Batten disease represents a group of inherited neurodegenerative diseases also referred to as the Neuronal Ceroid Lipofuscinoses (NCLs). There are at least 9 genetically distinct forms of NCL and collectively, they are the most common pediatric neurodegenerative disease. The defining characteristic of the NCLs is the progressive accumulation of autofluorescent material in cells of the CNS and other tissues. Clinically, this group of pediatric neurodegenerative diseases typically present first with visual deficits followed by cognitive decline, intractable seizures, and premature death. Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) is the most rapidly progressing form of NCL and is caused by the deficiency of the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1). There is currently no effective therapy for INCL. In fact, pre-clinical experiments in the murine model of INCL using a variety of approaches such as gene therapy, small molecule drugs, and neuronal stem cells have resulted in minor biochemical and histological improvements with little or no increase in life span. However, we recently showed that CNS-directed gene therapy using an AAV2/5 vector resulted in a 50% increase in life span (INCL ~8mo, AAV2/5-INCL ~12mo). Interestingly, when bone marrow transplantation (BMT) was combined with AAV2/5 the median life span increased to ~18.5mo with a sustained improvement in motor function. These results are truly striking in light of the fact that BMT alone resulted in no detectable PPT1 activity in the brain and provided no biochemical, histological, or clinical improvements. It is becoming clear that a combination approach targeting different aspects of disease can dramatically improve the clinical outcomes of INCL. We have identified several disease characteristics of INCL that can be targeted simultaneously. This combination approach could represent the foundation of therapies that will provide meaningful clinical benefit for affected children. The goals of this proposal are to: 1) better understand the interaction of BMT and CNS-directed gene therapy in the treatment of INCL and, 2) determine the efficacy of combining disparate therapeutic approaches that target different aspects of INCL. We will accomplish these goals with the following Specific Aims: 1) We will more completely characterize the response of INCL mice to AAV2/5 and BMT and determine the mechanism of synergy between these disparate approaches. 2) We will determine the efficacy of therapeutic combinations that target different aspects of INCL.

Public Health Relevance

The goals of this research are to better understand the mechanism of synergy between AAV2/5- mediated, CNS-directed gene therapy and bone marrow transplantation in the murine model of Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease). We will also determine the efficacy of various novel combinations of small molecule drugs, gene therapy and BMT in the murine model of INCL.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043205-11
Application #
8656814
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Morris, Jill A
Project Start
2002-04-01
Project End
2017-06-30
Budget Start
2014-08-06
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$320,352
Indirect Cost
$102,185
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Le, Steven Q; Kan, Shih-Hsin; Clarke, Don et al. (2018) A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I. Mol Ther Methods Clin Dev 8:42-51
Lange, Jenny; Haslett, Luke J; Lloyd-Evans, Emyr et al. (2018) Compromised astrocyte function and survival negatively impact neurons in infantile neuronal ceroid lipofuscinosis. Acta Neuropathol Commun 6:74
Benitez, Bruno A; Sands, Mark S (2017) Primary fibroblasts from CSP? mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis. Sci Rep 7:6332
Chandler, Randy J; Sands, Mark S; Venditti, Charles P (2017) Recombinant Adeno-Associated Viral Integration and Genotoxicity: Insights from Animal Models. Hum Gene Ther 28:314-322
Shyng, Charles; Nelvagal, Hemanth R; Dearborn, Joshua T et al. (2017) Synergistic effects of treating the spinal cord and brain in CLN1 disease. Proc Natl Acad Sci U S A 114:E5920-E5929
Kan, Shih-Hsin; Le, Steven Q; Bui, Quang D et al. (2016) Behavioral deficits and cholinergic pathway abnormalities in male Sanfilippo B mice. Behav Brain Res 312:265-71
Dearborn, Joshua T; Ramachandran, Subramania; Shyng, Charles et al. (2016) Histochemical localization of palmitoyl protein thioesterase-1 activity. Mol Genet Metab 117:210-6
Mikulka, Christina R; Sands, Mark S (2016) Treatment for Krabbe's disease: Finding the combination. J Neurosci Res 94:1126-37
Benitez, Bruno A; Cairns, Nigel J; Schmidt, Robert E et al. (2015) Clinically early-stage CSP? mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun 3:73
Dearborn, Joshua T; Harmon, Steven K; Fowler, Stephen C et al. (2015) Comprehensive functional characterization of murine infantile Batten disease including Parkinson-like behavior and dopaminergic markers. Sci Rep 5:12752

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