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Supplementary information S1 (table). Summary of recent clinical trials using adeno-associated virus.
Disease

AAV Serotype

Transgene

Clinical

Route of Ad-

Clinical Trial

Phase

ministration

Identifier

Phase I/II/III

Intramuscular

NCT01109498

Successes

Limitations

References

decrease of median tryglyceride levels seen in all patients

drop in triglyceride levels was transient, anti-

1, 2, 3

Skeletal Muscle
LPL Deficiency

AAV1

LPL

AAV capsid-specific T cells were detected in

half of subjects
NCT00891306

significant reduction in mean total plasma triglyceride levels;

1/5 patients did not have decreased triglyceride

improved postprandial chylomicron metabolism

levels; plasma glucose and insulin levels did not

change

Alpha 1 Antitrypsin Deficiency

AAV2

1 antrypsin

Phase I/II

Intramuscular

AAV1

Duchenne Muscu-

AAV1/AAV2

lar Dystrophy

chimera

NCT00377416
NCT00430768

Microdystrophin

Phase I

Intramuscular

NCT00428935

Phase I: vector DNA sequences detected in the blood of most pa-

Phase I: transgene expression was below thera-

tients receiving mid to high doses; one patient exhibited low-level

peutic levels in most patients, anti-AAV2 capsid

expression of AAT; Phase II: AAT expression oin serum was dose

antibodies were present and rose after vector

dependent, peaked on day 30, and

injection; Phase II: transgene expression was

persisted for at least 90 days

below therapeutic levels

first demonstration of safety of an engineered AAV vector; no

weak or undetectable transgene levels in

cellular immune response was mounted against capsid

biopsied muscle tissue 1.5-3 months post-

4, 5

administration
Limb-Girdle Mus-

AAV1

-sarcoglycan

Phase I

Intramuscular

NCT00494195

cular Dystrophy

persistent -sarcoglycan gene expression for six months in most

one patient had early rise in neutralizing

subjects, increase in muscle fiber size,

antibody titers and AAV capsid-specific T cells;

7, 8

and restoration of the full sarcoglycan complex

Eye
Lebers Congential

AAV2

RPE65

Phase I/II

Subretinal

NCT00516477

Amaurosis

sustained improvement in subjective and objective measure-

one patient developed an asymptomatic macular

9, 10, 11,

ments of vision (dark adaptometry, pupillometry, electroretin-

hole (but had some return of retinal function),

12, 13, 14

ography, nystagmus, and ambulatory behaviour), at least a 2

full normal vision was not achieved; older

log unit increase in pupillary light responses, 1 patient achieved

patients did not respond as well as younger

nearly the same level of light sensitivity as that in age-matched

patients

normal-sighted individuals, improvements persisted at 12 month

follow-up
NCT00643747

1/3 patients had significant improvement in visual function on

no significant change in visual acuity or in

microperimetry, dark-adapted perimetry, and a subjective test of

peripheral visual fields on Goldmann perimetry

visual mobility

in 3/3 patients, no change in retinal responses

on electroretinography

NCT00481546

all patients self-reported increased visual sensitivity in the study

visual acuity was not significantly different from

eye (especially noticeable under reduced ambient light condi-

baseline, one patient showed retinal thinning

tions), dark-adapted FST sensitivity was significantly increased;

at the fovea

improvements persisted at 12 month follow-up

Choroderemia

AAV2

REP1

Phase I/II

Subretinal

NCT01461213

increased maximal and mean retinal sensitivity in all patients

retinal detatchment seen in all patients; small

15

losses in visual acuity (measured by ETDRS

letters) in 4 patients

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Liver
Hemophilia B

AAV2

Factor IX

Phase I/II

Intramuscular

NCT00076557

safety was established; transgene expression was seen in all

circulating Factor IX levels were low

16, 17, 18

subjects
Phase I

AAV8

Phase I/II

Hepatic

Intravenous

NCT00515710

NCT00979238

circulating Factor

Factor IX levels

IX levels in the range of 1012% of normal for one patient

persisted for only approximately 10 weeks; anti-

administered the

AAV capsid neutralizing antibodies and T cells

highest dose tested

prevented transgene expression

FIX protein secretion into blood at sufficient levels to alleviate

2/6 patients were unable to completely discon-

the patients bleeding phenotype in all patients; 4/6 patients

tinue prophylactic injections of FIX protein;

discontinued FIX prophylaxis and remained free of spontaneous

highest dose cohort: transient (but asympto-

hemorrhage

matic) elevation of serum aminotransferase

levels and detection of AAV8-capsidspecific
T cells in the peripheral blood in one patient
and slight increase in liver-enzyme levels in the
other patient

Cardiac Muscle
Severe Heart

AAV1

Failure

SERCA2a

Phase I/II

Coronary Artery Infusion

NCT00454818

Phase I: decrease in symptoms, functional status, biomarker pres-

Phase I: 2/9 patients showed no improvement

ence, and left ventricular function; Phase II: significant increases

(although pre-exisiting anti-AAV antibodies

in the time to clinical events, decreased frequency of cardiovas-

were detected); individual patients did not show

cular events, and decreased mean duration of cardiovascular

improvements across all parameters; Phase II:

hospitalizations over 12 months post-administration

improvements in all primary end point success

19, 20

criteria was seen only in highest dose cohort

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Central Nervous System

Parkinsons

AAV2

GAD

Phase I/II

Intracranial

Disease

NCT00195143

Phase I: significant improvements in UPDRS motor scores up

Phase I: non-significant improvement in ADL

NCT00454818

to 12 months post-surgery, substantial reduction in thalamic

scores and non-significant change with time

metabolism; Phase II: significant improvements in UPDRS motor

in UPDRS dyskinesia ratings; Phase II: non-

scores over the 6-month course of the study

significant improvements compared to sham

21, 22

in secondary measures (dyskinesia rating scale,

brief parkinsonism rating scale score, PDQ-39
score, and the activities of daily living subscore
of the UPDRS)
Neurturin

Phase I/II

NCT00252850
NCT00400634

Phase I: UPDRS motor score and time without troublesome

Phase I: non-significant improvements in

dyskinesia were improved 1 year post-administration

secondary measures (timed walking test, the

23, 24

Purdue pegboard test of hand dexterity, the

reduction in off time, and the activities of daily
living subscore of the UPDRS, and F-levodopa-uptake); Phase II: did not meet its primary
clinical endpoint

AADC

Phase I

NCT00229736

improvement in UPDRS motor score and increases in AADC

non-significant improvements in stand-walk-

enzyme activity

sit test and UPDRS III scores; non-significant

25, 26

changes in the UPDRS ON state and the percent

of ON state hours in a day
Canavans Disease

AAV2

Aspartoacylase

Phase I

Intracranial

N/A

low to no anti-AAV capsid antibodies were present in blood

no efficiacy data reported

27

assessment of the neurologic rating scale (primary outcome vari-

mild, mostly transient, humoral response to the

28

able) demonstrated a significantly reduced rate of decline

vector developed in 4/10 subjects, measured

post-administration; minimal systemic signs of inflammation or

immune stimulation; complete absence of neutralizing antibody
titers and no overt signs of brain inflammation
Battens Disease

AAV2

CLN2

Phase I

Intracranial

NCT00151216

rates of decline of all MRI parameters were

slower, but not significant
Lungs
Cystic Fibrosis

AAV2

CFTR

Phase I/II

Aerosol

NCT00004533

vector was deemed safe and well-tolerated

trials did not meet primary clinical endpoints,

29, 30, 31,

transgene expression was transient

32, 33

34, 35

Synovial Joints
Rheumatoid

AAV2

arthritis

TNF Receptor Antibody fusion

Phase I/II

Intraarticular

NCT00617032

2/11 patients experienced decreased swelling; 30% decrease in

mild knee pruritus was reported in one patient;

NCT00126724

target joint global visual analog scale was observed in 21/50

dose-dependent, mild to moderate increases in

patients

tenderness and swelling of the injected joint,

occurred after 23/191 injections

AAV, adeno-associated virus; LPL, lipoprotein lipase; RPE65, Retinal Pigment Epithelium-Specific Protein 65 kDa; SERCA2a, sarcoplasmic reticulum calcium ATPase 2a; GAD, glutamic acid decarboxylase; AADC, L-amino acid decarboxylase; CLN2,
ceroid lipofuscinosis neuronal-2; CFTR, cystic fibrosis transmembrane conductance regulator; TNF, tumor necrosis factor.

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