late infantile neuronal ceroid lipofuscinosis (lincl) l rare, autosomal recessive, fatal lysosomal...
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Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)
Rare, autosomal recessive, fatal lysosomal storage disease with extensive CNS neurodegeneration
Caused by mutations in the CLN2 gene, coding for a tripeptidyl peptidase (TPP-I) that normally functions to remove waste membrane proteins
Prior studies have demonstrated high level, long term TPP-I expression in the brain following intracranial gene transfer using an AAV2-based vector expressing the human CLN2 cDNA (AAV2CUhCLN2)1
AAV2 mediated gene transfer to the CNS corrects the storage defect in CLN2 knockout mice2
1 Sondhi et al, ASGT Abstract #6602 Passini et al. ASGT Abstract #427
Clinical Assessment of LINCL
Challenge To develop a non-invasive strategy to assess
the efficacy of direct CNS administration of AAV2CUhCLN2 in clinical studies
Strategy Assess magnetic resonance spectroscopy as a
method to evaluate the status of the CNS in children with LINCL over time
Demographic Characteristics of Study Population
Subject Sex GenotypeAge at 1st MRS1
scan (yr)Interval between 1st and 2nd MRS (days) LINCL rating2
1 M G3556C / T3016A 8.4 74 3 (severe)
2 M G3556C / G3085A 9.2 92 3 (severe)
3 M G3556C / G3085A 6.6 127 3 (severe)
4 F C3670T / T4396G 13.6x nd1 3 (severe)
5 M G3556C / C3670T 6.2 336 5 (moderate)
6 F G3556C / G3556C 7.9 46 3 (severe)
7 F G3556C / G3556C 6.6 nd 3 (severe)
8 M G3556C / G3556C 6.0 nd 4 (severe)
9 M G3556C / T4383C 6.8 nd 4 (severe)
10 M C3670T / ? 5.0 nd 5 (moderate)
11 F G3556C / G3556C 5.4 nd 5 (moderate)
12 F C3670T / C3670T 4.4 39 4 (severe)
1 MRS = magnetic resonance spectroscopy; nd = not done2 LINCL rating scale based on Steinfeld et al, Am J Med Gen (2002); 112: 347-354
Magnetic Resonance Scan of Severe LINCL
Slice 1
Slice 2
Slice 3
Slice 4
1 2
3 4
Metabolite Levels in Voxels from Parenchyma and Ventricles Determined by Magnetic Resonance
Spectroscopy of Subject with Severe LINCL
LAC
CHO
CRNAA
CHO = cholineCR = creatineNAA = N-acetylaspartateLAC = lactic acid
Definition of Area in Cortex for Assessment by Magnetic Resonance
Spectroscopy
Metabolite concentrations assessed in voxels indicated in slice 2
Examples of Metabolites in the Cortex
BD001 Age 8
BD009, Age 5
BD005, Age 13
BD002, Age 9
CHOCR
NAA LAC CHOCR
NAA LAC
Metabolite Levels in the Cortex
Subject
Age
(Yr) LactateN-acetyl aspartate Creatine Choline
N-acetyl aspartate /
creatine
1 8.4 2.94 4.66 3.44 4.99 1.36
2 9.2 2.28 6.33 3.87 6.20 1.65
3 6.6 2.07 8.10 4.59 7.99 1.77
4 13.6x 17.90x 1.36 2.51 2.84 0.61
5 6.2 2.41 7.23 4.48 6.96 1.74
6 7.9 8.53 4.76 3.93 7.21 1.22
7 6.6 2.34 6.89 5.25 7.81 1.32
8 6.0 nd1 nd nd nd nd
9 6.8 2.63 7.40 6.45 8.99 1.16
10 5.0 1.31 4.72 3.01 5.01 1.59
11 5.4 3.21 10.74x 7.55 9.78 1.43
12 4.4 2.48 11.30x 8.38 11.11x 1.36
1. nd – not determined
Le
vel o
f N
-ac
ety
lasp
art
ate
LateralCaudal / rostral
0
2
4
6
8
Spatial Variation of N-acetylaspartate Levels in Subject with Severe LINCL
Due to substantial spatial variation, comparison of two MRS scans for the same subject requires careful alignment of the images
Age-dependence of Creatine and Lactate Levels in Cortex
Age (yr)
0
2
4
6
8
10
0 2 4 6 8 10 12 14
Cre
atin
e
0
5
10
15
20
0 2 4 6 8 10 12 14
Lac
tate
Subject
2
3
4
5
6
7
9
10
11
12
1
y = 8.9 - 0.53xr2 = 0.48
y = -5.1 + 1.2xr2 = 0.49
Age-dependence of Choline and N-acetylaspartate Levels in Cortex
Age (yr)
0
2
4
6
8
10
12
14
0 2 4 6 8 10 12 14
Ch
oli
ne
0
2
4
6
8
10
12
14
0 2 4 6 8 10 12 14
N-a
cety
lasp
arta
te
Subject
2
3
4
5
6
7
9
10
11
12
1
y = 12.7-0.74xr2 = 0.56
y = 13.6 - 0.90xr2 = 0.62
Reproducibility of N-acetylaspartate Level Between two MRS Scans of the Same Subject
Changes in N-acetylaspartate level are small and spatially uniform
Local increase
Local decrease
-6.0
-3.0
0.0
3.0
6.0
Ch
an
ge
in
NA
A l
ev
el
(1st s
ca
n –
2n
d s
ca
n)
Caudal Rostral
-6.0
-3.0
0.0
3.0
6.0
Ch
an
ge
in
NA
A l
ev
el
(1st s
ca
n –
2n
d s
ca
n)
Subject #1 Subject #3
Caudal Rostral
Left
Rig
ht
Left
Rig
ht
Summary Magnetic resonance spectroscopy scans of children with
LINCL show age-dependent decreases in the levels of choline, creatine and N-acetylaspartate, and an age dependent increase in levels of lactate
N-acetylaspartate provides the most reliable parameter of age-dependent changes
Duplicate MRS on the same subject can be registered, demonstrating similar local metabolite levels
Assessment of local N-acetylaspartate levels in serial MRS scans following gene transfer have the potential to show areas of the brain that are spared from progression of the disease
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