Globoid-cell leukodystrophy (GLD, Krabbe disease) is an inherited childhood disease caused by a deficiency in the lysosomal enzyme, galactocerebrosidase (GALC). GALC is responsible for degrading the galactosylated lipids, including the highly toxic sphingolipid, galactosylsphingosine [psychosine (Psy)]. In the absence of GALC activity Psy accumulates and preferentially causes the death of oligodendrocytes. The histological hallmark of GLD is the presence of multinucleated macrophages, """"""""globoid cells"""""""", primarily within the white matter tracts of the central nervous system (CNS). The most common form of GLD, infantile, is rapidly progressing with clinical signs typically appearing during the first 6 months of life and leading t death by 2-5 years of age. The clinical signs include irritability, sensory deterioration, motor defects, seizures, and cognitive deficits. The Twitcher mouse is a spontaneously-arising model of GLD that is deficient in GALC activity and shares most of the biochemical, histological and clinical signs with the human disease. The Twitcher mouse has been a powerful tool to better understand the underlying pathogenesis of GLD and develop therapies for this invariably fatal pediatric disease. The only currently available treatment for GLD is hematopoietic stem cell transplantation (HSCT) using either umbilical cord blood or allogeneic bone marrow. However, HSCT appears to simply slow disease progression rather than """"""""cure"""""""" it. We recently showed that HSCT synergizes with CNS- directed gene therapy to dramatically improve the biochemical, histological and clinical signs of disease in the Twitcher mouse. However, the life span was increased to only ~130 days of age. This is still far from an effective long-term treatment. We have preliminary data suggesting that if we target additional disease features there is a further and dramatic increase in life span (>450 days). The goals of this proposal are to: 1) determine the efficacy of various therapeutic combinations that target different aspects of GLD, and 2) determine the mechanism of synergy between HSCT and CNS-directed gene therapy. We will accomplish these goals with the following Specific Aims: 1) We will determine the efficacy of therapeutic combinations that target different aspects of GLD. 2) We will determine the mechanism of synergy between HSCT and CNS-directed gene therapy.
The goals of this research are to develop effective therapies for Globoid Cell Leukodystrophy which is an invariably fatal childhood neurodegenerative disease. In addition, this research will provide a better understanding of the mechanism/s by which bone marrow transplantation synergizes with brain-directed gene therapy.
|Benitez, Bruno A; Cairns, Nigel J; Schmidt, Robert E et al. (2015) Clinically early-stage CSPÎ± mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss. Acta Neuropathol Commun 3:73|
|Hawkins-Salsbury, Jacqueline A; Shea, Lauren; Jiang, Xuntian et al. (2015) Mechanism-based combination treatment dramatically increases therapeutic efficacy in murine globoid cell leukodystrophy. J Neurosci 35:6495-505|
|Sands, Mark S (2014) Mucopolysaccharidosis type VII: A powerful experimental system and therapeutic challenge. Pediatr Endocrinol Rev 12 Suppl 1:159-65|
|Sands, Mark S (2014) A Hitchhiker's guide to the blood-brain barrier: in trans delivery of a therapeutic enzyme. Mol Ther 22:483-4|
|Swain, G P; Prociuk, M; Bagel, J H et al. (2014) Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain. Gene Ther 21:28-36|
|Reddy, Adarsh S; Patel, Jigisha R; Vogler, Carole et al. (2014) Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy. PLoS One 8:e64647|
|Li, Yedda; Sands, Mark S (2014) Experimental therapies in the murine model of globoid cell leukodystrophy. Pediatr Neurol 51:600-6|
|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|
|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|
Showing the most recent 10 out of 13 publications