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
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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
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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
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Magnetic Resonance Scan of Severe LINCL
Slice 1
Slice 2
Slice 3
Slice 4
1 2
3 4
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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
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Definition of Area in Cortex for Assessment by Magnetic Resonance
Spectroscopy
Metabolite concentrations assessed in voxels indicated in slice 2
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Examples of Metabolites in the Cortex
BD001 Age 8
BD009, Age 5
BD005, Age 13
BD002, Age 9
CHOCR
NAA LAC CHOCR
NAA LAC
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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
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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
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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
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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
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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
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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