and were uncorrected for multiple regional
Viral vector
To create AAV-GAD vectors, AAV-GAD plasmids were
generated that contained DNA encoding the open reading
frame of human GAD65 or GAD67 under regulation of
the cytomegalovirus enhancer–chicken β-actin promoter
and woodchuck post-transcriptional regulatory element.
Recombinant AAV vectors were packaged in human
embryonic kidney (HEK) 293 cells and purifi ed by
heparin affi nity chromatography, according to standard
procedures and as previously described.
The fi nal
formulation buff er was 1× phosphate-buff ered saline
solution. The genomic vector titres were measured by
absolute quantifi cation with the ABI7000 Sequence
Detection System (Applied Biosystems, Foster City, CA,
USA). The viruses encoding GAD65 or GAD67 were
mixed in a 1-to-1 ratio and diluted to 1×10
viral genomes
(vg)/mL (low dose), 3×10
vg/mL (medium dose), and
vg/mL (high dose) with 1× phosphate-buff ered
saline solution. The bulk harvest and fi nal formulated
products were rigorously examined with lot-release
testing, as per FDA guidelines. Biosafety testing for
mycoplasma, endotoxin, sterility, and adventitious
viruses, and a general safety test were undertaken
(AppTec Laboratory Services, Philadelphia, USA).
The subthalamic nucleus was localised with the Leksell
stereotactic frame and MRI image guidance. Standard
intraoperative microelectrode recording was done with
patients awake to verify the precise location of the
subthalamic nucleus.
The tip of the microelectrode was
then withdrawn to what was believed to be the centre of
the subthalamic nucleus. 20 µL of 20% mannitol followed
by 45 µL of vector solution at the appropriate dose
concentration were drawn into a 100 µL Hamilton
syringe. A 165-µm diameter vitreous silica infusion
cannula was attached to the syringe and the system was
ushed until fl uid was seen from the cannula tip. The
syringe was inserted into a Harvard PicoPlus pump
(Harvard, Holliston, MA, USA), which was briefl y run at
2 µL/min to assess fl ow. The tungsten microwire was
withdrawn from the centre of the bipolar microelectrode
and the infusion cannula was inserted, placing the tip at
the same point in the centre of the subthalamic nucleus.
Infusions were done for 100 min at 0∙5 µL/min. After
completion, the catheter was left in place for 5 min to
reduce refl ux. The catheter and outer tube were then
withdrawn to place the catheter tip at the dorsal edge of
the subthalamic nucleus, which was left in place for a
further 5 min. The guide tube and infusion catheter were
then removed together to establish the integrity of the
system, and then the pump was run again to verify
patency and fl ow after completion.
Patients were divided into three equal groups (low,
medium, or high dose), and all received the same fi nal
injection volume of 50 µL. To retain one intact hemisphere
should an unexpected serious adverse event happen,
AAV-GAD vectors were infused unilaterally into the
subthalamic nucleus of the more symptomatic hemis-
phere, as requested by government reviewers. This
procedure also enabled the untreated side to serve as a
control for comparison with the AAV-GAD-injected
hemispheres. The small microinfusion volume and rate
combined with a single penetration of 200 µm or less in
the subthalamic nucleus of every patient reduced the risk
that damage to the subthalamic nucleus might result in
confounding persistent clinical or physiological
To measure titres of anti-AAV antibodies in peripheral
blood, an ELISA assay was developed with standard
methods. ELISA plates (Costar 96 wells, Corning, Acton,
MA, USA) were coated with 1×10
AAV serotype 2 (AVV2)
particles per well in 50 µL coating buff er (15 mmol/L
, 10∙5 mmol/L NaHCO
, pH 9∙6). After application
of serum or blank controls, affi nity-purifi ed goat anti-human
IgA, IgG, and IgM conjugated to horseradish peroxidise
(1 in 2000; Sigma-Aldrich, St Louis, MO, USA) or blanks
were applied to appropriate wells. After washing, plates
were incubated with 3,3´,5,5´-tetramethylbenzidine
substrate (Pierce, Rockford, IL, USA). The optical densities
at 450 nm were read on a plate reader (Bio-Rad Laboratories,
Hercules, CA, USA).
Titres for neutralising antibodies were also measured.
HEK293 cells were plated at a concentration of 4000 cells
per well in a 96-well plate, 16–24 h before addition of AAV
and serum samples. Duplicate serial 5-fold dilutions
from one in 20 to one in 62 500 were prepared for every
patient serum sample, anti-AAV (intact particle) positive
control antibody (Progen, Heidelberg, Germany), or
blank negative controls in a fi nal volume of 30 µL culture
media containing 2∙25×10
vg of AAV vector expressing
the luciferase reporter gene. After 1 h incubation at 37°C,
25 µL of every sample was added to the appropriate well
of the plate. After 48 h, luciferase transgene expression
Page 3
2100 Vol 369 June 23, 2007
was measured with Bright-Glo (Promega, Madison, WI,
USA) and a Turner BioSystems luminometer (Sunnyvale,
Anti-GAD65 antibodies from patient serum samples
were quantifi ed with an ELISA kit (W-12; Kronus, Boise
ID, USA), according to the manufacturer’s instructions.
Healthy blood-donor serum samples have less than
5 U/mL of anti-GAD65 antibodies, with positive controls
in the range of 42–62 U/mL. A comparable assay for
anti-GAD67 antibodies is not commercially available,
therefore an immunoblotting-based method was
developed. HEK293 cell lysates, which were transfected
with either GAD67 or plasmids expressing enhanced
green fl uorescent protein, were run on a sodium dodecyl
sulfate polyacrylamide gel, which was blotted and probed
with dilutions of an anti-GAD antibody (AB1511,
Chemicon, Temecula, CA, USA) with the patient serum
samples. The commercial anti-GAD antibody detected
the 67 kDa GAD protein at a sensitivity of one in 32 000.
Analysis of serum samples for immune reaction was
done by Neurologix.
Statistical analysis
Adverse events were tabulated and rated for severity
(mild, moderate, and severe) and for relation to the study
intervention (unlikely, possibly, probably, and likely).
Secondary eff ectiveness measures (UPDRS and activity
of daily living) were analysed by one-way repeated
measures analysis of variance (RMANOVA) with all fi ve
timepoints (baseline, 1, 3, 6, and 12 months), with posthoc
Bonferroni’s test to assess the statistical signifi cance of
changes at follow-up timepoints with respect to baseline.
Changes in regional metabolic activity between baseline
and 12 months were analysed by two-way RMANOVA,
with hemisphere (treated and untreated) and time
(baseline and 12 months) as within-subject repeated
measures. Changes from baseline to 12 months in
neuropsychological test performance and dopaminergic
drug use were assessed by paired t tests.
Role of the funding source
The funding source had no role in study design,
monitoring, or clinical data collection or analysis. This
study was done according to an investigator-initiated
FDA Investigational New Drug (IND) application held by
MJD. MGK, AF, and MJD had full access to all data in the
study. MJD had fi nal responsibility for the decision to
submit for publication.
All patients who enrolled had surgery; during the study,
no dropouts or loss of patient follow-up occurred, and
there were no adverse events related to the gene therapy.
No MRI evidence of haemorrhage or oedema was seen at
the infusion site after surgery, and no abnormalities were
noted on any of the postsurgical MRIs up to 1 year, with
the exception of expected routine signal changes, which
were seen on T2 images along the penetration tract. All
patients were discharged from the hospital 2 days after
surgery. No fever or medically relevant alteration in routine
blood and physiological indices were seen during this
time. Various adverse events took place that were rated as
mild and unrelated to the study intervention (table 2).
Three serious adverse events (defi ned as events that
need hospitalisation) took place, but they were unrelated
to the study intervention. One patient who received
low-dose AAV-GAD was treated in hospital for 1 night,
5 months after surgery, for a severe freezing episode in
the off state after discontinuing entecapone. 200 mg
entecapone was resumed, and the patient was discharged
the day after, with no subsequent adverse events. One
patient who received medium-dose AAV-GAD was treated
in hospital for exacerbation of a pre-existing chronic
obstructive pulmonary disease, 6 months after receiving
gene therapy. The patient recovered to baseline and had
no further such episodes. Finally, one patient who
received high-dose AAV-GAD needed an arthroscopic
knee procedure 9 months after surgery, with no
subsequent complications. No deaths and no new
neurological defi cits were reported in any patient during
the planned 1 year course of the study. At present, three
patients have had subthalamic nucleus AAV-GAD surgery
3 or more years previously, four 2–3 years previously, and
Patients Events Severity Relation to
Bronchitis 1 1 Mild Unrelated
Incisional pain 1 1 Mild N/A
Fatigue 1 1 Mild Unrelated
Bursitis 1 1 Mild Unrelated
Worsening PD 1 1 Severe (SAE) Unrelated
Rash 1 1 Mild Unrelated
Painful dyskinesias 1 1 Moderate Unrelated
Falls 4 5 Mild Unrelated
Rotator cuff injury 1 1 Mild Unrelated
*Pneumonia 2 1
Severe (SAE)
Insomnia 1 1 Mild Unrelated
Oedema 2 2 Mild Unrelated
Toothache 1 1 Mild Unrelated
Headache 1 1 Mild Unrelated
↑White blood cells 1 1 Mild Unrelated
↑Glucose 1 1 Mild Unrelated
Urinary frequency 2 3 Mild Unrelated
Urinary tract infection 1 1 Mild Unrelated
Depression 1 1 Mild Unrelated
Thumb fracture 1 1 Mild Unrelated
Data are numbers. PD=Parkinson’s disease. N/A=not determined. SAE=severe
adverse event. ↑=raised. *One patient had pneumonia, but did not need
hospital admission because pneumonia resolved with oral antibiotics, and one
patient had SAE.
Table 2: Adverse events
Page 4
Articles Vol 369 June 23, 2007
the remaining fi ve at least 1∙5 years previously. No deaths
or reports of new unexpected neurological complications
were recorded in any patients during these extended
periods, although patients’ examinations were not
routinely done beyond 1 year.
Clinical outcome
Figures 1 and 2 show that unilateral AAV-GAD treatment
of the subthalamic nucleus leads to a substantial
improvement in UPDRS motor ratings in both the off
and on states (F[4,44]=5∙23, p=0∙0015 for the off state;
F[4,44]=3∙78, p=0∙01 for the on state). Posthoc testing
showed no signifi cant change in the clinical ratings at
1 month after surgery compared with those at baseline.
However, both the off and on state ratings improved at
3 months (19%, p=0∙0244; and 25%, p=0∙0182), 6 months
(28%, p=0∙0006; and 26%, p=0∙0126), and 12 months
(24%, p=0∙0038; and 27%, p=0∙0098).
Ten of the 12 patients showed improvement in UPDRS
off scores at 12 months. Four patients improved
between 0% and 20%; two improved between 20%
and 40%; and four improved more than 40% in whole
body off period motor UPDRS with this unilateral
intervention. Table 3 shows off and on state UPDRS
scores for all participants at all timepoints.
Analysis of UPDRS ratings by body side showed a
consistent benefi t in limbs contralateral to the gene
therapy (fi gures 1 and 2). A signifi cant eff ect of time was
noted for the body side opposite the treated hemisphere
(off state: p=0∙0035; on state: p=0∙0007; RMANOVA).
Off state UPDRS scores on the treated side improved by
33% (p=0∙0012), and 29% (p=0∙0057) at 6 and 12 months,
respectively. There was no substantial eff ect of time on
the untreated body side.
Improvement in the ADL scores (off and on states)
were not signifi cant during the course of the study.
However, there was a trend towards improvement in the
off state ratings at 12 months (18%, p=0∙06; paired t test).
There was no signifi cant change with time in UPDRS
dyskinesia ratings, although a trend towards improvement
was noted at 12 months compared with that at baseline
(p=0∙0558, paired t test). Importantly, the amount of
antiparkinsonian medication per day did not change
signifi cantly during the course of the study (fi gure 3).
There were also no substantial changes in any of the
neuropsychological tests.
An unbiased blinded voxel-based comparison of the
PET scans at 12 months and baseline showed a substantial
reduction in glucose metabolism of the thalamus in the
operated hemisphere (p<0∙001, uncorrected; SPM paired
t test) (fi gure 4). This change was not present in the
mirror-image region on the non-operated side. Changes
in regional metabolism were diff erent for the two
hemispheres (interaction eff ect: p=0∙0096, two-way
RMANOVA). There was a signifi cant decline in metabolic
activity on the treated side (p=0∙007, posthoc test with
Bonferroni’s correction). No change was evident on the
untreated side. Improvements in motor UPDRS ratings
at 12 months were highly correlated with localised
metabolic increases in the supplementary motor area of
the operated hemisphere (p<0∙001, uncorrected; SPM
correlation analysis) (fi gure 5). No correlation was
detected between clinical outcome with gene therapy and
metabolic changes in the mirror-image cortical region of
the untreated hemisphere.
13 6 12
01 3 6
Total “off” UPDRS (motor)
Unilateral limb “off” UPDRS (motor)
Figure 1: Clinical improvement in motor ratings
At each timepoint, the motor component of the UPDRS was measured 12 h after
discontinuation of oral medications (off state). (A) Time-dependent
improvement in motor ratings. (B) Changes in motor ratings for both body
sides. *p<0·05; †p<0·01; ‡p<0·005.
01 3 6
01 3 6 12
Total “on” UPDRS (motor)
Unilateral limb “on” UPDRS (motor)
Figure 2: Clinical improvement in motor ratings
At each timepoint, the motor component of the UPDRS was measured 1 h after
administration of the usual morning dose of medication (on state).
(A) Time-dependent improvement in motor ratings. (B) Changes in motor
ratings for both body sides. *p<0·05; †p<0·01; ‡p<0·005.
Page 5
2102 Vol 369 June 23, 2007
At baseline, two patients showed evidence of substantial
anti-AAV2 immunity, with antibody titres of one in 6400
and one in 1600, respectively. All other patients had titres
of one in 200 or lower, with fi ve below the lowest dilution
of one in 50. None of these titres changed in any patient
at any of the postsurgical timepoints tested (1, 3, 6, and
12 months). There were no changes in IgA or IgM
concentrations in any patient over time, except for a
small IgM spike at 6 months in one patient, which was
not accompanied by a subsequent IgG spike and which
fell at 12 months. This range of baseline immunoglobulin
titres is very similar to what has been previously seen in
healthy populations,
and the absence of change with
time suggests that the vector infusion into the brain did
not induce immunity against AAV2.
The presence of high titres of antibodies, such as those
seen in two patients, would not necessarily preclude
AAV-mediated gene transfer unless their binding can
prevent AAV from entering cells and delivering genetic
material (ie, neutralising AAV transduction). Serum
samples were therefore also tested for the presence of
neutralising antibodies. With this assay, the same two
patients with high baseline IgG titres had titres of
neutralising antibodies of one in 12 500 and one in 2560,
respectively, in their presurgical serum samples, and the
titres remained constant at all postsurgery timepoints.
All serum samples from the remaining ten patients were
negative for neutralising antibodies at the lowest dilution
of one in 20 at baseline and throughout the study.
Although the number of patients was very small, a
correlation between pre-existing immunity and clinical
outcome did not seem to exist. The patient with a titre of
neutralising antibodies of one in 12 500 had an
8∙7% improvement in off period motor UPDRS at
12 months (patient 4, table 3), whereas the patient with a
titre of neutralising antibodies of one in 2560 had a
46% improvement at 6 months and 18% at 12 months,
which is greater than that in four patients who had very
low titres of neutralising antibodies (patient 10, table 3).
Finally, there was no evidence of pre-existing anti-GAD65
or anti-GAD67 autoantibodies, and no induction of such
antibodies at any timepoint during the 1 year of study in
any patient.
Our results show that AAV-mediated gene transfer can be
done safely in the human brain, with no evidence of
substantial toxic eff ects or adverse events in the
perioperative period and for at least 1 year after treatment.
Most patients have been followed up for more than
2 years after surgery, with some for more than 3 years.
No deaths and no evidence of substantial adverse events
were reported.
The promise of gene therapy has yet to be fulfi lled;
however, the ability to alter cellular function genetically
remains a powerful potential opportunity for treatment of
Dose Baseline 1 month* 3 months* 6 months* 12 months*
Off states
Patient 1 Low 35 26 (–26%) 18 (–49%) 25 (–29%) 15 (–57%)
Patient 2 Low 48 52 (8%) 45 (–6%) 48 (0%) 52 (8%)
Patient 3 Low 31 25 (–19%) 39 (26%) 22 (–29%) 27 (–13%)
Patient 4 Low 46 49 (7%) 44 (–4%) 52 (13%) 42 (–9%)
Patient 5 Medium 37 35 (–5%) 30 (–19%) 28 (–24%) 36 (–3%)
Patient 6 Medium 30 33 (10%) 30 (0%) 15 (–50%) 18 (–40%)
Patient 7 Medium 33 22 (–33%) 18 (–45%) 34 (3%) 22 (–33%)
Patient 8 Medium 38 19 (–50%) 17 (–55%) 18 (–53%) 16 (–58%)
Patient 9 High 36 43 (19%) 43 (19%) 33 (–8%) 49 (36%)
Patient 10 High 56 51 (–9%) 48 (–14%) 30 (–46%) 46 (–18%)
Patient 11 High 45 29 (–36%) 22 (–51%) 18 (–60%) 16 (–64%)
Patient 12 High 35 23 (–34%) 25 (–29%) 16 (–54%) 19 (–46%)
Mean .. 39·2 33·9 31·6 28·3 29·8
Change in group means relative to
–13·4% –19·4% –27·9% –23·8%
On states
Patient 1
Low 19 17 (–11%) 13 (–32%) 17 (–11%) 12 (–37%)
Patient 2
Low 29 25 (–14%) 22 (–24%) 29 (0%) 22 (–24%)
Patient 3
Low 9 14 (56%) 16 (78%) 15 (67%) 16 (78%)
Patient 4
Low 27 22 (–19%) 16 (–41%) 20 (–26%) 20 (–26%)
Patient 5
Medium 27 24 (–11%) 22 (–19%) 24 (–11%) 28 (4%)
Patient 6
Medium 19 18 (–5%) 16 (–16%) 7 (–63%) 9 (–53%)
Patient 7
Medium 24 17 (–29%) 12 (–50%) 20 (–17%) 10 (–58%)
Patient 8
Medium 12 14 (17%) 13 (8%) 10 (–17%) 8 (–33)
Patient 9
High 15 16 (7%) 20 (33%) 16 (7%) 26 (73%)
Patient 10
High 35 35 (0%) 33 (–6%) 24 (–31%) 32 (–9%)
Patient 11
High 33 15 (–55%) 9 (–73%) 8 (–76%) 5 (–85%)
Patient 12
High 16 9 (–44%) 6 (–63%) 5 (–69%) 5 (–69%)
.. 22·1 18·8 16·5 16·3 16·1
Change in group means relative to
–14·7% –25·3% –26·4% –27·2%
*Data are numbers (percentage change from baseline).
Table 3: Off and on state UPDRS scores
Medium dose
High dose
Low dose
Levodopa equivalency
Figure 3: Changes of daily dose of dopaminergic medication
Page 6
Articles Vol 369 June 23, 2007
various devastating diseases. Safety and effi cacy issues
continue to raise concerns, especially when gene therapy is
applied to diseases such as neurological disorders, in which
there is limited prior experience. Indeed, our original
protocol was modifi ed by federal reviewers to restrict
treatment to only one hemisphere of the brain because of
the concern that unexpected toxic eff ects might produce a
more devastating outcome if they happened bilaterally.
After approval and initiation of our study, several
additional AAV-mediated clinical gene therapy studies
have been undertaken, including two approaches to gene
therapy for Parkinson’s disease
NCT00252850), one for Alzheimer’s disease (ClinicalTrial.
gov, NCT00087789); and a paediatric study of Batten
disease (, NCT00151216). These studies
emphasise the interest in further development of gene
therapy for neurological diseases.
Direct introduction of genetic material into neurons is
increasingly interesting for various neurological diseases.
The only previous in-vivo gene therapy study for a
non-neoplastic neurological disorder was done in young
children aff ected by lethal neurogenetic Canavan disease.
Immunological data indicated detectable neutralising
antibodies in one of ten children before receiving a total
of 1×10
vector genomes; however, three of ten children
showed detectable neutralising antibodies after
Although we reported a slightly higher rate of
pre-existing neutralising antibodies (two of 12), there was
no change at any timepoint after surgery. Half of the
Figure 4: Reduction of thalamic metabolic activity after gene therapy of the
subthalamic nucleus
(A) Representative axial (top) and sagittal (bottom) slices at 12 months after
gene therapy. (B) Metabolic activity in this region was plotted for the operated
and non-operated hemispheres at baseline and 12 months. *p<0·02.
Figure 5: Changes in cortical metabolism after gene therapy of the
subthalamic nucleus
(A) Representative sagittal slice showing a signifi cant correlation between
clinical outcome at 12 months and postoperative metabolic changes in the
supplementary motor area of the operated hemisphere. (B) Regression line
showing this highly signifi cant clinical–metabolic correlation on the operated
hemisphere. No correlation was evident in the untreated side.
Thalamus (–4, –8, 6)
Metabolic activity
12 months
–1 –0·5
Medium dose
High dose
Low dose
Change in metabolic activity
Change in UPDRS (%)
SMA (–8, 4, 74)
Page 7
2104 Vol 369 June 23, 2007
patients with Canavan disease also had postoperative
fever, and four of ten patients developed small
subarachnoid haematoma, subdural haematoma, or
both, after surgery, whereas these clinical signs were not
reported in our study. It is likely that, in our study, the
use of a lower amount of virus delivered via a single brain
injection to a deep target accounts for these diff erences,
because in the study of patients with Canavan disease
many injections in the brain involving more viral vectors
might have increased the risk of immune reactions and
haemorrhagic events. Furthermore, the adult brain might
react diff erently to in-vivo gene therapy compared with
the brains of children. The absence of antibody responses
to either the AAV vector or the GAD genes after infusion,
even in preimmune individuals, also suggests that
immune-mediated reduction of gene expression, which
has been reported in a previous haemophilia gene therapy
study, might be a less serious issue for gene therapy in
the brains of most patients.
This open label, non-randomised phase I study was not
designed to assess the eff ectiveness of the intervention.
Nonetheless, the clinical outcomes were encouraging.
Substantial improvements in both the off and on states
were evident, beginning at 3 months after surgery and
continuing until the end of the trial. This improvement
was localised predominantly to the side of the body
contralateral to the treatment. The absence of change at
the earliest timepoint after surgery suggests that the
improvement that was seen was probably not due to
surgical lesions of the target region, which typically give
rise to an immediate perioperative benefi t. This result is
also consistent with previous studies of AAV-mediated
gene therapy in which gene expression gradually increases
to a maximum in a period of weeks.
In this study,
posthoc analysis showed a signifi cant improvement in
UPDRS scores from the visit at 1 month to those at
6 months and 12 months, further supporting a persis tent
eff ect of gene therapy rather than of a static lesion.
Despite the non-blinded nature of the clinical
assessments that were done in this study, these fi ndings
were in accord with PET imaging blinded to treatment
side. We reported that a substantial metabolic decline in
the ipsilateral thalamus happened 12 months after
unilateral gene therapy of the subthalamic nucleus.
Thalamic neurons in this brain region receive inhibitory
projections from the internal globus pallidus and the
substantia nigra pars reticularis, which are the primary
targets of output of the subthalamic nucleus. Glucose
use in the thalamus is consistently correlated with
pallidal neuronal activity in patients with Parkinson’s
and has been shown to fall after therapeutic
lesions of the globus pallidus and the subthalamic
Therefore, the drop in thalamic metabolism
after AAV-GAD injection into the subthalamic nucleus
is consistent with the changes that have been reported
after eff ective surgical interventions for this disorder.
We also showed that improvements in UPDRS motor
ratings at 12 months were highly correlated with
increases in the metabolism of premotor regions, as
also reported after surgery of patients with Parkinson’s
Overall, the fi ndings of the imaging studies
suggest that the clinical improvement after gene therapy
of the subthalamic nucleus is associated with objective
changes in the activity of thalamocortical motor
pathways, as described with other treatment strategies
for this disorder.
If eff ectiveness is confi rmed in larger, more defi nitive
studies, several potential advantages for the gene therapy
approach compared with traditional deep brain stimulation
exist. The absence of indwelling hardware reduces the risk
of infection, and some patients with Parkinson’s disease
simply prefer not to have an implanted device.
Additionally, frequent visits for deep brain stimulation
adjustments are not needed. Finally, gene therapy might
be a more physiological method to correct basal ganglia
motor circuitry. Although deep brain stimulation of the
subthalamic nucleus uses a fi xed voltage to regulate the
activity of this area locally, AAV-GAD gene therapy might
make the motor network function return to normal
through activity-dependent release of GABA both locally
within the subthalamic nucleus and throughout the
network via connections to other hyperactive areas, as
shown in our preclinical study
(ie, with loss of
dopaminergic tone and consequent disinhibition of the
subthalamic nucleus, the transduced neurons increased
ring and GABA release). The locally released GABA acts
as an autoregulatory negative feedback mechanism on
receptors of the subthalamic nucleus to
hyperpolarise and reduce neuronal fi ring, leading to a
reduction in the ectopically-derived GABA release and
providing homeostatic physiological control. Indeed, the
magnitude of the improvement in the on state UPDRS, an
eff ect not usually seen to this degree with deep brain
stimulation of the subthalamic nucleus, lends support to
this possibility.
We did not see a clear eff ect of viral-vector dose on
clinical outcome in this small study. Several factors might
have contributed to the absence of such an eff ect. First,
the small sample size per dose group is not powered to
detect diff erences in eff ectiveness by the clinical outcome
measures reported here. Second, Parkinson’s disease can
be quite heterogeneous in presentation, and it is possible
that this therapy might be most eff ective for some rather
than all of the symptoms. Because this study was not
randomised, the diff erent dose groups were not tightly
matched for disease severity and symptom expression.
Finally, more uniform and pronounced eff ects might be
achieved if bilateral surgery had been done. Although the
apparent laterality and time course of benefi ts lend
support to a specifi c biological eff ect and this hypothesis
is reinforced by the blinded regional hemispheric
18F-fl uorodeoxyglucose PET metabolic changes in these
patients, concerns regarding possible placebo eff ects
cannot yet be completely excluded from this study.
Page 8
Articles Vol 369 June 23, 2007
MGK, AF, DE, and MJD designed the study. MJD sponsored the FDA
IND. Preparation and characterisation of viral vectors were done by PAL,
RJB, HLF, and DY. Surgical procedures were done by MGK, and
infusions were done by MGK and MJD. Pre-surgical clearance was done
by MGK and KS. All UPDRS ratings, other clinical measurements, and
PET studies, before surgery and at all subsequent timepoints, were
undertaken by AF and DE. AF and DE also had fi nal control over patient
recruitment and entry into the study. HLF measured immunoglobulins
in the serum of patients. Statistical analysis was done by CT. Data
interpretation and writing of the article were primarily done by MGK,
AF, DE, and MJD, with contributions from all authors. MGK and AF,
and DE and MJD, contributed equally to this study.
Confl ict of interest statement
MGK and MJD are founders of and consultants to Neurologix, which
funded this study. They and their families have substantial ownership
interest in the company. HLF and RJB are employees of Neurologix. The
remaining authors, including those responsible for the assessment of
study eligibility, and for the clinical measurements and statistical analyses,
have no involvement in Neurologix and declare no confl ict of interest.
We thank Weidong Xiao and Lei Cao for rAAV infectious titre and rcAAV
assays, respectively, and Dahna Fong and Claudia Leichtlein for technical
assistance. The study was funded by Neurologix. We thank Sumit
Raniga, Scott McPhee, and Meryl Latsko for help in preparing and fi ling
the NIH Recombinant DNA Advisory Committee and FDA
Investigational New Drug applications.
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  • Source
    • "Rigorous toxicity , and serological and cellular immune assessments have been performed for AAV1 , AAV2 , AAV5 AAV8 and AAVrh10 . These serotypes have been used in clinical trials for lipoprotein lipase deficiency ( LPLD ; AAV - 1 ; Scott , 2015 ) , Canavan disease , PD and AD ( AAV - 2 ; Leone et al . , 2000 , 2012 ; Kaplitt et al . , 2007 ; Richardson et al . , 2011 ; Bartus et al . , 2013 ; Rafii et al . , 2014 ) , liver mediated diseases ( AAV5 ; Grosios and Pañeda , 2013 ) , San Fillipo B ( AAV5 , AAVrh10 ; Tardieu et al . , 2014 ) 1 and Hemeophilia B ( AAV - 5 , AAV - 8 ; Nathwani et al . , 2014 ) . Although most humans have natural occurring neutralizing antibodies "
    [Show abstract] [Hide abstract] ABSTRACT: Clinical phase I/II studies have demonstrated the safety of gene therapy for a variety of central nervous system disorders, including Canavan's, Parkinson's (PD) and Alzheimer's disease (AD), retinal diseases and pain. The majority of gene therapy studies in the CNS have used adeno-associated viral vectors (AAV) and the first AAV-based therapeutic, a vector encoding lipoprotein lipase, is now marketed in Europe under the name Glybera. These remarkable advances may become relevant to translational research on gene therapy to promote peripheral nervous system (PNS) repair. This short review first summarizes the results of gene therapy in animal models for peripheral nerve repair. Secondly, we identify key areas of future research in the domain of PNS-gene therapy. Finally, a perspective is provided on the path to clinical translation of PNS-gene therapy for traumatic nerve injuries. In the latter section we discuss the route and mode of delivery of the vector to human patients, the efficacy and safety of the vector, and the choice of the patient population for a first possible proof-of-concept clinical study.
    Full-text · Article · Jul 2015 · Frontiers in Molecular Neuroscience
    • "An open label trial evaluated the safety and tolerability of unilateral subthalamic viral vector (AAV-GAD) in 12 patients with advanced PD, and reported significant improvements in motor symptoms 3 months after gene therapy that persisted for up to 12 months. No adverse events related to gene therapy were observed (Kaplitt et al., 2007). These findings suggested that AAV-GAD gene therapy of the subthalamic nucleus was safe and well tolerated by patients with advanced PD. "
    [Show abstract] [Hide abstract] ABSTRACT: The prevalence of Parkinson’s disease (PD) increases with age and is projected to increase in parallel to the rising average age of the population. The disease can have significant health-related, social, and financial implications not only for the patient and the caregiver, but for the health care system as well. While the neuropathology of this neurodegenerative disorder is fairly well understood, its etiology remains a mystery, making it difficult to target therapy. The currently available drugs for treatment provide only symptomatic relief and do not control or prevent disease progression, and as a result patient compliance and satisfaction are low. Several emerging pharmacotherapies for PD are in different stages of clinical development. These therapies include adenosine A2A receptor antagonists, glutamate receptor antagonists, monoamine oxidase inhibitors, anti-apoptotic agents, and antioxidants such as coenzyme Q10, N-acetyl cysteine, and edaravone. Other emerging non-pharmacotherapies include viral vector gene therapy, microRNAs, transglutaminases, RTP801, stem cells and glial derived neurotrophic factor (GDNF). In addition, surgical procedures including deep brain stimulation, pallidotomy, thalamotomy and gamma knife surgery have emerged as alternative interventions for advanced PD patients who have completely utilized standard treatments and still suffer from persistent motor fluctuations. While several of these therapies hold much promise in delaying the onset of the disease and slowing its progression, more pharmacotherapies and surgical interventions need to be investigated in different stages of PD. It is hoped that these emerging therapies and surgical procedures will strengthen our clinical aramamentum for improved treatment of PD.
    No preview · Article · Nov 2014 · Pharmacology [?] Therapeutics
  • Source
    • "Moreover, Y4 receptor knockout mice have also revealed a potential role for Y4 receptors in both anxiety-and depression-like behaviours (Painsipp et al., 2008). Gene therapy with viral vectors is under investigation as a future treatment option for brain disorders, particularly of neurological origin (Alexander et al., 2010; Hudry et al., 2010; Kaplitt et al., 2007; Manfredsson and Mandel, 2010; Mitra and Sapolsky, 2010; Woldbye Funding: This work was supported by The "
    [Show abstract] [Hide abstract] ABSTRACT: Neuropeptide Y (NPY) causes anxiolytic- and antidepressant-like effects after central administration in rodents. These effects could theoretically be utilized in future gene therapy for anxiety and depression using viral vectors for induction of overexpression of NPY in specific brain regions. Using a recombinant adeno-associated viral (rAAV) vector, we addressed this idea by testing effects on anxiolytic- and depression-like behaviours in adult mice after overexpression of NPY transgene in the amygdala and/or hippocampus, two brain regions implicated in emotional behaviours. In the amygdala, injections of rAAV-NPY caused significant anxiolytic-like effect in the open field, elevated plus maze, and light-dark transition tests. In the hippocampus, rAAV-NPY treatment was associated with anxiolytic-like effect only in the elevated plus maze. No additive effect was observed after combined rAAV-NPY injection into both the amygdala and hippocampus where anxiolytic-like effect was found in the elevated plus maze and light-dark transition tests. Antidepressant-like effects were not detected in any of the rAAV-NPY injected groups. Immobility was even increased in the tail suspension and forced swim tests after intra-amygdaloid rAAV-NPY. Taken together, the present data show that rAAV-NPY treatment may confer non-additive anxiolytic-like effect after injection into the amygdala or hippocampus, being most pronounced in the amygdala.
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