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243Shunji Tomatsu MD. PhD. <p>Principal Research Scientist, Director, Skeletal Dysplasia Center Pediatric Orthopedic Surgery </p>(302) 298-7336 (302) 651-6782 stomatsu@nemours.org ARB 331 Alfred I. duPont Institute Hospital for Children 1600 Rockland Rd.,Wilmington, DE. 19899-0269 <p>1978 – 1984 MD Gifu University School of Medicine Gifu, Japan Major: Medicine, M.D., 1985 – 1989 PhD Department of Pediatrics, Gifu University School of Medicine, Gifu, Japan Major: Inherited Metabolic Disease, Ph.D.</p> <p>Postgraduate Training and Fellowship Appointments: (list chronologically starting with earliest</p> <p>position, give years, institutions, type of training – include intern, resident, fellowship, postdoctoral fellow, research associate))</p> <p>1984 - 1986 Junior Resident Department of Pediatrics, Gifu University Duties: General medicine as a pediatrician</p> <p>1986 - 1989 Graduate Student and Research Fellow, Institute of Genetic Information & Experiment of Kyushu Univ. Duties: The organization and complete nucleotide sequence of the human NADH-cytochrome b5 reductase gene</p> <p>1989 - 1991 Senior Resident and Research Fellow, Department of Pediatrics, Gifu University Duties: Inherited metabolic disease as a pediatrician.</p><p>I. I have been working on the mucopolysaccharidoses (MPS, which represent 11 diseases) for the past 25 years, from the clinical and basic research aspects, both in Japan and in the United States. This type of lysosomal storage disease has common clinical features that include bone deformities, hepatosplenomegaly, abnormal faces, mental retardation (not MPS IVA), short stature, herniation, hump back, scoliosis, kyphosis, hearing loss, corneal clouding, dysplasia of odontoid process, platyspondyly of the vertebrae, etc. These diverse clinical manifestations result from the storage of mucopolysaccharides in lysosomes of various tissues. Bone, especially, is a target tissue. Most of the bones are destroyed by dysplasia. Because of multiple dysplasia of bones, many patients suffer from hip dislocation, cervical myelopathy, quadriplegia, hump back, restriction of breathing, and gait disturbances. Morquio disease patients will usually die between ages 20 and 30 from pneumonia, valvular heart disease, or neck injuries from a fall. Since 1991, we have cloned the cDNA of the enzyme deficient in MPS IVA (Morquio disease) and identified various mutations in MPS I (Hurler syndrome), II (Hunter syndrome), IVA, and VII (Sly syndrome) patients. In an extensive study, I am making several different mouse models of MPS VII and MPS IVA in humans. Establishing mouse models of MPS diseases and other metabolic diseases like hereditary hemochromatosis is expected to lead to clarification of the pathogenesis, advanced therapy (BMT, gene therapy, and enzyme replacement therapy [ERT]), and genotype/phenotype correlations. To date, we have established five different types of mouse models for MPS VII and five different types of hereditary hemochromatosis. Three different MPS IVA mice (Morquio disease mouse) are currently established. After establishment of these mouse models, we now study the response to enzyme replacement treatment on affected mice using a purified beta-glucuronidase (GUSB) for MPS VII and N-acetyl-galactoseamine-6-6sulfate sulfatase (GALNS) for MPS IVA.</p> <p>Moreover, recently we and our collaborators developed <u>the bone targeting system</u> (a new drug delivery system) in conjunction with enzyme replacement therapy or other types of molecules. This DDS would lead to an additive effectiveness and could be applied to a variety of genetic bone diseases whose enzyme is deficient. Thus, this unique strategy has allowed us to open the new field such as treatment of congenital bone diseases (hypoparathoidism, hypopohspatasia, achondodysplasia etc). Our new DDS is also applicable to any systematic bone diseases such as osteoporosis, infection, cancer, and other genetic diseases.</p> <p>Our goals are</p> <p>1. Compare the pathology and features among skeletal dysplasia, especially growth plate and articular cartilage region.</p> <p>2. Find common pathogenesis of Skeletal Dysplasia at the pathological and molecular levels.</p> <p>3. Based upon the pathogenesis, develop a new type of drug.</p> <p>4. To establish the skeletal dysplasia research center (Fig. 1).</p> <p><img src="/sites/default/files/docs/Shunji-Fig1.png" alt="" style="height:466px;width:566px;" /></p> <p>Figure 1. Skeletal Dysplasia Center</p> <p>II. Newborn screening and biomarker for mucopolysaccharidoses:</p> <p>Glycosaminoglycans (GAGs) are accumulated in both mucopolysaccharidoses (MPS). Each type of MPS stores a different type(s) of GAG(s):  MPS I and II patients by dermatan sulfate (DS) and heparan sulfate (HS); MPS III by HS; MPS IV by keratan sulfate (KS) and chondroitin-6-sulfate (C6S); MPS VI by DS and C4S; MPS VII by DS, HS, and CS. Recent successful achievements of treatment on MPS patients by bone marrow transplantation and enzyme replacement therapy made it possible to improve the clinical manifestations. However, most patients treated are already at a progressive stage and some clinical features involving brain and bone are irreversible. Since MPS patients appear normal at birth, it is impossible to separate normal healthy newborns and MPS newborns. Therefore, if an appropriate treatment has been done at newborns, the quality of life of the MPS patients will be dramatically improved. In spite of the importance of early diagnosis and early treatment, no newborn screening is available. To develop a newborn screening system, we will establish the tandem mass spectrometry method to assay KS, HS, and DS levels in blood and have compared each GAG level between control group and each type of MPS group (Figs. 2 and 3).</p> <p><img src="/sites/default/files/docs/Shunji-Fig2.png" alt="" style="height:222px;width:687px;" /></p> <p><strong>Figure 2. Development of detection of GAG by tandem mass spectrometry for Mucopolysaccharidoses.</strong></p><p><strong>Bone-Targeting Therapies for Morquio A Disease. </strong></p> <p>Morquio A disease (mucopolysaccharidosis IVA: MPS IVA) is caused by a deficiency of N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), leading to accumulation of the glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate within lysosomes, especially in bone. This lysosomal storage disorder (LSD) is characterized by <strong>systemic skeletal dysplasia</strong>, <strong>leading to</strong> <strong>severe handicaps or early death.</strong>  The broad goal of this research is to develop an innovative enzyme replacement therapy (ERT) and viral gene therapy for Morquio A disease and other systemic bone diseases by applying a delivery system targeted to bone.</p> <p><strong>Aim 1: </strong><strong>Assess the response to long-term ERT with AAA-tagged enzyme.</strong> We hypothesize that tagged enzymes will be delivered to bone more efficiently and will improve bone pathology more effectively than untagged enzymes in the MPS IVA murine model. We will: i) characterize glycosylation and phosphorylation profiles of the tagged enzyme to understand the mechanism of the prolonged clearance, ii) investigate the efficacy of long term ERT in the mouse model by using bolus injections and continuous infusions.</p> <p><strong>Aim 2: Assess the efficacy of bone-targeting gene therapy by using virus with multiple copies of AAA oligopeptide on the viral capsid.</strong> We hypothesize that AAV2 vector targeted with multiple copies of AAA will achieve increased expression level of the enzyme in bone, resulting in improvement of bone lesions. We will: i) transduce human MPS IVA chondrocytes to assess reduction of intracellular KS and, ii) perform <em>in vivo</em> gene therapy experiments by using Morquio A mouse models to evaluate efficacy of the treatment. </p> <p><img src="/sites/default/files/docs/Shunji-fig3.jpg" alt="" style="height:279px;width:371px;" /></p> <p><strong>Figure 2. Mechanism of bone-targeting system. </strong>Negatively-charged AAA-tagged enzyme will circulate in blood for longer time: 1) will be delivered to bone more efficiently, 2) will bind with calcium sites on HA, 3) will be released from HA by proteolytic process, and 4) will be taken up by the receptor mediated pathways.</p> <p><strong>Newborn Screening and Biomarkers for Mucopolysaccharidoses</strong></p> <p>The major goals of this project are to develop a highly specific, sensitive, and simple newborn screening (NBS) system for mucopolysaccharidoses (MPS), a group of lysosomal storage diseases. The proposed system consists of a two-tiered approach. The first-tier screen will involve the identification of an "at increased risk" population based on specific glycosaminoglycan (GAG) markers using dried blood spots (DBS), followed by specific second-tier enzyme assays from DBS for definitive diagnosis using the same DBS (Fig. 3).</p> <p>Since cost-effectiveness is a key for NBS, a highly efficient, sensitive, specific and inexpensive screening method is required. The cost of screening each type of MPS would be high and prohibitive as the incidence rates range from about 1:100,000 births to less than 1:2,000,000 births. However, screening for MPS as a group with a combined incidence of about 1:25,000 births would be comparable to other genetic disorders currently targeted by existing screening programs.  The new LC/MS/MS method enables the simultaneous detection of a group of MPS and is promising for NBS.</p> <p>We will establish a NBS method for MPS with simultaneous determination of three major GAGs (DS, HS and KS) as biomarkers. In addition to the NBS application we will measure GAGs as biomarkers for assessing disease severity and monitoring the effects of evolving therapies over a long clinical course.</p> <p>Our research proposal addresses development of a novel newborn screening method for MPS that enables early diagnosis and potential treatment, preventing serious irreversible damage and leading to a better quality of life.</p> <p><img src="/sites/default/files/docs/Shunji-Fig4.png" alt="" style="height:420px;width:619px;" /></p> <p><strong>Figure 3</strong><strong>. Algorithm of pilot study for newborn screening (NBS) program of MPS.</strong> The algorithm above is designed to maintain the de-identified status of each sample until a confirmed positive result is obtained. Subsequent contact testing laboratory at AIDHC with parents of an infant with a positive result will be arranged through the Japanese testing centers after necessary informed consent has been obtained. *First-tier negative results may include false negative samples from patients with attenuated forms of MPS. These patients with attenuated MPS may develop clinically apparent features until after the conclusion of this study.**Second-tier negative results will identify the false positive findings from the first-tier screening. AIDHC: Alfred I. DuPont Hospital for Children, SLU: Saint Louis University</p> <p><strong>Functional assessment and pathogenesis of Morquio A</strong></p> <p>The broad goals of this research proposal are: 1) to provide a complete and methodical collection of key clinical manifestations in mucopolysaccharidosis IVA (MPS IVA, Morquio A Disease) to understand the progression and pathogenesis of the cervical instability and stenosis, hyperlaxity of joints, obstructive and restrictive pulmonary disease, and muscle weakness 2) to detail the pathogenesis of bone dysplasia using  tissues obtained during surgical procedures (bone, cartilage, ligament, and muscle), and 3) to define relation between keratan sulfate (KS) (or other bone markers) and key clinical manifestations. All patients with MPS IVA present major anesthetic risks due to airway narrowing and death can result if appropriate precautions are not taken. The collective information will contribute to establishment of non-invasive standard assessment tests for evaluation of the clinical severity, progression and therapeutic efficacy and clarification of mechanism of characteristic skeletal dysplasia.</p> <p><strong>Aim 1. Conduct a non-invasive assessment program of Morquio A patients to define clinically valid outcome measurements. Hypothesis: </strong>1) Longitudinal non-invasive tests for 100 Morquio A patients will demonstrate accurate assessment of daily activity, cervical instability/stenosis and cord compression, hyperlaxity of joints, thoracopulmonary function patterns and muscle weakness 2) non-invasive measurements will evaluate the condition of pre and post-operative patients and the risk factors for anesthesia as a function of age and physical handicaps (see Fig. 4).</p> <p><img src="/sites/default/files/docs/Shunji-Fig5.png" alt="" style="height:483px;width:633px;" /></p> <p><strong>Figure 4. Assessment methods for the key clinical features.</strong></p> <p><strong>Aim 2. Explore the pathogenesis of key clinical features and establish relation between KS (or other bone markers) and disease progression and clinical features. Hypothesis:</strong>  1) Biopsied specimens from surgical operations and an autopsied case will define qualitative and quantitative distribution pattern of the storage materials leading to pathogenesis of skeletal dysplasia, cervical cord compression and hyperlaxity of joints (Fig. 5). 2) KS and other potential bone biomarkers will define relation between biomarkers and key clinical features as well as the progression of the disease and clinical severity.</p> <p><img src="/sites/default/files/docs/Shunji-fig6.jpg" alt="" style="height:327px;width:523px;" /></p> <p><strong>Figure 5. Hypothesis of pathogenesis of cervical instability and stenosis (cord compression). </strong>Spinal cord compression is the most critical key feature to recognize in MPS IVA patients. Odontoid hypoplasia, ligamentous laxity and extradural GAG deposition, can result in atlantoaxial subluxation withcord compression, leading to cervical myelopathy. A history of exercise intolerance in patients with MPS IVA often predicts the presence of occult cervical myelopathy, which can also cause bowel and bladder dysfunction and weakness or paralysis. Mortality and morbidity rates are primarily related to the atlantoaxial instability and subsequent cervical myelopathy. Severely affected patients, primarily related to cervical instability, often do not survive beyond the second or third decade of life. A minor fall or extension of the neck can result in cord transection and subsequent quadriparesis or sudden death.</p> <p>Non-invasive clinical assessments will be considered as “candidate” clinical endpoints for the broad spectrum of patients to judge effectiveness of ERT, HSCT, and surgical procedures. Objective knowledge of pathological mechanism through human affected targeted tissues will shed light on a new therapeutic approach of this unique skeletal dysplasia.</p><p><strong>Eriko Yasuda, MS, Pharmacist:</strong> Research Fellow (Master degree, Kanazawa University).  Pharnacokinetic study, tandem mass spectrometry, treatment of mouse models</p> <p><strong>Kristen D. Ruhnke, BS:</strong>  Research Assistant, culture for cartilage cells, tandem mass spectrometry.</p> <p><span style="color:#000080;"><strong>Internal collaborators:</strong></span></p> <p><strong>William Mackenzie MD:</strong> Chairman, Pediatric Orthopedic Surgery</p> <p><strong>Michael B. Bober: M.D., Ph.D.:</strong> Director, Division of Medical Genetics, Department of Pediatrics</p> <p><em><strong>Thomas H. Shaffer, MS.E., Ph.D.:</strong></em> Professor of Physiology and Pediatrics<br>Associate Director of Research, pulmonary function for skeletal dysplasia patients</p> <p><strong>Tariq Rahman, PhD: </strong>Senior Research Engineer, Director, Center for Orthopedics</p> <p><span style="color:#000080;"><strong>Research and Development Biomedical Research:</strong></span></p> <p><strong>Larry Holmes, Jr. M.D., Ph.D.:</strong> Statistician, Pediatric Orthopedic Surgery</p><p><strong>Selected peer-reviewed publications </strong><strong>(Selected from 127 peer-reviewed publications)</strong></p> <ul> <li>Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA. Pediatr Res. 55:592-597, 2004. </li><li>Tomatsu S, Dieter T, Schwartz IV, Sarmient P, Giugliani R, Barrera LA, Guelbert N, Kremer R, Repetto GM, Gutierrez MA, Nishioka T, Serrato OP, Montaño  AM, Yamaguchi S, Noguchi A. Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate. J Hum Genet 49:490-494, 2004. </li><li><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16151906&query_hl=1">Tomatsu S, Gutierrez MA, Ishimaru T, Pena OM, Montaño  AM, Maeda H, Velez-Castrillon S, Nishioka T, Fachel AA, Cooper A, Thornley M, Wraith E, Barrera LA, Laybauer LS, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Noguchi A.</a> Heparan sulfate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 28:743-57, 2005. </li><li><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Oguma+T%22%5bAuthor%5d">Oguma T</a>, <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Tomatsu+S%22%5bAuthor%5d">Tomatsu S</a>, <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Okazaki+O%22%5bAuthor%5d">Okazaki O</a>. Analytical method for determination of disaccharides derived from keratan sulfates in human serum and plasma by high-performance liquid chromatography/turbo-ionspray ionization tandem mass spectrometry. Biomed Chromatogr 21:356-62, 2007. </li><li>Oguma T, Tomatsu S, Montaño AM, Okazaki O. Analytical method for determination of disaccharides derived from keratan, heparan and dermatan sulfates in human serum and plasma by high-performance liquid chromatography / turbo-ionspray ionization tandem mass spectrometry. Analytical Biochem 368:79-86, 2007. </li><li>Tomatsu S, Montaño AM, Oguma T, DunG VC, Oikawa H, Carvalho TG, Gutiérrez MG, Yamaguchi S, Suzuki Y, Fukushi M, Kida K, Kubota M, Kida K, Kubota M, Orii T. (2010) Validation of dermatan sulfate and heparan sulfate levels in mucopolysaccharidoses and mucolipidoses by tandem mass spectrometry. Mol Genet Metab 99: 124–131. </li><li>Tomatsu S, Montaño AM, Oguma T, Dung VC, Oikawa H, Carvalho TG, Gutiérrez MG, Yamaguchi S, Suzuki Y, Fukushi M, Kida K, Kubota M, Kida K, Kubota M, Orii T. Validation of keratan sulfate level in Mucopolysaccharidosis IVA by liquid tandem mass spectrometry method.  J Inherit Metab Dis 2010 Jan 27. [Epub ahead of print]. </li><li>Tomatsu S, Montaño AM, Oguma T, Dung VC, Oikawa H, de Carvalho TG, Gutiérrez ML, Yamaguchi S, Suzuki Y, Fukushi M, Sakura N, Barrera L, Kida K, Kubota M, Orii T. (2010) <a href="http://www.ncbi.nlm.nih.gov/pubmed/20162367">Dermatan sulfate and heparan sulfate as a biomarker for mucopolysaccharidosis I.</a> J Inherit Metab Dis. 33:141-150. </li><li><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12403825&dopt=Abstract">Tomatsu S, Orii KO, Vogler C, Grubb JH, Snella EM, Gutierrez MA, Dieter T, Sukegawa K, Orii T, Kondo N, Sly WS.</a>( 2002) Missense models [Gustm(E536A)Sly, Gustm(E536Q)Sly, and Gustm(L175F)Sly] of murine mucopolysaccharidosis type VII produced by targeted mutagenesis.Proc Natl Acad Sci USA. 99:14982-14987. PMCID: PMC137531 </li><li><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12700165&dopt=Abstract">Tomatsu S, Orii KO, Vogler C, Grubb JH, Snella EM, Gutierrez M, Dieter T, Holden CC, Sukegawa K, Orii T, Kondo N, Sly WS.</a> (2003) Production of MPS VII mouse (Gus(tm(hE540A.mE536A)Sly)) doubly tolerant to human and mouse beta-glucuronidase. Hum Mol Genet.12:961-73. PMCID: PMC1567498 </li><li><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16219627&query_hl=1">Tomatsu S, Gutierrez M, Nishioka T, Yamada M, Yamada M, Tosaka Y, Grubb JH, Montano AM, Vieira MB, Trandafirescu GG, Pena OM, Yamaguchi S, Orii KO, Orii T, Noguchi A, Laybauer L.</a> (2005) (Development of MPS IVA mouse (Galns<sup>tm(hC79S•mC76S)slu</sup>) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase. Hum Mol Genet. 14:3321-3335. </li><li>Tomatsu S, Montano AM, Ohashi A, Oikawa H, Oguma T, Dung VC, Nishioka T, Orii T, Sly WS. <em>Enzyme replacement therapy in a murine model of Morquio A syndrome. (2008) </em>Hum Mol Genet 17:815-824. </li><li>Montaño AM, Tomatsu S#, Brusius A, Smith M, Orii T. (2008) Growth charts for patients affected with Morquio A Disease. Am J Med Genet. 15;146A:1286-95. #Corresponding author. </li><li>Montaño AM*, Oikawa H*, Tomatsu*#, Nishioka T, Vogler C, Gutierrez MA, Oguma T, Tan Y, Grubb JH, Dung VC, Ohashi A, Miyamoto K, Orii T, Yoneda Y, Sly WS. (2008) Acidic amino acid tag enhances response to enzyme replacement in mucopolysaccharidosis type VII mice. Mol Genet Metab 94:178-89. *Equally contributed, #Corresponding author </li><li>Tomatsu S, Montaño AM, DunG VC, Ohashi A, Oikawa H,  Oguma T, Orii T, Barrera L, Sly WS. (2010) Enhancement of drug delivery: enzyme replacement therapy for murine Morquio A syndrome. Mol Ther 18: 1094-10102. </li><li>Tomatsu S, Montaño AM, Oikawa H, Smith M, Barrera L, Chinen Y, Thacker MM, Mackenzie WG, Suzuki Y, Orii T. (2011) Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. Cur Pharm Biotech 12: 931-945 </li><li>Hintze JP, Tomatsu S, Fujii T, Montaño AM, Yamaguchi S, Suzuki Y, Fukushi M, Ishimaru T, Orii T (2011) <a href="http://www.ncbi.nlm.nih.gov/pubmed/21792275">Comparison of liquid chromatography-tandem mass spectrometry and sandwich ELISA for determination of keratan sulfate in plasma and urine.</a> Biomark Insights. 6: 69-78. </li></ul> <p><strong>Books</strong>:</p> <ul> <li value="18">Tomatsu S, Montaño AM, Nishioka T, Orii T. Chapter: Mucopolysaccharidosis IV (Morquio syndrome; MPS IV). Lysosomal biology and Molecular Therapy of Storage Diseases (2007) pp. 433-446 Springer publisher. </li><li value="19">Tomatsu S, Montaño AM. Growth References, 3rd edition: Growth charts for Morquio A disease. Greewood Genetic Center; 2011. </li><li value="20">Tomatsu S, Adriana M. Montaño, Oikawa H, Giugliani R, Harmatz P, Smith M, Suzuki Y, Orii T. Chapter 126: Impairment of Body Growth in Mucopolysaccharidoses. In: Preedy VR, editor. Handbook of growth monitoring and health and disease. London: Springer Publications; 2011. </li><li value="21">Braverman NE, Tomatsu S. Mucopolysaccharidosis Type IV. eMedicine from WebMD. Updated April 21, 2009. Available at: <a href="http://emedicine.medscape.com/article/947254-overview">http://emedicine.medscape.com/article/947254-overview</a>. </li><li value="22">Tomatsu S, Adriana M. Montaño. Etiology and Pathogenesis of Mucopolysaccharidoses. In: Orii T, editor. Mucopolysaccharidoses Update. E-N Medix; 2011 (Japanese) </li><li value="23">Tomatsu S, Montaño AM, Molano C, Rowan D, Hintze JP, Carvalho CG, Federhen A, Vieira TA, Giugliani R, Węgrzyn G, Tanaka A, Suzuki Y, Orii T. Chapter 8: Enzyme Replacement Therapy for Lysosomal Storage Diseases. Neurochem​istry of Metabolic Diseases: Lysosomal Storage Diseases, Phenylketo​nuria and Canavan Disease. Editors: Sankar Surendran, pp. ISBN 978-1-61209-671-1 (2011) Nova Science Publishers, Inc. </li></ul> <p><strong>Patents</strong>:</p> <ul> <li>Method for detecting lysosomal storage diseases. Published: October 6, 2005 Filed: May 10, 2005 United States Patent Application: 20050221407 A1. Inventors: Okamura, Kazuo; (Saitama, JP) ; Miyaura, Shuichi; (Kanagawa, JP) ; Tomatsu, Shunji; (Clayton, MO) </li><li>PROTEINS WITH AN ATTACHED SHORT PEPTIDE OF ACIDIC AMINO ACIDS Filed: June 10, 2004 Published: December 15, 2005 United States Patent Application: 20050276796 A1 <ul> <li>US Pub No US 2005/0276796 (U.S. Patent App 10/864,758); </li><li>Int’l Patent Pub No WO 2005/121344 (PCT Patent App No PCT/JP2005/010760) </li><li>EPO Pub No EP 1766024 (EPO Patent App No 05748127.7) </li></ul> </li><li>Beta-glucuronidase with an attached short peptide of acidic amino acids Filed: October 7, 2005. Published: April 12, 2007. United States Patent Application: 20070081986 A1 Inventors: Tomatsu; Shunji; (Missouri, MO) ; Miyamoto; Ken'jchi; (Ishikawa, JP) ; Yamada; Masamichi; (Hyogo, JP) ; Tosaka; Yasuhiro; (Hyogo, JP) ; Yamada; Mana; (Hyogo, JP) ; Grubb; Jeffrey H.; (Missouri, MO) </li><li>Diagnostic Method of Mucopolysaccharidoses. Application number: 60/753,413 Published: July 12, 2007. Filed: December 27, 2006. United States Patent Application: 20070161074 A1 Inventors: Tomatsu; Shunji; (St. Louis, MO); Oguma; Toshihiro; (Tokyo, JP) </li><li>Compositions and methods for treating hypophosphatasia. SLU case number 05-023. United States Application number: 20070081984 A1. Published: April 12, 2007. Filed: July 11, 2006. Inventors: Tomatsu; Shunji; (St. Louis, MO) ; Sly; William S.; (St. Louis, MO) ; Grubb; Jeffrey H.; (St. Louis, MO) ; Nishioka; Tatsuo; (US) ; Miyamoto; Ken-Ichi; (Kanazawa, JP) ; Yamaguchi; Seiji; (Izumo, JP) </li><li>ENHANCING THE EFFECT OF THERAPEUTIC PROTEINS ON THE CENTRAL NERVOUS SYSTEM Serial Number 11/614,970, filed December 21, 2006 (117263 (SLU 06-051). Application number: 20070207139. Published: September 6, 2007. Filed: December 21, 2006. Inventors: Tomatsu; Shunji; (St. Louis, MO) ; Montaño ; Adriana; (Hyogo, JP) ; Nishioka; Tatsuo; (Ishikawa, JP) ; Grubb; Jeffrey H.; (St. Louis, MO) ; Sly; William S.; (St. Louis, MO) ; Gutierrez; Monica A.; (US) ; Rodriguez; Amelia Ortigoza; (Cucuta Norte de Santander, CO) </li><li>DELIVERY OF THERAPEUTIC AGENTS TO THE BONE . Filed on 7/17/08: A provisional patent application No. 61081711. SLU NDA 08-042. Inventors: Tomatsu; Shunji; (St. Louis, MO); Montaño ; Adriana; (St. Louis, MO) ; Carlos Javier Almeciga Diaz (Bogota, Colombia); Luis Alejandro Barrera (Bogota, Colombia) </li></ul><img alt="" src="/Images%20Bios/stomatsu-edit.jpg" style="BORDER:0px solid;" />

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