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Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

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

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Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

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  1. 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

  2. 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

  3. Demographic Characteristics of Study Population 1 MRS = magnetic resonance spectroscopy; nd = not done 2 LINCL rating scale based on Steinfeld et al, Am J Med Gen (2002); 112: 347-354

  4. Magnetic Resonance Scan of Severe LINCL 1 2 Slice 1 Slice 2 Slice 3 Slice 4 4 3

  5. Metabolite Levels in Voxels from Parenchyma and Ventricles Determined by Magnetic Resonance Spectroscopy of Subject with Severe LINCL CHO NAA CR LAC CHO = choline CR = creatine NAA = N-acetylaspartate LAC = lactic acid

  6. Definition of Area in Cortex for Assessment by Magnetic Resonance Spectroscopy • Metabolite concentrations assessed in voxels indicated in slice 2

  7. Examples of Metabolites in the Cortex BD001 Age 8 BD009, Age 5 CR CR CHO NAA LAC CHO NAA LAC BD005, Age 13 BD002, Age 9

  8. Metabolite Levels in the Cortex 1. nd – not determined

  9. Spatial Variation of N-acetylaspartate Levels in Subject with Severe LINCL 8 6 Level of N-acetylaspartate 4 2 0 Caudal / rostral Lateral • Due to substantial spatial variation, comparison of two MRS scans for the same subject requires careful alignment of the images

  10. Age-dependence of Creatine and Lactate Levels in Cortex Subject 5 1 10 2 6 11 3 12 7 4 9 20 10 8 y = 8.9 - 0.53x r2 = 0.48 15 y = -5.1 + 1.2x r2 = 0.49 6 Creatine Lactate 10 4 5 2 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Age (yr)

  11. Age-dependence of Choline and N-acetylaspartate Levels in Cortex Subject 5 1 10 2 6 11 3 12 7 4 9 14 14 12 12 y = 12.7-0.74x r2 = 0.56 y = 13.6 - 0.90x r2 = 0.62 10 10 8 8 Choline N-acetylaspartate 6 6 4 4 2 2 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Age (yr)

  12. Reproducibility of N-acetylaspartate Level Between two MRS Scans of the Same Subject Left Right Left Right Local increase Subject #3 Subject #1 Local decrease 6.0 6.0 3.0 3.0 0.0 0.0 Change in NAA level (1st scan – 2nd scan) Change in NAA level (1st scan – 2nd scan) -3.0 -3.0 -6.0 -6.0 Caudal Rostral Caudal Rostral • Changes in N-acetylaspartate level are small and spatially uniform

  13. 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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