N Matthew Ellinwood

Iowa State University, Ames, Iowa, United States

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Publications (37)124.9 Total impact

  • Molecular Genetics and Metabolism 02/2013; 108(2):S35. · 2.83 Impact Factor
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    ABSTRACT: The mucopolysaccharidosis type I (MPS I) dog model has been important in the development of therapies for human patients. We treated dogs with enzyme replacement therapy (ERT) by various approaches. Dogs assessed included untreated MPS I dogs, heterozygous carrier dogs, and MPS I dogs treated with intravenous ERT as adults (beginning at age 13 to 16 mo), intrathecal and intravenous ERT as adults (beginning at age 13 to 16 mo), or intrathecal ERT as juveniles (beginning at age 4 mo). We then characterized the neuroimaging findings of 32 of these dogs (age, 12 to 30 mo). Whole and midsagittal volumes of the corpus callosum, measured from brain MRI, were significantly smaller in affected dogs compared with unaffected heterozygotes. Corpus callosum volumes in dogs that were treated with intrathecal ERT from 4 mo until 21 mo of age were indistinguishable from those of age-matched carrier controls. Dogs with MPS I showed cerebral ventricular enlargement and cortical atrophy as early as 12 mo of age. Ventricular enlargement was greater in untreated MPS I dogs than in age-matched dogs treated with intrathecal ERT as juveniles or adults. However, treated dogs still showed some ventricular enlargement or cortical atrophy (or both). Understanding the progression of neuroimaging findings in dogs with MPS I and their response to brain-directed therapy may improve preclinical studies for new human-directed therapies. In particular, corpus callosum volumes may be useful quantitative neuroimaging markers for MPS-related brain disease and its response to therapy.
    Comparative medicine 01/2013; 63(2):163-73. · 1.12 Impact Factor
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    ABSTRACT: The GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor shows age-related declines in expression across the frontal cortex and hippocampus. This decline is strongly correlated to age-related memory declines. This study was designed to determine if increasing GluN2B subunit expression in the frontal lobe or hippocampus would improve memory in aged mice. Mice were injected bilaterally with either the GluN2B vector, containing cDNA specific for the GluN2B subunit and enhanced Green Fluorescent Protein (eGFP); a control vector or vehicle. Spatial memory, cognitive flexibility, and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression, exhibited improved long-term spatial memory, comparable to young mice. However, memory was rescued on different days in the Morris water maze; early for hippocampal GluN2B subunit enrichment and later for the frontal lobe. A higher concentration of the GluN2B antagonist, Ro 25-6981, was required to impair long-term spatial memory in aged mice with enhanced GluN2B expression, as compared to aged controls, suggesting there was an increase in the number of GluN2B-containing NMDA receptors. In addition, hippocampal slices from aged mice with increased GluN2B subunit expression exhibited enhanced NMDA receptor-mediated excitatory post-synaptic potentials (EPSP). Treatment with Ro 25-6981 showed that a greater proportion of the NMDA receptor-mediated EPSP was due to the GluN2B subunit in these animals, as compared to aged controls. These results suggest that increasing the production of the GluN2B subunit in aged animals enhances memory and synaptic transmission. Therapies that enhance GluN2B subunit expression within the aged brain may be useful for ameliorating age-related memory declines.
    Behavioural brain research 10/2012; · 3.22 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type IIIB (MPS IIIB) is a neuropathic lysosomal storage disorder (LSD) resulting from an inherited deficiency of N-acetyl-α-d-glucosaminidase (Naglu) activity, an enzyme required to degrade the glycosaminoglycan heparan sulfate (HS). A deficiency in Naglu activity leads to lysosomal accumulation of HS as a primary storage substrate, and the gangliosides GM2 and GM3 as secondary accumulation products. To test the effect on neuropathogenesis of ganglioside accumulation, we bred mice deficient in both Naglu and GalNaAcT activities. The latter is the enzyme required for synthesis of GM2 and other complex gangliosides. Contrary to our expectation and to double knockout (DKO) studies where GalNAcT was knocked out in combination with other LSDs, our DKO mice showed a drastically shortened lifespan (24.5±1.4weeks, versus 50.5±0.9weeks (MPS IIIB), and 38.6±1.2weeks (GalNAcT)). To confirm that HS storage was the primary element resulting in the accelerated disease in our DKO mice, and not a locus tightly linked to the Naglu gene, we replicated our study with MPS IIIA mice, and found a virtually identical result (27.5±1.8weeks, versus 53.8±1.6weeks). All DKO mice showed motor signs of hind limb ataxia and hyper-extension, which were not seen in single KO or normal mice. At approximately 5months of age, the MPS IIIB-DKO showed a unique pattern of vacuolization and nerve fiber degeneration in the corpus callosum, seen only in the DKO mice, as well as the relatively early intracytoplasmic vacuolation of many neurons and glia characteristic of the MPS IIIB mice. We analyzed motor performance on a rocking Rota-Rod beginning at 3months of age. The MPS IIIA-DKO and MPS IIIB-DKO mice showed impaired performance and were statistically different from all parental lines. In particular, the MPS IIIB-DKO mice were significantly different from the parent MPS IIIB strains at 3, 5, and 6months (p≤0.0245). In conclusion we identified an accelerated phenotype associated with MPS IIIB within a DKO model system which showed white matter changes, with attendant performance deficits and a drastically shortened lifespan. This was in stark contrast to our expectations of a salutary response to the elimination of GM2. Despite this, the accelerated pathology and clinical signs represent a potentially improved system to study MPS IIIB neuropathogenesis as well as the role of complex gangliosides in normal CNS function.
    Molecular Genetics and Metabolism 07/2012; 107(1-2):129-35. · 2.83 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis (MPS) VI is due to a deficiency in the activity of N-acetylgalactosamine 4-sulfatase (4S), also known as arylsulfatase B. Previously, retroviral vector (RV)-mediated neonatal gene therapy reduced the clinical manifestations of MPS I and MPS VII in mice and dogs. However, sulfatases require post-translational modification by sulfatase-modifying factors. MPS VI cats were injected intravenously (i.v.) with a gamma RV-expressing feline 4S, resulting in 5 ± 3 copies of RV per 100 cells in liver. Liver and serum 4S activity were 1,450 ± 1,720 U/mg (26-fold normal) and 107 ± 60 U/ml (13-fold normal), respectively, and were directly proportional to the liver 4S protein levels for individual cats. This study suggests that sulfatase-modifying factor (SUMF) activity in liver was sufficient to result in active enzyme despite overexpression of 4S. RV-treated MPS VI cats achieved higher body weights and longer appendicular skeleton lengths, had reduced articular cartilage erosion, and reduced aortic valve thickening and aortic dilatation compared with untreated MPS VI cats, although cervical vertebral bone lengths were not improved. This demonstrates that therapeutic expression of a functional sulfatase protein can be achieved with neonatal gene therapy using a gamma RV, but some aspects of bone disease remain difficult to treat.
    Molecular Therapy 03/2012; 20(5):898-907. · 7.04 Impact Factor
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    ABSTRACT: Intrathecal enzyme replacement therapy is an experimental option to treat central nervous system disease due to lysosomal storage. Previous work shows that MPS I dogs receiving enzyme replacement with recombinant human alpha-l-iduronidase into the cisterna magna showed normal brain glycosaminoglycan (GAG) storage after three or four doses. We analyzed MPS I dogs that received intrathecal enzyme in a previous study using an assay that detects only pathologic GAG (pGAG). To quantify pGAG in MPS I, the assay measures only those GAG which display terminal iduronic acid residues on their non-reducing ends. Mean cortical brain pGAG in six untreated MPS I dogs was 60.9±5.93 pmol/mg wet weight, and was 3.83±2.64 in eight normal or unaffected carrier animals (p<0.001). Intrathecal enzyme replacement significantly reduced pGAG storage in all treated animals. Dogs with low anti-iduronidase antibody titers showed normalization or near-normalization of pGAG in the brain (mean 8.17±6.17, n=7), while in dogs with higher titers, pGAG was reduced but not normal (mean 21.9±6.02, n=4). Intrathecal enzyme therapy also led to a mean 69% reduction in cerebrospinal fluid pGAG (from 83.8±26.3 to 27.2±12.3 pmol/ml CSF). The effect was measurable one month after each dose and did not differ with antibody titer. Prevention of the immune response to enzyme may improve the efficacy of intrathecal enzyme replacement therapy for brain disease due to MPS I.
    Molecular Genetics and Metabolism 02/2012; 106(1):68-72. · 2.83 Impact Factor
  • Molecular Genetics and Metabolism 02/2012; 105(2):S28. · 2.83 Impact Factor
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    ABSTRACT: Genetic management of Mexican gray wolves includes semen banking, but due to the small number of animals in the population and handling restrictions, improvements in semen collection and cryopreservation rely on results from studies of domestic dogs. Semen collection from wolves requires anesthesia and electroejaculation, which introduce potentially important variables into species comparisons, as dog semen is typically collected manually from conscious animals. To investigate possible effects of collection method on semen quality, we compared semen collection by the traditional manual method and by electroejaculation (EE) in a group of dogs (n = 5) to collection by EE only in wolves (n = 7). Samples were divided into two aliquots: neat or diluted in Tris/egg yolk extender, with motility evaluated at intervals up to 24 h. There were no differences (P > 0.10) in sperm motility in either neat or extended samples at 24 h from EE dogs and wolves, although motility of the wolf neat samples declined more rapidly (P < 0.05). However, there were differences (P < 0.01) between EE and manually collected dog semen in motility at 24 h, in both the neat and extended samples. Therefore, general motility patterns of dog and wolf semen collected by EE were similar, especially when diluted with a Tris/egg yolk extender, but sperm collected from dogs by EE did not maintain motility as long as manually collected samples, perhaps related to the longer exposure of EE samples to more prostate fluid.
    Theriogenology 09/2011; 76(5):975-80. · 2.08 Impact Factor
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    ABSTRACT: Intrathecal (IT) recombinant human α-l-iduronidase (rhIDU) has been shown to reduce mean brain glycosaminoglycans (GAGs) to normal levels in mucopolysaccharidosis I (MPS I) dogs. In this study, we examined storage in neuroanatomical regions of the MPS I dog brain, including frontal lobe, cerebellum, basal ganglia, thalamus, hippocampal formation, and brainstem, to determine the response of these functional regions to treatment with IT rhIDU. GAG storage in untreated MPS I dogs was significantly different from normal dogs in all examined sections. GAG levels in normal dogs varied by region: frontal lobe (mean: 2.36 ± 0.54 μg/mg protein), cerebellum (2.67 ± 0.33), basal ganglia and thalamus (3.51 ± 0.60), hippocampus (3.30 ± 0.40), and brainstem (3.73 ± 1.10). Following IT treatment, there was a reduction in GAG storage in each region in all treatment groups, except for the brainstem. Percent reduction in GAG levels from untreated to treated MPS I dogs in the deeper regions of the brain was 30% for basal ganglia and thalamus and 30% for hippocampus, and storage reduction was greater in superficial regions, with 61% reduction in the frontal lobe and 54% in the cerebellum compared with untreated MPS I dogs. Secondary lipid storage in neurons was also reduced in frontal lobe, but not in the other brain regions examined. Response to therapy appeared to be greater in more superficial regions of the brain, particularly in the frontal lobe cortex.
    Apmis 08/2011; 119(8):513-21. · 2.07 Impact Factor
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    ABSTRACT: The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPSI brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 μg/mg) and 1 month (0.9 and 1.1 μg/mg) which approached levels observed in normal animals (0.7 μg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I.
    Molecular Genetics and Metabolism 07/2011; 103(3):268-74. · 2.83 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of α-L-iduronidase (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety of parenchymal cell types and connective tissues. The fundamental link between genetic mutation and tissue GAG accumulation is clear, but relatively little attention has been given to the morphology or pathogenesis of associated lesions, particularly those affecting the vascular system. The terminal parietal branches of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I affected) or heterozygous (unaffected carrier) for an IdU mutation that eliminated all enzyme activity, and in affected animals treated with human recombinant IdU. High-resolution computed tomography showed that vascular wall thickenings occurred in affected animals near branch points, and associated with low endothelial shear stress. Histologically these asymmetric 'plaques' entailed extensive intimal thickening with disruption of the internal elastic lamina, occluding more than 50% of the vascular lumen in some cases. Immunohistochemistry was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, fibroblasts and smooth muscle cells, with loss of overlying endothelial basement membrane and claudin-5 expression. Lesions contained scattered cells expressing nuclear factor-κβ (p65), increased fibronectin and transforming growth factor β-1 signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. Intimal lesion development and morphology was improved by intravenous recombinant enzyme treatment, particularly with immune tolerance to this exogenous protein. The progressive sclerotic vasculopathy of MPS-I shares some morphological and molecular similarities to atherosclerosis, including formation in areas of low shear stress near branch points, and can be reduced or inhibited by intravenous administration of recombinant IdU.
    Laboratory Investigation 03/2011; 91(5):665-74. · 3.96 Impact Factor
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    ABSTRACT: Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.
    Molecular Therapy 02/2011; 19(2):251-9. · 7.04 Impact Factor
  • Molecular Genetics and Metabolism - MOL GENET METAB. 01/2011; 102(2).
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    ABSTRACT: Feline breeding colonies face genetic constraints involving founder effects. A Siamese-founded colony used to study primary congenital glaucoma displayed coat colors additional to the Siamese coat. Genes affecting pigment can exhibit pleiotropy on ocular development and function. To remove potentially confounding phenotypes from our colony, we documented the source and frequency of the Siamese allele at the gene for tyrosinase (TYR), the dilution allele at melanophilin (MLPH), and the brown allele at tyrosinase-related protein 1 (TYRP1). We used PCR-RFLP diagnostics to genotype cats in our colony for the published alleles. A commercially acquired phenotypically normal tom was the source of the dilute allele. A founding Siamese queen was the source of the brown allele. Founders also were blood-typed and screened for disease-associated alleles segregating in Siamese cats at 3 loci (ASB, GLB1, and CEP290). Siamese founders were normal at all loci except ASB, at which both animals carried the hypomorpic allele. Current stock is being managed to limit production of glaucomatous cats with brown, dilute, or Siamese phenotypes or homozygosity for the ASB hypomorphic allele. Genotyping will aid in the elimination of these alleles. The clinical effect of these phenotypes and alleles on the glaucoma phenotype is uncertain, but their elimination will remove potentially confounding effects. In conclusion, when founding a colony, stock should be selected or screened to limit potentially confounding phenotypes. When studying the immune, nervous, and visual systems, screening stock for alleles known to be associated with coat color may be warranted.
    Comparative medicine 01/2011; 61(3):251-7. · 1.12 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-l-iduronidase and attendant accumulation of the glycosaminoglycans dermatan sulfate and heparan sulfate. Current treatments are suboptimal and do not address residual disease including corneal clouding, skeletal deformities, valvular heart disease, and cognitive impairment. We treated neonatal dogs with MPS I with intravenous recombinant α-l-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 56 to 81 weeks. In contrast to previous results in animals and patients treated at a later age, the dogs failed to mount an antibody response to enzyme therapy, consistent with the induction of immune tolerance in neonates. The higher dose of enzyme led to complete normalization of lysosomal storage in the liver, spleen, lung, kidney, synovium, and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and function were restored, and there were improvements in skeletal disease as shown by clinical and radiographic assessments. Glycosaminoglycan levels in the brain were normalized after intravenous enzyme therapy, in the presence or absence of intrathecal administration of recombinant α-l-iduronidase. Histopathological evidence of glycosaminoglycan storage in the brain was ameliorated with the higher-dose intravenous therapy and was further improved by combining intravenous and intrathecal therapy. These findings argue that neonatal testing and early treatment of patients with MPS I may more effectively treat this disease.
    Science translational medicine 12/2010; 2(60):60ra89. · 10.76 Impact Factor
  • Veterinary Radiology & Ultrasound - VET RADIOL ULTRASOUND. 01/2010; 51(4):361-373.
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    ABSTRACT: Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-l-iduronidase (IV rhIDU) is a treatment for patients with mucopolysaccharidosis I (MPS I). Spinal cord compression develops in MPS I patients due in part to dural and leptomeningeal thickening from accumulated glycosaminoglycans (GAG). We tested long-term and every 3-month intrathecal (IT) and weekly IV rhIDU in MPS I dogs age 12-15months (Adult) and MPS I pups age 2-23days (Early) to determine whether spinal cord compression could be reversed, stabilized, or prevented. Five treatment groups of MPS I dogs were evaluated (n=4 per group): IT+IV Adult, IV Adult, IT + IV Early, 0.58mg/kg IV Early and 1.57mg/kg IV Early. IT + IV rhIDU (Adult and Early) led to very high iduronidase levels in cervical, thoracic, and lumber spinal meninges (3600-29,000% of normal), while IV rhIDU alone (Adult and Early) led to levels that were 8.2-176% of normal. GAG storage was significantly reduced from untreated levels in spinal meninges of IT + IV Early (p<.001), IT+IV Adult (p=.001), 0.58mg/kg IV Early (p=.002) and 1.57mg/kg IV Early (p<.001) treatment groups. Treatment of dogs shortly after birth with IT+IV rhIDU (IT + IV Early) led to normal to near-normal GAG levels in the meninges and histologic absence of storage vacuoles. Lysosomal storage was reduced in spinal anterior horn cells in 1.57mg/kg IV Early and IT + IV Early animals. All dogs in IT + IV Adult and IV Adult groups had compression of their spinal cord at 12-15months of age determined by magnetic resonance imaging and was due to protrusion of spinal disks into the canal. Cord compression developed in 3 of 4 dogs in the 0.58mg/kg IV Early group; 2 of 3 dogs in the IT + IV Early group; and 0 of 4 dogs in the 1.57mg/kg IV Early group by 12-18months of age. IT + IV rhIDU was more effective than IV rhIDU alone for treatment of meningeal storage, and it prevented meningeal GAG accumulation when begun early. High-dose IV rhIDU from birth (1.57mg/kg weekly) appeared to prevent cord compression due to protrusion of spinal disks.
    Molecular Genetics and Metabolism 01/2010; 101(2-3):115-22. · 2.83 Impact Factor
  • Molecular Genetics and Metabolism - MOL GENET METAB. 01/2010; 99(2).
  • Molecular Genetics and Metabolism - MOL GENET METAB. 01/2010; 99(2).
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    ABSTRACT: Issues of cost and genetics can result in inbreeding of canine genetic disease colonies. Beagles often are used to maintain such colonies, providing stock for outcrosses. Factor VII (FVII) deficiency is a hemostatic disorder found at increased frequency in beagles and has been characterized at the DNA level. Deficiency of FVII presents obstacles in colonies founded with beagles. An initial finding of a FVII-deficient pup from a longstanding colony prompted us to evaluate FVII deficiency fully in this colony. Current and archival records and tissues were used to reconstruct the colony pedigree, assess the contribution from beagles, and test samples to document the source and frequency of the mutant FVII allele. As part of this study we developed a PCR-based diagnostic assay that was simpler than what was previously available. Pedigree analysis revealed a founder effect implicating beagles that led to high frequency (55%) of the mutant allele. In addition, affected animals were identified. The complete picture of the clinical effect within the colony remains unclear, but unusual neonatal presentations, including hemoabdomen, have occurred in pups affected with FVII deficiency. Use of a PCR-based diagnostic assay to screen all potential beagle breeding stock will prevent similar occurrences of FVII deficiency in future canine research colonies.
    Comparative medicine 09/2009; 59(4):378-82. · 1.12 Impact Factor

Publication Stats

479 Citations
124.90 Total Impact Points


  • 2007–2013
    • Iowa State University
      • • Department of Animal Science
      • • Center for Integrated Animal Genomics (CIAG)
      Ames, Iowa, United States
  • 2003–2012
    • University of Pennsylvania
      • • Department of Pathobiology
      • • Division of General Internal Medicine
      Philadelphia, Pennsylvania, United States
  • 2002–2012
    • University of Washington Seattle
      • Division of General Internal Medicine
      Seattle, WA, United States
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2010
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      Torrance, California, United States