Our hypothesis is that advanced magnetic resonance imaging (MRI) techniques in combination with the quantitative evaluation of cerebrospinal fluid (CSF) metabolites can be exploited to develop a comprehensive set of biomarkers for assessing disease severity and therapeutic response in children with late infantile neuronal ceroid lipofuscinosis (LINCL). The ultimate goal of our work is to accurately and objectively assess therapeutic efficacy and thereby improve the medical management of LINCL subjects, especially as new treatment options for LINCL become available. Our specific goal is to develop an imaging biomarker panel for assessing LINCL disease severity and therapeutic response at the level of individual substructures in the brain, and compare this with the results of CSF metabolomics.
Our Specific Aims are as follows:
Aim 1) To develop a brain-region-specific magnetic resonance imaging biomarker panel, including diffusion coefficients, diffusion fractional anisotropy, T2 relaxation times, T2* relaxation times, the volume percentage of CSF, and proton spectroscopic metabolite ratios. We will examine over 30 brain regions in 16 LINCL subjects in a control group at the time of enrollment, and again 18 months later.
Aim 2 : To develop a CSF metabolite biomarker panel that includes the evaluation of over 1000 compounds, and test its correlation with the MRI biomarkers, clinical indicators of disease severity, and subject age. CSF will be collected from the 16 LINCL subjects in the control group via lumbar puncture performed under anesthesia at one day prior to administration of gene therapy and again 18 months later.
Aim 3 : To apply the MRI biomarker panel in the evaluation of therapeutic efficacy of AAVrh.10 mediated gene therapy for LINCL. Sixteen subjects in a treatment group will be examined at 5 MRI time points, including at the time of screening, one day before administration of therapy, and again at 6, 12 and 18 months post therapy.

Public Health Relevance

Our goal is to develop an objective measure of disease severity and therapeutic response in late infantile neuronal ceroid lipofuscinosis using advanced magnetic resonance imaging methods and chemical analysis of cerebrospinal fluid. If our work is successful, clinicians will have new diagnostic tools for the management of this deadly disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Morris, Jill A
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University of Minnesota Twin Cities
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Ou, Li; Przybilla, Michael J; Whitley, Chester B (2018) Metabolomics profiling reveals profound metabolic impairments in mice and patients with Sandhoff disease. Mol Genet Metab :
McIntosh, Paul T; Hobson-Webb, Lisa D; Kazi, Zoheb B et al. (2018) Neuroimaging findings in infantile Pompe patients treated with enzyme replacement therapy. Mol Genet Metab 123:85-91
Nestrasil, Igor; Ahmed, Alia; Utz, Josephine M et al. (2018) Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. Mol Genet Metab 123:97-104
Ou, Li; Przybilla, Michael J; Koniar, Brenda et al. (2018) RTB lectin-mediated delivery of lysosomal ?-l-iduronidase mitigates disease manifestations systemically including the central nervous system. Mol Genet Metab 123:105-111
Desai, Ankit K; Walters, Crista K; Cope, Heidi L et al. (2018) Enzyme replacement therapy with alglucosidase alfa in Pompe disease: Clinical experience with rate escalation. Mol Genet Metab 123:92-96
Sindelar, Miriam; Dyke, Jonathan P; Deeb, Ruba S et al. (2018) Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease). Sci Rep 8:15229
Shapiro, Elsa G; Whitley, Chester B; Eisengart, Julie B (2018) Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome. Orphanet J Rare Dis 13:76
Ou, L; Przybilla, M J; Whitley, C B (2018) SAAMP 2.0: An algorithm to predict genotype-phenotype correlation of lysosomal storage diseases. Clin Genet 93:1008-1014
Eisengart, Julie B; Rudser, Kyle D; Xue, Yong et al. (2018) Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison. Genet Med 20:1423-1429
Kazi, Zoheb B; Desai, Ankit K; Troxler, R Bradley et al. (2018) An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease. Genet Med :

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