Qin, EY, Hawkins-Salsbury, JA, Jiang, X, Reddy, AS, Farber, NB, Ory, DS et al.. Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy. Mol Genet Metab 107: 186-196

Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 06/2012; 107(1-2):186-96. DOI: 10.1016/j.ymgme.2012.05.021
Source: PubMed


Globoid cell leukodystrophy (GLD, Krabbe disease), is an autosomal recessive, neurodegenerative disease caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). In the absence of GALC, the toxic metabolite psychosine accumulates in the brain and causes the death of the myelin-producing cells, oligodendrocytes. Currently, the only therapy for GLD is hematopoietic stem cell transplantation using bone marrow (BMT) or umbilical cord blood. However, this is only partially effective. Previous studies have shown that enzyme replacement therapy (ERT) provides some therapeutic benefit in the murine model of GLD, the Twitcher mouse. Experiments have also shown that two disparate therapies can produce synergistic effects when combined. The current study tests the hypothesis that BMT will increase the therapeutic effects of ERT when these two treatments are combined. Twitcher mice were treated with either ERT alone or both ERT and BMT during the first 2-4days of life. Recombinant enzyme was delivered by intracerebroventricular (ICV) and intrathecal (IT) injections. Twitcher mice receiving ERT had supraphysiological levels of GALC activity in the brain 24h after injection. At 36days of age, ERT-treated Twitcher mice had reduced psychosine levels, reduced neuroinflammation, improved motor function, and increased lifespan. Twitcher mice receiving both ERT and BMT had significantly increased lifespan, improved motor function, reduced psychosine levels, and reduced neuroinflammation in certain areas of the brain compared to untreated or ERT-treated Twitcher mice. Together, these results indicate that BMT enhances the efficacy of ERT in GLD.

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    • "Animal models, especially the twitcher (twi) mouse, have been used for many treatment trials. These include bone marrow transplantation (BMT) [7] [8], stem cell transplantation [9] [10] [11] [12], substrate reduction therapy [13], pharmacological chaperone therapy [14], gene therapy [15] [16] [17] [18] [19] [20] [21], enzyme replacement therapy [22] [23], anti-oxidant therapy and various combinations of these treatments [18] [19] [24] [25]. While some have resulted in prolonged life for the treated affected mice, others have been less successful. "
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    ABSTRACT: Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessive disorder resulting from the defective lysosomal enzyme galactocerebrosidase (GALC). The lack of GALC enzyme leads to severe neurological symptoms. While most human patients are infants who do not survive beyond 2years of age, older patients are also diagnosed. In addition to human patients, several naturally occurring animal models, including dog, mouse, and monkey, have also been identified. The mouse model of Krabbe disease, twitcher (twi) mouse has been used for many treatment trials including gene therapy. Using the combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of the adeno-associated virus serotype rh10 (AAVrh10) expressing mouse GALC in neonate twi mice we previously have demonstrated a significantly extended normal life and exhibition of normal behavior in treated mice. In spite of the prolonged healthy life of these treated mice and improved myelination, it is unlikely that using multiple injection sites for viral administration will be approved for treatment of human patients. In this study, we have explored the outcome of the single iv injection of viral vector at post-natal day 10 (PND10). This has resulted in increased GALC activity in the central nervous system (CNS) and high GALC activity in the peripheral nervous system (PNS). As we have shown previously, an iv injection of AAVrh10 at PND2 results in a small extension of life beyond the typical lifespan of the untreated twi mice (~40days). In this study, we report that mice receiving a single iv injection at PND10 had no tremor and continued to gain weight until a few weeks before they died. On average, they lived 20-25days longer than untreated mice. We anticipate that this strategy in combination with other therapeutic options may be beneficial and applicable to treatment of human patients. Copyright © 2014 Elsevier Inc. All rights reserved.
    Molecular Genetics and Metabolism 12/2014; 114(3). DOI:10.1016/j.ymgme.2014.12.300 · 2.63 Impact Factor
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    • "The extension of lifespan reported here is moderate and in line with that observed in Twi mice that underwent other CNS-directed treatments, i.e. transplantation of gene-corrected neural stem cells (NSCs) (15) or mesenchymal stem cells (16), intratechal administration of recombinant GALC (49), and likely reflects failure of these approaches to provide sufficient levels of functional enzyme to correct the somatic pathology and particularly the PNS, which is likely the ultimate cause of lethality in this mouse model. In fact, treatments able to correct the systemic disease associated with GLD, such as HCT, alone or in combination with systemic delivery of GALC-expressing vectors (14,20–23) as well as novel HSC GT protocols (50), significantly extend the lifespan of relevant GLD models. However, these approaches hardly achieve timely and consistent metabolic correction of CNS tissues. "
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    ABSTRACT: Globoid Cell Leukodystrophy (GLD) is an inherited lysosomal storage disease caused by β-galactocerebrosidase (GALC) deficiency. Gene therapy (GT) should provide rapid, extensive and lifetime GALC supply in CNS tissues to prevent or halt irreversible neurologic progression. Here we used a lentiviral vector (LV) to transfer a functional GALC gene in the brain of Twitcher mice, a severe GLD model. A single injection of LV.GALC in the external capsule of Twitcher neonates resulted in robust transduction of neural cells with minimal and transient activation of inflammatory and immune response. Importantly, we documented a proficient transduction of proliferating and post-mitotic oligodendroglia, a relevant target cell type in GLD. GALC activity (30-50% of physiological levels) was restored in the whole CNS of treated mice as early as 8 days post-injection. The early and stable enzymatic supply ensured partial clearance of storage and reduction of psychosine levels, translating in amelioration of histopathology and enhanced lifespan. At 6 months post-injection in non-affected mice, LV genome persisted exclusively in the injected region, where transduced cells overexpressed GALC. Integration site analysis in transduced brain tissues showed no aberrant clonal expansion and preferential targeting of neural-specific genes. This study establishes neonatal LV-mediated intracerebral GT as a rapid, effective, and safe therapeutic intervention to correct CNS pathology in GLD and provides a strong rationale for its application in this and similar leukodystrophies, alone or in combination with therapies targeting the somatic pathology, with the final aim of providing an effective and timely treatment of these global disorders.
    Human Molecular Genetics 01/2014; 23(12). DOI:10.1093/hmg/ddu034 · 6.39 Impact Factor
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    ABSTRACT: Natural killer (NK) cells exert important immunoregulatory functions by releasing several inflammatory molecules, such as IFN-γ and members of chemokines, which include CCL3/MIP-1α and CCL4/MIP-1β. These cells also express heptahelical receptors, which are coupled to heterotrimeric G proteins that guide them into inflamed and injured tissues. NK cells have been shown to recognize and destroy transformed cells and virally-infected cells, but their roles in neurodegenerative diseases have not been examined in detail. In this review, I will summarize the effects of NK cells in two neurodegenerative diseases, namely multiple sclerosis and globoid cell leukodystrophy. It is hoped that the knowledge obtained from these diseases may facilitate building rational protocols for treating these and other neurodegenerative or autoimmune diseases using NK cells and drugs that activate them as therapeutic tools.
    Toxins 03/2013; 5(2):363-75. DOI:10.3390/toxins5020363 · 2.94 Impact Factor
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