Substrate reduction intervention by l-cycloserine in twitcher mice (globoid cell leukodystrophy) on a B6;CAST/Ei background

Biswas, Sanjib; Biesiada, Homigol; Williams, Todd D.; Levine, Steven M.

doi:10.1016/s0304-3940(03)00633-5

Cited by 21 publications

(15 citation statements)

References 20 publications

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“…This is consistent with preclinical experiments showing that bone marrow transplantation (BMT) performed at 9–10 d of age only increases the life span of the twitcher mice on the C57BL/6 background from 40 to ~80 d (Yeager et al, 1984). Hence, other therapies like gene therapy (Shen et al, 2002; Lin et al, 2005; Rafi et al, 2005), substrate reduction therapy (Biswas et al, 2003), and combination therapies (Biswas and LeVine, 2002; Lin et al, 2007; Galbiati et al, 2009) should be considered.…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Transplantation Augments the Effect of Brain- and Spinal Cord-Directed Adeno-Associated Virus 2/5 Gene Therapy by Altering Inflammation in the Murine Model of Globoid-Cell Leukodystrophy

Reddy¹,

Kim

Hawkins-Salsbury³

et al. 2011

Journal of Neuroscience

104

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Globoid-cell leukodystrophy (GLD) is an inherited demyelinating disease caused by the deficiency of the lysosomal enzyme galactosylceramidase (GALC). A previous study in the murine model of GLD (twitcher) demonstrated a dramatic synergy between CNS-directed adeno-associated virus 2/5 (AAV2/5) gene therapy and myeloreductive bone marrow transplantation (BMT). However, the mechanism by which these two disparate therapeutic approaches synergize is not clear. In addition, the therapeutic efficacy may have been limited since the CNS-directed gene therapy was restricted to the forebrain and thalamus. In the current study, intrathecal and intracerebellar injections were added to the therapeutic regimen and the mechanism of synergy between BMT and gene therapy was determined. Although AAV2/5 alone provided supraphysiological levels of GALC activity and reduced psychosine levels in both the brain and spinal cord, it significantly increased CNS inflammation. Bone marrow transplantation alone provided essentially no GALC activity to the CNS and did not reduce psychosine levels. When AAV2/5 is combined with BMT, there are sustained improvements in motor function and the median life span is increased to 123 d (range, 92–282 d) compared with 41 d in the untreated twitcher mice. Interestingly, addition of BMT virtually eliminates both the disease and AAV2/5-associated inflammatory response. These data suggest that the efficacy of AAV2/5-mediated gene therapy is limited by the associated inflammatory response and BMT synergizes with AAV2/5 by modulating inflammation.

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Section: Introductionmentioning

confidence: 99%

Bone Marrow Transplantation Augments the Effect of Brain- and Spinal Cord-Directed Adeno-Associated Virus 2/5 Gene Therapy by Altering Inflammation in the Murine Model of Globoid-Cell Leukodystrophy

Reddy¹,

Kim

Hawkins-Salsbury³

et al. 2011

Journal of Neuroscience

104

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“…MLD and Krabbe disease, as NB-DNJ appear not to inhibit the galactosylceramidesynthesizing enzyme (Butters et al 2003), and no inhibitor for this enzyme has been described. The only reported trial of SRT in animal models of Krabbe disease was performed using L-cycloserine (inhibiting the first step of de novo sphingolipid synthesis), which significantly delayed disease progression in twitcher mice (Biswas et al 2003). However, because of the high toxicity of L-cycloserine, this approach will probably not be an option for human patients.…”

Section: Substrate Reduction Therapymentioning

confidence: 99%

Pathology and Current Treatment of Neurodegenerative Sphingolipidoses

Eckhardt

2010

Neuromol Med

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Sphingolipidoses constitute a large subgroup of lysosomal storage disorders (LSDs). Many of them are associated with a progressive neurodegeneration. As is the case for LSDs in general, most sphingolipidoses are caused by deficiencies in lysosomal hydrolases. However, accumulation of sphingolipids can also result from deficiencies in proteins involved in the transport or posttranslational modification of lysosomal enzymes, transport of lipids, or lysosomal membrane proteins required for transport of lysosomal degradation end products. The accumulation of sphingolipids in the lysosome together with secondary changes in the concentration and localization of other lipids may cause trafficking defects of membrane lipids and proteins, affect calcium homeostasis, induce the unfolded protein response, activate apoptotic cascades, and affect various signal transduction pathways. To what extent, however, these changes contribute to the pathogenesis of the diseases is not fully understood. Currently, there is no cure for sphingolipidoses. Therapies like enzyme replacement, pharmacological chaperone, and substrate reduction therapy, which have been shown to be efficient in non-neuronopathic LSDs, are currently evaluated in clinical trials of neuronopathic sphingolipidoses. In the future, neural stem cell therapy and gene therapy may become an option for these disorders.

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“…Oligodendrocytes are selectively destroyed because psychosine formation occurs primarily in these cells. 169 Studies of transplantation of neural cells and direct infection of the brain with viral vector containing GalC, are in progress in experimental animals. 164 Psychosine-induced apoptosis in human oligodendrocyte cell line studies in animal models, particularly the canine model and the twitcher mouse, have been of great value for the studies of pathogenesis of GLD and its therapy.…”

Section: Pathogenesismentioning

confidence: 99%