Batten disease represents a group of inherited neurodegenerative diseases also referred to as the Neuronal Ceroid Lipofuscinoses (NCLs). There are at least 8 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 essentially 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 aloneresulted in no detectable PPT1 activity in the brain and provided no biochemical or histological 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 determine the mechanism of synergy between BMT and CNS-directed gene therapy. 2) We will determine the efficacy of therapeutic combinations that target different aspects of INCL.

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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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Developmental Brain Disorders Study Section (DBD)
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Morris, Jill A
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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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
Dearborn, Joshua T; Ramachandran, Subramania; Shyng, Charles et al. (2016) Histochemical localization of palmitoyl protein thioesterase-1 activity. Mol Genet Metab 117:210-6
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
Sands, Mark S (2013) Considerations for the treatment of infantile neuronal ceroid lipofuscinosis (infantile Batten disease). J Child Neurol 28:1151-8
Sands, Mark S (2013) Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology. EMBO Mol Med 5:799-801
Heldermon, C D; Qin, E Y; Ohlemiller, K K et al. (2013) Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo Syndrome type B mice. Gene Ther 20:913-21
Linterman, Kathryn S; Palmer, David N; Kay, Graham W et al. (2011) Lentiviral-mediated gene transfer to the sheep brain: implications for gene therapy in Batten disease. Hum Gene Ther 22:1011-20
Hawkins-Salsbury, Jacqueline A; Reddy, Adarsh S; Sands, Mark S (2011) Combination therapies for lysosomal storage disease: is the whole greater than the sum of its parts? Hum Mol Genet 20:R54-60
Heldermon, Coy D; Ohlemiller, Kevin K; Herzog, Erik D et al. (2010) Therapeutic efficacy of bone marrow transplant, intracranial AAV-mediated gene therapy, or both in the mouse model of MPS IIIB. Mol Ther 18:873-80
Woloszynek, Josh C; Kovacs, Atilla; Ohlemiller, Kevin K et al. (2009) Metabolic adaptations to interrupted glycosaminoglycan recycling. J Biol Chem 284:29684-91