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This presentation contains forward-looking statements. All statements other than statements of historical fact
are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,”
“estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,”
"will,” “would” and similar expressions. Forward-looking statements are based on management's beliefs and
assumptions and on information available to management only as of the date of this press release. These
forward-looking statements include, but are not limited to, statements regarding the development of our gene
therapies, the success of our collaborations, and the risk of cessation, delay or lack of success of any of our
ongoing or planned clinical studies and/or development of our product candidates. Our actual results could
differ materially from those anticipated in these forward-looking statements for many reasons, including, without
limitation, risks associated with collaboration arrangements, our and our collaborators’ clinical development
activities, regulatory oversight, product commercialization and intellectual property claims, as well as the risks,
uncertainties and other factors described under the heading "Risk Factors" in uniQure’s Quarterly Report on
Form 10-Q filed on November 1, 2017. Given these risks, uncertainties and other factors, you should not place
undue reliance on these forward-looking statements, and we assume no obligation to update these forward-
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D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 3
1. McColgan P, Tabrizi SJ. Eur J Neurol. 2018;25(1):24-34; 2.Tabrizi SJ, et al. Lancet Neurol 2009;8(9):791-801; 3. Nopoulos PC, et al. Neurobiol Dis 2010;40(3):544-54 Figure adapted from Brundin P, et al. Nat Rev Mol Cell Biol 2010;11:301-7.
The shading and arrows
indicate the progression of
pathology. Darker shading
represents earlier onset.
Occipital
lobe
Frontal
lobe
Somatomotor
cortex
Parietal
lobe
1
2 3
3
Somatosensory
cortex
Huntington’s Disease
• Autosomal dominant neurodegenerative disorder
• Expansion of CAG trinucleotide huntingtin (HTT) exon 1
• No disease-modifying therapies available
• Prevalence of 60,000 to 70,000 patients in US and EU
• Significant additional patients undiagnosed
Expected progression of brain pathology
• The striatum is the primary site of pathology
• Premanifest stage: atrophy spread and cortical thinning
• Motor symptoms manifest as atrophy increases
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 4
One-time intracranial injection of AMT-130 into striatum (caudate nucleus and putamen)
What is AMT-130 and how do we deliver it?
1. Samaranch L, et al. Gene Ther 2017;24:253-261;
2. Evers M, et al. Mol Ther 2017;5(Suppl. 1);247. AAV5, adeno-associated viral vector serotype;
CED, convection-enhanced delivery; MRI, magnetic resonance imaging
Image reproduced from:
https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum
Caudate nucleus
Putamen
AAV5
capsid
Expression
cassette
miR-451-HTTCAG promoter
ITR
polyA
ITR
AAV5-miHTT (Company name AMT-130)
• Replication deficient AAV5
• Targeting toxic huntingtin (HTT) exon1
• miQURE® technology
• Phase I/II study to start in 2H19
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 5
Mechanism of Action of AMT-130
miQURE® technology1. PoI II expression
Tissue specificity and regulation
2. Guide strand activity only
Lower risk of off-target
3. No saturation of cellular RNAi
Increased safety profile
4. Nuclear and cytoplasmic effect
Increased efficacy
5. Indication of spread via
extracellular vesicles
Increased efficacy
[ASGCT abstract #228]
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 6
Proof-of-Concept of AMT-130 gene therapyFrom patient cells to large animals
NHP HD pigshuman neurons Diseased rodent models
Safety
Efficacy
Safety
Efficacy
Distribution
4 types HD Mouse3 tgHD Minipig2
HD Rat4
1. Samaranch L, et al. Gene Ther 2017;24:253-261; 2. Evers M, et al. Mol Ther 2017;5(Suppl. 1):247;3. Spronck EA, et al. Hum Gene Ther 2017;28:A78; 4. Miniarikova J, et al. Gene Therapy 2017;24:630-639
Non-human primate1
No off-target effects
Well tolerated in GLP-TOX studies
Safety
Efficacy
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 7
Assessment of AMT-130 persistence in a large brainLong-term study in tgHD minipigs
Baxa et al., J Huntingtons Dis (2013) 2:47 | Evers et al., Mol Ther (2018) 26:2163
Human
HTT promoter
124 CAG/CAA repeat
Truncated human HTT
(Exon 1 to 12)
Libechov minipig:
Life-span: 12-20 years
Body weight: 50-140 kg
Brain weight: 90-100 g
Highly developed immune system
• Good model to assess biodistribution and target engagement in large brain
• Ubiquitous expression of human mtHTT(548aa N-terminal fragment)
putamen
caudate
• Treatment groups:
Control (untreated)
AAV5-miHTT (1.2 x 1013 gc/animal)
(100μL/structure, max rate 3 μL/min)
• CSF collection
• Per treatment group, interim sacrifices:
6 months (n=3/group)
12 months (n=4/group)
>24 months (n=8/group) [in-life]MRI-guided CED
Study design
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 8
• Brains cut in n=12 (4mm-thick) slices (4mm punches)
• One hemisphere used for bioanalysis
6 months interim sacrifice → n=54 punches (alternate slices)
12 months interim sacrifice → n=170 punches (all slices)
Assessment of AMT-130 biodistribution and efficacyExtensive brain dissection and bioanalysis
sagittal view
coronal view
• DNA isolation → vector DNA (Q-PCR)
• RNA isolation → miHTT (RT-QPCR)
• Tissue lysate and CSF → mHTT protein
(2B7-MW1 Singulex immunoassay)
Bioanalysis
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 9
Widespread vector DNA distribution across cortical regions
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s /
μg
DN
A
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
12
m
6m
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
T31
T29
T34
T55
T58
T62
T63
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
T31
T29
T34
T55
T58
T62
T63
Animal ID#
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 10
Widespread vector DNA distribution across cortical regions
prefronta
l
moto
r
cingula
te
insu
lar
som
atose
nsory
som
atom
otor
perirh
inal
/ret
rosp
lenia
l
tem
poral
visu
al
103
104
105
106
107
Cortex
VG
co
pie
s / μ
g D
NA
LLoQ
12 months
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 11
Vector DNA in subcortical regions:detected in all brain regions except brainstem and cerebellum
40
60
62
80
42
64
66
82
84
44
68
10
01
02
12
4
12
01
44
102
103
104
105
106
107
108
VG
co
pie
s /
μg
DN
A
Caudate
Puta
men
Glo
bus palli
dus
Acc
umbe
ns
Am
ygda
la
Hip
pocam
pus
Striatum andLimbic areas
LLoQ
10
41
26
13
8
10
6
10
81
28
13
0
14
0
14
2
15
2
15
0
16
4
17
0
15
41
56
15
81
60
16
61
68
18
22
56
92
96
13
41
62
102
103
104
105
106
107
108
Thalamus, Mesencephalon,Brainstem and Cerebellum
LLoQ
Thala
mus,
L
Thala
mus
, MD
Thala
mus
, VL
Tha
lam
us, Z
I
Thala
mus
, VPM
/VPL
Red n
ucleus
Mes
enceph
alon
Pons
Med
ulla
Cere
bellum
Whi
te m
atte
r
12
m
6m
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
T31
T29
T34
T55
T58
T62
T63
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
T31
T29
T34
T55
T58
T62
T63
Animal ID#
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 12
Highly comparable vector DNA brain distributionat 6 and 12 months post-administration
Pre
fronta
l
Som
ato-S
/M
Tempora
l
Cau
date
Puta
men
Am
ygdal
a
Thalam
us
Pons
Cer
ebel
lum
White
mat
ter
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
12 months
6 monthsCortex Striatum
LLoQ
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 13
Expression of therapeutic miHTT strongly correlates with vector DNA levels in all brain regions
2 41
01
22
42
62
8 81
43
43
64
62
04
87
23
85
87
89
8 61
63
03
25
47
47
65
05
28
89
01
10
11
41
16
13
21
22
14
87
08
61
12
94
11
81
36
14
64
06
06
28
04
26
46
68
28
44
46
81
00
10
21
24
12
01
44
10
41
26
13
81
06
10
81
28
13
01
40
14
21
52
15
01
64
17
01
54
15
61
58
16
01
66
16
81
82
25
69
29
61
34
16
2
10 -1
100
101
102
103
104
105
miH
TT
(m
ole
c/c
ell
)
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Caudate
Puta
men
Glo
bus palli
dus
Acc
umbe
ns
Am
ygda
la
Hip
pocam
pus
Thalam
ic n
ucle
i
Tempo
ral
Mes
enceph
alon
Pons
Med
ulla
Cortex
Striatum and
Limbic areas Thalamus
Mesenceph., Brainst.,
Cerebellum
Cere
bellum
Whi
te m
atte
r
LLoQ
102 103 104 105 106 107 108
10 -1
100
101
102
103
104
105
VG copies/ug DNA
miH
TT
(m
ole
cu
les/c
ell) 0.8963Pearson r
<0.0001p
12
m
2 41
01
22
42
62
8 81
43
43
64
6
20
48
72
38
58
78
98 6
16
30
32
54
74
76
50
52
88
90
11
01
14
11
61
32
12
21
48
70
86
11
2
94
11
81
36
14
6
102
103
104
105
106
107
108
VG
co
pie
s / μ
g D
NA
Pre
front
al
Mot
or
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Visual
Perir
hinal
Retr
osple
nial
Tempo
ral
Cortex
LLoQ
T31
T29
T34
T55
T58
T62
T63
Animal ID#
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 14
Strong long-term lowering of mutant HTT protein in the tgHD minipig brain, comparable at 6 and 12 months
Pre
fronta
l
Moto
r
Cin
gulate
Insu
lar
Som
atose
nsory
Som
atom
otor
Vis
ual
Per
irhin
al
Ret
rosp
lenia
l
Tempora
l
Cau
date
Puta
men
Glo
bus pal
lidus
Acc
umben
s
Am
ygdal
a
Hip
pocam
pus
Thalam
us, L
Thalam
us, M
D
Thalam
us, V
PL
Thalam
us, V
PM
Thalam
us, V
L
Thalam
us, Z
I
Red
nucl
eus
Mes
ence
phalon
Pons
Med
ulla
Cer
ebel
lum
White
mat
ter
0
20
40
60
80
mu
tan
t H
TT
(p
g/μ
g t
ota
l p
rot.
)
Control (untreated) AAV5-miHTT (12 months)
CortexStriatum and
Limbic areas ThalamusMesenceph., Brainst.,
Cerebellum
***
**
**
##
#
*
***
*******
**
***
****
* *
** ***
**
*
*
* *
****
Pre
fronta
l
Som
ato-S
/M
Tempora
l
Cau
date
Puta
men
Am
ygdal
a
Thalam
us
Pons
Cer
ebel
lum
White
mat
ter
0
25
50
75
100
125
mu
tan
t H
TT
pro
tein
(% f
rom
na
ive
)
6 months
12 months
Cortex Striatum
30%
50%
70%
Two-tailed t-test (#p<0.1, *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001)
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 15
Mutant HTT protein in CSF is also lowered, but does not accurately reflect mHTT lowering in brain tissue
Increase in CSF mHTT levels with age
predose 6 12
0
100
200
300
400
Time post-injection (months)C
SF
mH
TT
(fM
)
Control (untreated)
AMT-130
6 9 12 15 18
0
100
200
300
400
tgHD minipig age (months)
CS
F m
tHT
T(f
M)
AMT-130 datapoints from 3-12 months post-injection
predose 6m 12
m
0
25
50
75
100
125
CS
F m
HT
T (
% f
rom
co
ntr
ol)
70%
50%
30%
→ Prefrontal cortex
→ Caudate
→ Putamen
→ Thalamus
40%
80%
85%
45%
45%
75%
70%
55%
Brain mHTT lowering
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 16
Conclusions
• Strong and sustained target engagement and efficacy of one-time intrastriataladministration of AMT-130 in tgHD minipigs
• Significant correlation between vector DNA, miHTT and mHTT protein lowering
• Highly comparable between 6 and 12 months post-administration
• First time that sustained and non-toxic mHTT protein lowering is shown in a large brain
• Widespread effects, both in target regions (striatum) and more distal areas (thalamus and cortex)
D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S A A V 5 - m i H T T m e d i a t e d H T T l o w e r i n g i n t g H D m i n i p i g s | A S G C T M a y 1 , 2 0 1 9 | 17
Acknowledgements
Institute of Animal Physiology and Genetics (Czech Republic)
Jiri Klima | Bozena Bohuslavova | Zdenka Ellederova | Jan Motlik
CHDI (USA)
Doug Macdonald | David Howland
IRBM (Italy)
Roberta Pintauro | Valentina Fodale | Alberto Bresciani
uniQure (The Netherlands)
Anouk Stam | Cynthia Brouwers | Lieke Paerels
Marina Sogorb-Gonzalez | Bas Blits
Melvin Evers | Pavlina Konstantinova | Sander van Deventer