Mark Curtis

Thomas Jefferson University, Filadelfia, Pennsylvania, United States

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Publications (9)41.33 Total impact

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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; DOI:10.1016/j.ymgme.2014.12.300 · 2.83 Impact Factor
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    ABSTRACT: PURPOSE: This study is directed at identifying the cell source(s) of immunomodulatory cytokines in high grade gliomas and establishing whether the analysis of associated markers has implications for tumor grading. EXPERIMENTAL DESIGN: Glioma specimens classified as WHO Grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing IL-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, Principal Component Analysis (PCA) and Mixture Discriminant Analysis (MDA) were used to investigate associations between expressed genes and glioma grade. RESULTS: The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163 and CD204, which are elevated in high grade gliomas, and the neutrophil/MDSC subset marker CD15, which is reduced, provide the best index of glioma grade. CONCLUSIONS: Grade II and IV astrocytomas can be clearly differentiated based on the expression of certain M2 markers in tumor tissues while Grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163+ cells distinguishes Grade III astrocytoma subsets with different prognosis.
    Clinical Cancer Research 06/2013; 19(14). DOI:10.1158/1078-0432.CCR-12-1940 · 8.19 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). This deficiency results in accumulation of certain galactolipids including psychosine which is cytotoxic for myelin-producing cells. Treatment of human patients at this time is limited to hematopoietic stem cell transplantation (HSCT) that appears to slow the progression of the disease when performed in presymptomatic patients. In this study, adeno-associated virus (AAV) serotype rh10-(AAVrh10) expressing mouse GALC was used in treating twitcher (twi) mice, the mouse model of GLD. The combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of viral particles in neonate twi mice resulted in high GALC activity in brain and cerebellum and moderate to high GALC activity in spinal cord, sciatic nerve, and some peripheral organs. Successfully treated mice maintained their weight with no or very little twitching, living up to 8 months. The physical activities of the long-lived treated mice were comparable to wild type for most of their lives. Treated mice showed normal abilities to mate, to deliver pups, to nurse and to care for the newborns. This strategy alone or in combination with other therapeutic options may be applicable to treatment of human patients.
    Molecular Therapy 07/2012; DOI:10.1038/mt.2012.153 · 6.43 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency results in a progressive demyelination of the central and peripheral nervous systems. Inflammatory cells and increased levels of cytokines and chemokines are present in the CNS of GLD mice and may play a significant role in the pathogenesis of the disease. In this study we evaluate the effect of non-steroidal anti-inflammatory drugs, such as indomethacin and ibuprofen, and minocycline, a tetracycline analog with neuroprotective and anti-apoptotic properties, on the progression of the disease using a transgenic mouse model of GLD. Real-time quantitative PCR was used to analyze the expression of several markers of the immune/inflammatory response. IL-6, TNF-alpha, MIP-1beta, MCP-1, iNOS/NOS2, CD11b, CD68, CD4 and CD8 mRNA levels were measured in cortex, cerebellum and spinal cord of untreated and treated affected mice at different ages. In addition, the pharmacological treatments were compared to bone marrow transplantation (BMT). The pharmacological treatments significantly extended the life-span of the treated mice and reduced the levels of several of the immuno-related factors studied. However, BMT produced the most dramatic improvements. In BMT-treated mice, factors in the spinal cord were normalized faster than the cerebellum, with the exception of CD68. There was a decrease in the number of apoptotic cells in the cerebellum of mice receiving anti-inflammatory drugs and BMT. These studies indicate a possible role for combined therapy in the treatment of GLD.
    Brain research 09/2009; 1300:146-58. DOI:10.1016/j.brainres.2009.09.017 · 2.83 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder that affects both the central and peripheral nervous system (CNS and PNS). The deficiency of the lysosomal enzyme galactocerebrosidase (GALC) leads to the accumulation of psychosine, resulting in the death of oligodendrocytes and Schwann cells. Bone marrow transplantation (BMT) of the mouse models of GLD can prolong their lives up to one year compared to 40-50 days if untreated. Intracranial and intraventricular injections of adeno-associated virus (AAV) types 1 and 5 containing mouse GALC cDNA into affected mice results in widespread GALC expression in the brain, pathological improvement and modest extension of life span compared to untreated mice. Mice treated with either BMT or viral therapy still demonstrate mild twitching and premature death at least partially due to lack of correction of PNS pathology. In an attempt to improve the biochemical and pathological condition of the peripheral nerves in affected mice, AAV2/1-mGALC viral particles were injected into the gastrocnemius muscles of affected mice. Biochemical analysis of the different tissues from the treated mice demonstrated very high GALC activity in the injected muscle and significantly increased GALC activity in the contralateral muscles. This was confirmed by histochemical staining of GALC activity where a large number of myofibers and the sciatic nerve in the injected side were strongly positive. The sciatic nerve on the contralateral side was also positive for GALC activity. While the sciatic nerve of untreated affected mice was thickened due to edema, initial studies following intramuscular injection showed that the sciatic nerve was much thinner and similar to control mice. Sections from the spinal cord also demonstrated some GALC-positive motoneurons indicating retrograde transfer of AAV2/1-GALC from the intramusclar injections. Transgene expression in the injected muscle was still very strong three months after injection. Combining intramuscular injections with other therapeutic approaches that improve the CNS pathology may have additional advantages in the successful treatment of the animal models of GLD.
    Molecular Therapy 05/2006; 13. DOI:10.1016/j.ymthe.2006.08.237 · 6.43 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (GLD) is a disorder of the central and peripheral nervous systems caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). The pathological changes associated with the disease include accumulation of globoid cells and loss of myelin due to production of psychosine, a toxic metabolite responsible for the apoptosis of oligodendrocytes. While most patients present with symptoms before 6 months of age, older patients are also diagnosed. Treatment at this time is limited to hematopoietic stem cell transplantation in asymptomatic and late-onset patients. GLD occurs naturally in several animal species including mice, dogs, and monkeys. In addition, a transgenic (trs) mouse model of GLD was generated in our laboratory. Trs mice develop symptoms slower than twitcher mice and survive an average of 10 days longer. In this study, we evaluated the therapeutic effects of bone marrow transplantation (BMT) using trs mice. BMT prolonged the life of some treated animals to over one year. After BMT, GALC activity reached 15-20% of normal in brain and near normal values in liver and sciatic nerve. In long-lived transplanted animals psychosine levels were normalized in the brain and greatly reduced in the sciatic nerve. Staining of brain sections showed more abundant and better quality myelin and near absence of globoid cells. Electron micrographs of sciatic nerves showed reduced endoneurial edema, increased axon density, and abundant onion bulb structures associated with remyelinating axons. Therefore, BMT can ameliorate many of the biochemical and pathological features of GLD. However, additional therapies may be required to completely correct the features of this disease.
    Molecular Genetics and Metabolism 09/2005; 86(1-2):150-9. DOI:10.1016/j.ymgme.2005.06.023 · 2.83 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by a deficiency of galactocerebrosidase (GALC) activity. GALC is required for the lysosomal degradation of galactosylceramide, psychosine, and possibly other galactolipids. This process is extremely important during active myelination. In the absence of functional GALC, psychosine accumulates, resulting in the apoptotic death of myelin-producing cells. While most patients are infants who do not survive beyond 2 years of age, some older patients are also diagnosed. Hematopoietic stem cell transplantation has proven to have a positive effect on the course of some patients with late-onset Krabbe disease. Murine models of this disease provide an excellent opportunity to evaluate therapeutic alternatives including gene therapy. In this study we used serotype 1 AAV to express mouse GALC under the control of the human cytomegalovirus promoter. Direct administration of these viral particles into the brains of neonatal mice with GLD resulted in sustained expression of GALC activity, improved myelination, attenuated symptoms, and prolonged life span. While this treatment also resulted in significant pathological improvements, the treated mice died with symptoms similar to those of the untreated mice. Additional initiatives may be required to prevent the onset of disease and reverse the course of the disease in animal models and human patients.
    Molecular Therapy 06/2005; 11(5):734-44. DOI:10.1016/j.ymthe.2004.12.020 · 6.43 Impact Factor
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    ABSTRACT: In order to investigate a role for insulin-like growth factor-1 (IGF-1) in ameliorating the effects of demyelinating events and potentiating remyelination, we have generated transgenic (tg) mice expressing IGF-1 under the control of the myelin basic protein promoter. Heterozygous tg mice expressed the highest levels of IGF-1 in brain during the most active periods of myelination as determined by Western and Northern blotting. A high level of expression was found throughout the lives of the tg mice. There was no increased expression of IGF-1 in other organs. The brains of heterozygous mice were larger than those of normal mice by 2 weeks of age, and they continued to increase in size for several months. Light and electron microscopy showed extensive myelination of axons. Behavioral studies of the older heterozygous mice documented difficulty with balance. This new tg mouse model can be bred to mice that are heterozygous for genetic leukodystrophies to produce eventually mice that are affected with a given leukodystrophy but overexpress IGF-1 during myelination and remyelination. It will be interesting to see if overexpression of IGF-1 can modulate the pathological and clinical features of the inherited leukodystrophies with or without supplemental therapies.
    Neurochemical Research 06/2004; 29(5):881-9. DOI:10.1023/B:NERE.0000021233.79076.72 · 2.55 Impact Factor
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    ABSTRACT: Globoid cell leukodystrophy (Krabbe disease) is a severe leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene leading to extremely low (less than 5% of normal activity) GALC activity. Human patients include primarily severely affected infants as well as patients with a later onset of symptoms. The infants usually die before 2 years of age, but it is difficult to predict the clinical course in older patients. In addition to these patients, additional individuals identified in this laboratory have 10--20% of normal GALC activity measured in accessible tissues. These individuals have a wide range of clinical presentations involving neurological degeneration. On molecular analysis of the GALC gene they all have three or more mutations considered to be normal polymorphisms resulting in amino acid changes in the two copies of the GALC gene. In order to investigate the role these amino acid changes may play on clinical, biochemical, and pathological findings, a new transgenic mouse was generated by homologous recombination. After preliminary studies determined what effect each amino acid change had on mouse GALC activity in transient transfection experiments, mice containing a cysteine residue at codon 168 instead of histidine (H168C) were produced. These mice developed symptoms, but they were delayed by 10--15 days from the well-characterized twitcher (twi) mouse. They accumulated psychosine slightly slower than twi mice, showed pathological changes less severe than twi mice in the central and peripheral nervous systems, and live about 15 days longer than twi mice. They have large litters and will play a role in therapy trials using new procedures currently under development.
    Molecular Genetics and Metabolism 08/2001; 73(3):211-23. DOI:10.1006/mgme.2001.3194 · 2.83 Impact Factor

Publication Stats

151 Citations
41.33 Total Impact Points


  • 2012–2014
    • Thomas Jefferson University
      • Department of Pathology, Anatomy & Cell Biology
      Filadelfia, Pennsylvania, United States
  • 2001–2006
    • Jefferson College
      Хиллсборо, Missouri, United States