Late infantile neuronal ceroid lipofuscinosis (LINCL) is a progressive hereditary neurodegenerative disease of childhood that is due to a deficiency in the lysosomal protease tripeptidyl peptidase I (TPP1). Disease progression is characterized by increasingly severe seizures, loss of vision and motor skills, and dementia. Early death is inevitable, typically at 8-15 years of age. There is currently no effective treatment for LINCL. Previous research has resulted in the identification of the molecular basis for LINCL, development of definitive diagnostic tests, large-scale production of the TPP1 enzyme, in-depth biochemical and structural characterization of the protein, development of mouse models, and exploration of potential therapies. Exciting new developments in the field suggest that it may be possible to increase survival of an LINCL mouse model by administration of recombinant human TPP1. Building on this collective research, the current proposal has four specific aims to address critical aspects of LINCL and the role of TPP1 in biology and medicine.
SPECIFIC AIM 1 is to develop an effective therapy by administering recombinant human TPP1 to a LINCL mouse model. To date, enzyme replacement therapy (ERT) is the most successful treatment for visceral manifestations of lysosomal storage disorders but delivery to the brain remains a significant challenge. Experiments will be conducted to extend promising studies on direct administration of TPP1 to the cerebrospinal fluid (CSF), determining dose and dosing intervals for chronic treatment regimens, and also determining when treatment needs to be initiated. Studies will also be conducted to pursue intriguing preliminary results that suggest that high dose peripheral administration may be effective in delivering enzyme to the brain.
SPECIFIC AIM 2 is to use mouse genetics to investigate critical aspects of LINCL disease, progression and therapy. Experiments will be conducted using mice with inducible TPP1 activity to determine the reversibility of disease and to provide a benchmark to judge efficacy of therapies that restore TPP1 activity. In addition, this will create a valuable model for the community that can be used to explore additional therapies for LINCL and other neurodegenerative diseases.
SPECIFIC AIM 3 is to use computational protein design to engineer TPP1 variants with improved therapeutic properties. Initial efforts will be to lengthen the lifetime of active TPP1 in the lysosome without affecting activity or proenzyme stability. Such properties could greatly facilitate use of TPP1 as a drug in ERT. In addition, this will provide further understanding of the structure and dynamics of this protein and this will facilitate future design efforts to engineer proteins with improved pharmaceutical properties.
SPECIFIC AIM 4 is a proteomic analysis of LINCL specimens including CSF and storage material with the primary objective of identifying potential biomarkers to monitor disease progression and therapeutic response. In addition, this should provide basic information on the biological function of TPP1 in lysosomal digestion and also identify potential targets for therapeutic intervention.

Public Health Relevance

The proposed research is focused on developing a cure for a fatal hereditary neurodegenerative disease of children, late infantile neuronal ceroid lipofuscinosis (Batten Disease). This research may also be applicable to a number of closely-related diseases and to more widespread human disorders such as Alzheimer disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037918-14
Application #
8431357
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Morris, Jill A
Project Start
1998-04-01
Project End
2013-06-30
Budget Start
2012-12-01
Budget End
2013-06-30
Support Year
14
Fiscal Year
2013
Total Cost
$204,408
Indirect Cost
$75,075
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Solé-Domènech, Santiago; Rojas, Ana V; Maisuradze, Gia G et al. (2018) Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar A? by multiple endoproteolytic cleavages within the ?-sheet domain. Proc Natl Acad Sci U S A 115:1493-1498
Nemtsova, Yuliya; Wiseman, Jennifer A; El-Banna, Mukarram et al. (2018) Inducible transgenic expression of tripeptidyl peptidase 1 in a mouse model of late-infantile neuronal ceroid lipofuscinosis. PLoS One 13:e0192286
Sleat, David E; Tannous, Abla; Sohar, Istvan et al. (2017) Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers. J Proteome Res 16:3787-3804
Jadot, Michel; Boonen, Marielle; Thirion, Jaqueline et al. (2017) Accounting for Protein Subcellular Localization: A Compartmental Map of the Rat Liver Proteome. Mol Cell Proteomics 16:194-212
Wiseman, Jennifer A; Meng, Yu; Nemtsova, Yuliya et al. (2017) Chronic Enzyme Replacement to the Brain of a Late Infantile Neuronal Ceroid Lipofuscinosis Mouse Has Differential Effects on Phenotypes of Disease. Mol Ther Methods Clin Dev 4:204-212
Meng, Yu; Wiseman, Jennifer A; Nemtsova, Yuliya et al. (2017) A Basic ApoE-Based Peptide Mediator to Deliver Proteins across the Blood-Brain Barrier: Long-Term Efficacy, Toxicity, and Mechanism. Mol Ther 25:1531-1543
Sleat, David E; Gedvilaite, Erika; Zhang, Yeting et al. (2016) Analysis of large-scale whole exome sequencing data to determine the prevalence of genetically-distinct forms of neuronal ceroid lipofuscinosis. Gene 593:284-91
Huang, Ling; Pike, Douglas; Sleat, David E et al. (2014) Potential pitfalls and solutions for use of fluorescent fusion proteins to study the lysosome. PLoS One 9:e88893
Meng, Yu; Sohar, Istvan; Sleat, David E et al. (2014) Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain. Mol Ther 22:547-553
Meng, Yu; Sohar, Istvan; Wang, Lingling et al. (2012) Systemic administration of tripeptidyl peptidase I in a mouse model of late infantile neuronal ceroid lipofuscinosis: effect of glycan modification. PLoS One 7:e40509

Showing the most recent 10 out of 35 publications