| 243 | Shunji Tomatsu MD. PhD. | <p>Professor, Principal Research Scientist, and Director of Skeletal Dysplasia Center Pediatric Orthopedic Surgery, Nemours Children's Health</p><p>Professor, Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA</p><p>Professor, Department of Pediatrics, St. Louis University, St. Louis, MO</p><p>Affiliated Scientist, University of Delaware, Newark, DE</p><p>Adjunct Professor, Department of Pediatrics Shimane University, Matsue, Japan</p><p>Adjunct Professor, Department of Pediatrics Gifu University, Gifu, Japan<br></p> | (302) 298-7336 | (302) 651-6782 | stomatsu@nemours.org | | | 200 Powder Mill Rd, Wilmington, DE 19803 | <p><strong>MD.</strong> - Gifu University School of Medicine, Gifu, Japan</p><p><strong>Ph.D.</strong> - Gifu University School of Medicine, Department of Pediatrics, Gifu, Japan<br></p> | | <p>For over thirty-five years, our group focuses on bench to bed diagnosis and treatment for a rare hereditary disease Mucopolysaccharidosis (MPS), especially the type IV MPS (Morquio A syndrome). We identified the disease related genes, generated animal models, established diagnostic approaches, and developed therapeutic strategies including AAV and lenti virus gene therapies. And finally awarded FNIH AMP® BGTC grant * (May, 2023), to conduct a first-of-its-kind gene therapy clinical trial for Morquio A. We are also engaged in other cutting-edge methods including the small molecular therapy.</p><p>*FNIH AMP® BGTC, a public-private partnership between the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), biopharmaceutical and life science companies, and non-profit and other organizations</p>
<img src="/Images%20Bios/tomatsu-diagram.jpg" alt="Interactive and Virtuous Circle diagram" style="margin:5px;width:600px;height:302px;" />
<p><strong>Natural History of Morquio A</strong></p><p>Since 2007, we have investigated the natural history of Morquio A and have established the Morquio registry (over 400 patients) and Morquio growth chart (2008) as well as two autopsied cases. We have found unique skeletal features of Morquio A; marked short stature, low bone mineral density, narrowing trachea, abnormal gait pattern, etc and described over 50 related publications along with the new drug development to provide an impact on the bone. These findings make us ready to conduct a systemic natural history program with non-invasive methods for Morquio A patients, and these non-invasive tests will be applied to clinical endpoints in clinical trials.<br></p><p><strong>Development of non-invasive tests for Morquio A</strong></p><p>Children with MPS IVA often have obstructive and restrictive lung disease, which can be life-threatening. In clinical practice, chest wall and formal respiratory function tests are difficult to perform owing to the small size and cooperation. Moreover, most wheel-chair bound or post-operative patients with severe muscle weakness (atrophy) cannot perform physical assessments like the 6-min walk or 3-min stair climb tests. Therefore, objective non-invasive measurements are required to demonstrate the feasibility of daily activity, and severity of cervical compression and stenosis and hyperlaxity of joints and thoracopulmonary function patterns. We have
investigated feasible non-invasive studies on Morquio A; non-invasive pulmonary function tests, assessment of tracheal obstruction, bone mineral density, hearing loss, gait analysis, ADL, etc.<br></p><p><strong>Establishment of glycosaminoglycans (GAGs) analysis and biomarker for MPS</strong></p><p>We developed GAG assay for MPS using molecular biology, ELISA, and LC-MS analysis. Studies on GAG assay for MPS have been performed: 1) development of KS and HS assays by ELISA, 2) development of CS, DS, HS, and KS assays by tandem mass spectrometry, 3) evaluation of GAG levels in MPS patients and mice.</p><p><strong>Newborn screening for MPS</strong><br></p><p>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. We established GAG assay for newborn DBS and identified 1 MPS patient out of 17000 samples. This screening system can be used for either 1st or 2nd tier screening.</p><p><strong>Development of innovative therapies for MPS</strong></p><p>We have developed and evaluated therapeutic efficacy of HSCT, gene therapy and enzyme replacement therapy for MPS in human and animal models. Bone-targeting is directly related with the primary concern on MPS type IV (Morquio A).<br></p> | <ol><li>Non-invasive functional assessment and pathogenesis of Morquio A.<br></li><li>Enhancement of Newborn Screening Diagnostic Paradigms to Improve the Efficacy of Treatment for Krabbe Disease, Pompe Disease, and Mucopolysaccharidosis Type 1<br></li><li>Identification of glycosaminoglycans for newborn screening and therapeutic monitoring of mucopolysaccharidoses.<br></li><li>AAV Gene Therapy for Mucopolysaccharidosis IVA Protocol NEM101<br></li><li><em>In vivo</em> lentiviral gene therapy for Mucopolysaccharidosis IVA<br></li><li><em>Ex vivo</em> lentiviral gene therapy for Mucopolysaccharidosis IVA<br></li><li>Glycosaminoglycan assay for mucopolysaccharidosis II specimens<br></li><li>Molecular and cellular validation of CRISPR/Cas9-based genome editing in hematopoietic stem cells for mucopolysaccharidoses IVA<br></li><li>Natural history of Morquio B disease and late onset gangliosidosis GM1<br></li></ol> | <p>
<strong>Shaukat Khan</strong>: PhD, research scientist and assistant professor.<br></p><ul><li>Tissue specific AAV and tandem promoters for treatment of Mucopolysaccharidosis type IV.<br></li><li>Evaluate the effect of prolonged GALNS enzyme exposure on bone pathology of MPS IVA mouse model.<br></li><li>High throughput screening of newborn and MPS dried blood spot by RapidFire.<br></li><li>Impact of small molecules in vitro and in vivo<br></li><li>Small activating RNA therapy for mucopolysaccharidosis type I<br></li><li>Glycosaminoglycans analysis in plasma, soft tissue, and bone<br></li><li>Glycosaminoglycans analysis in 100,000 dried blood spots<br></li></ul><p>
<strong>Yasuhiro Ago</strong>: MD, PhD, and visiting scholar. Accessing novel biomarkers of MPS IVA available in a clinical setting.<br></p><p>
<strong>Andrés Felipe Leal</strong>: PhD, and post doc fellow.<br></p><ul><li>Assessment of an iron oxide-coupled CRISPR/nCas9 gene editing on mucopolysaccharidosis type IVA mouse model.<br></li><li>CRISPR/Cas9-based ex vivo gene therapy for Morquio A syndrome.<br></li></ul><p>
<strong>Angelica Maria Herreño-Pachon</strong>: PhD student.<br></p><ul><li>Molecular and Cellular Validation of CRISPR/nCas9-based Genome Editing in Hematopoietic Stem Cells for Mucopolysaccharidoses IVA.<br></li><li>Induction of Immune Tolerance to Cas9 protein in MPS IVA mice.<br></li></ul><p>
<strong>Betül ÇELİK</strong>: PhD student.<br></p><ul><li>
<em>In vivo</em> and
<em>ex vivo</em> lentiviral gene therapy applications for Mucopolysaccharidoses IVA mouse models.<br></li><li>Engineered CART cells for GALNS tolerance induction.<br></li><li>Bone targeting lentiviral gene therapy for the treatment of MPS IVA (grant awarded by the National MPS Society)<br></li></ul><p>
<strong>Nidhi Fnu</strong>: PhD student.<br></p><ul><li>Integrase-Deficient Lentiviral Vector as a platform for efficient CRISPR/Cas9-mediated gene editing for Morquio A Syndrome<br></li><li>Efficacy of CRISPR-Cas9 gene editing in Morquio A mouse model with induced Cas9 immune tolerance.<br></li><li>CRISPR-Cas9 mediated knock-in effectiveness at different safe harbor sites in MPS IVA fibroblasts.<br></li><li>Evaluation of Integrase-Deficient Lentiviral vector based CRISPR-Cas9 gene edited hematopoietic stem cells in MPS IV A.<br></li><li>Newborn screening for mucopolysaccharidoses; Measurement of GAGs by automated high- throughput mass spectrometry/RapidFire<br></li></ul><p>
<strong>Sampurna Saikia</strong>: PhD student. Oral administration of peptides into mucopolysaccharidosis IVA mice to produce immune tolerance for the enzyme N-acetylgalactosamine-6-sulfate sulfatase in AVV9 gene therapy treatment.<br></p>
<p>
<strong>Amali Karunathilaka</strong>: PhD student.<br></p><ul><li>Fetal AAV mediate gene therapy for mucopolysaccharidosis IVA and Hyperphosphatasia<br></li><li>Neonatal AAV mediated gene therapy with tandem promoters for mucopolysaccharidosis IVA<br></li><li>Neonatal scAAV mediated gene therapy for mucopolysaccharidosis IVA<br></li><li>Signal sequence effect on AAV mediated gene therapy for mucopolysaccharidosis IVA<br></li></ul><p>
<strong>Krishna Sai Musini</strong>: PhD student. CRISPR/nCas9-based gene therapy for mucopolysaccharidosis IVA using non-viral vectors</p><p>
<strong>Georgina Neema Baya</strong>: PhD student.<br></p><p>
<strong>Eliana Patricia Benincore-Flórez</strong>: MS, research assistant. Works with Dr. Khan.</p><p>
<strong>Allison Bradford</strong>: BC, graduate student, and clinical research assistant. Non-invasive Functional Assessment and Pathogenesis of Morquio A.<br></p><p>
<strong>Abigail Weiser</strong>: undergraduate student.</p><p>
<strong>Alexa Shih</strong>: undergraduate student.</p><p>
<strong>Lan He</strong>: PhD, lab manager.</p>
<img src="/Images%20Bios/tomatsu-group.jpg" alt="Shunji Tomatsu research group" style="margin:5px;width:600px;height:450px;" />
<br> | <ol><li>Leal, A. F., Fnu, N., Benincore-Flórez, E., Pachón, A. M. H., Echeverri-Peña, O. Y., Alméciga-Díaz, C. J., &
<strong>Tomatsu, S.</strong> (2022). The landscape of CRISPR/Cas9 for inborn errors of metabolism.
<em>Molecular Genetics and Metabolism</em>, 106968.<br></li><li>Leal, A. F., Benincore-Flórez, E., Rintz, E., Herreño-Pachón, A. M., Celik, B., Ago, Y., ... &
<strong>Tomatsu, S.</strong> (2023). Mucopolysaccharidoses: Cellular Consequences of Glycosaminoglycans Accumulation and Potential Targets.
<em>International Journal of Molecular Sciences</em>, 24(1), 477.<br></li><li>Rintz E, Higuchi T, Kobayashi H, Galileo DS, Wegrzyn G,
<strong>Tomatsu S</strong>. Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases. Mol Ther Methods Clin Dev. 2021 Nov 24;24:71-87. doi: 10.1016/j.omtm.2021.11.007. PMCID:
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688940/" target="_blank" title="PubMed Central">PMC8688940</a><br></li><li>Sawamoto K, Karumuthil-Melethil S, Khan S, Stapleton M, Bruder JT, Danos O,
<strong>Tomatsu S</strong>. Liver targeted AAV8 gene therapy ameliorates skeletal and cardiovascular pathology in mucopolysaccharidosis IVA murine model. Mol Ther: Methods & Clinical Development 2020 18; 50-61. PMCID:
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301175/" target="_blank" title="PubMed Central">PMC7301175</a><br></li><li>Piechnik M, Sawamoto K, Ohnishi H, Kawamoto N, Ago Y,
<strong>Tomatsu S</strong>.
<a href="https://pubmed.ncbi.nlm.nih.gov/32414007/" target="_blank" title="PubMed">Evading the AAV Immune Response in Mucopolysaccharidoses</a>. Int J Mol Sci. 2020 May 13;21(10):3433. doi: 10.3390/ijms21103433 PMCID:
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279460/" target="_blank" title="PubMed Central">PMC7279460</a><br></li><li>Sawamoto K,
<strong>Tomatsu S</strong>.
<a href="https://pubmed.ncbi.nlm.nih.gov/31450640/" target="_blank" title="PubMed">Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model</a>. Int J Mol Sci. 2019, 20(17). pii: E4139. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747109/" target="_blank" title="PubMed Central">PMC6747109</a><br></li><li>Wang Z, Xu Y, Jiang E, Wang J,
<strong>Tomatsu S</strong>, Shen K. Pathophysiology of hip disorders in patients with Mucopolysaccharidosis IVA. Diagnostics 2020, 10, 264; doi:10.3390/diagnostics10050264 PMCID:
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277472/" target="_blank" title="PubMed Central">PMC7277472</a><br></li><li>Chen H, Khan S, Celik B, Suzuki Y, Ago Y,
<strong>Tomatsu S</strong>. Activity of daily living in mucopolysaccharidoses MPS IVA. Mol Genet Genomic Med. 2021 Nov;9(11):e1806. doi: 10.1002/mgg3.1806 PMCID:
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606213/" target="_blank" title="PubMed Central">PMC8606213</a><br></li><li>Averill LW, Kecskemethy HH, Theroux MC, Mackenzie WG, Pizarro C, Bober MB, Ditro CP, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/33608742/" target="_blank" title="PubMed">Tracheal narrowing in children and adults with mucopolysaccharidosis type IVA: evaluation with computed tomography angiography</a>. Pediatr Radiol. 2021;51(7):1202-1213. doi: 10.1007/s00247-020-04946-0. PMID: 33608742<br></li><li>Ratnagiri MV, Zhu Y, Rahman T, Theroux M, <strong>Tomatsu S</strong>, Shaffer TH. <a href="https://pubmed.ncbi.nlm.nih.gov/34063456/" title="PubMed" target="_blank">Automated Assessment of Thoracic-Abdominal Asynchrony in Patients with Morquio Syndrome</a>. Diagnostics (Basel). 2021 May 15;11(5):880. doi: 10.3390/diagnostics11050880. PMCID: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156300/" target="_blank" title="PubMed Central">PMC8156300</a><br></li><li>Nagao K, Morlet T, Haley E, Padilla J, Nemith J, Mason RW, <strong>Tomatsu S</strong>. Hearing Function in Patients with Mucopolysaccharidosis type IV (Morquio disease). Mol Genet Metab. 2018, 123:472-478.<br></li><li>Kecskemethy HH, Kubaski F, Harcke HT, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/26670863/" target="_blank" title="PubMed">Bone mineral density in MPS IV A (Morquio syndrome type A)</a>. Mol Genet Metab. 2016, 117:144-9. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755850/" target="_blank" title="PubMed Central">PMC4755850</a>.<br></li><li><strong>Tomatsu S</strong>, Averill LW, Sawamoto K, Mackenzie WG, Bober MB, Pizarro C, Goff CJ, Xie L, Orii T, Theroux M. <a href="https://pubmed.ncbi.nlm.nih.gov/26432669/" target="_blank" title="PubMed">Obstructive airway in Morquio A syndrome, the past, the present and the future</a>. Mol Genet Metab. 2016, 117(2):150-6. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755902/" target="_blank" title="PubMed Central">PMC4755902</a>.<br></li><li>Kubaski F, <strong>Tomatsu S</strong>, Patel P, Shimada T, Xie L, Yasuda E, Mason R, Mackenzie WG, Theroux M, Bober MB, Oldham HM, Orii T, Shaffer TH. <a href="https://pubmed.ncbi.nlm.nih.gov/26116954/" target="_blank" title="PubMed">Non-invasive pulmonary function test on Morquio patients</a>. Mol Genet Metab. 2015,115:186-92. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706533/" title="PubMed Central" target="_blank">PMC4706533</a>.<br></li><li>Amendum PC, Khan S, Yamaguchi S, Kobayashi H, Ago Y, Suzuki Y, Celik B, Rintz E, Hossain J, Xiao W, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/34573906/" target="_blank" title="PubMed">Glycosaminoglycans as Biomarkers for Mucopolysaccharidoses and Other Disorders</a>. Diagnostics (Basel). 2021 Aug 28;11(9):1563. doi: 10.3390/diagnostics11091563. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468223/" target="_blank" title="PubMed Central">PMC8468223</a><br></li><li>Arunkumar N, Vu DC, Khan S, Kobayashi H, Ngoc Can TB, Oguni T, Watanabe J, Tanaka M, Yamaguchi S, Taketani T, Ago Y, Ohnishi H, Saikia S, Álvarez JV, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/34441282/" target="_blank" title="PubMed">Diagnosis of Mucopolysaccharidoses and Mucolipidosis by Assaying Multiplex Enzymes and Glycosaminoglycans</a>. Diagnostics (Basel). 2021 Jul 27;11(8):1347. doi: 10.3390/diagnostics11081347. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394749/" target="_blank" title="PubMed Central">PMC8394749</a><br></li><li>Khan SA, Mason RW, Kobayashi H, Yamaguchi S, <strong>Tomatsu S</strong>. Advances in glycosaminoglycan detection. Mol Genet Metab 2020, 130;101–109. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198342/" target="_blank" title="PubMed Central">PMC7198342</a><br></li><li>Khan SA, Mason RW, Giugliani R, Orii K, Fukao T, Suzuki Y, Yamaguchi S, Kobayashi H, Orii T, <strong>Tomatsu S</strong>. Glycosaminoglycans analysis in blood and urine of mucopolysaccharidoses by tandem mass spectrometry. Mol Genet Metab. 2018, 125:44-52. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175648/" target="_blank" title="PubMed Central">PMC6175648</a>.<br></li><li>Stapleton M, Kubaski F, Mason RW, Shintaku H, Kobayashi H, Yamaguchi S, Taketani T, Suzuki Y, Orii K, Orii T, Fukao T, <strong>Tomatsu S</strong>. Newborn screening for Mucopolysaccharidoses: Measurement of glycosaminoglycans by LC-MS/MS. Mol Genet Metab Rep. 2020 Jan 10;22:100563. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957835/" target="_blank" title="PubMed Central">PMC6957835</a><br></li><li>Langan TJ, Jalal K, Barczykowski AL, Carter RL, Stapleton M, Orii K, Fukao T, Kobayashi H, Yamaguchi S, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/32154058/" target="_blank" title="PubMed">Development of a newborn screening tool for mucopolysaccharidosis type I based on bivariate normal limits: Using glycosaminoglycan and alpha-L-iduronidase determinations on dried blood spots to predict symptoms</a>. JIMD Rep. 2020, 52:35-42. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052686/" target="_blank" title="PubMed Central">PMC7052686</a><br></li><li>Kubaski F, Mason RW, Nakatomi A, Shintaku H, Xie L, van Vlies N, Church H, Giugliani R, Kobayashi H, Yamaguchi S, Suzuki Y, Orii T, Fukao T, Montaño AM, <strong>Tomatsu S</strong>. Newborn screening for mucopolysaccharidoses: A pilot study of measurement of glycosaminoglycans by tandem mass spectrometry. J Inherit Metab Dis. 2017, 40:151-158. PMC5203965.<br></li><li>Arunkumar N, Langan TJ, Stapleton M, Kubaski F, Mason RW, Singh R, Kobayashi H, Yamaguchi S, Suzuki Y, Orii K, Orii T, Fukao T, <strong>Tomatsu S</strong>. <a href="https://pubmed.ncbi.nlm.nih.gov/32277174/" target="_blank" title="PubMed">Newborn screening of mucopolysaccharidoses: past, present, and future</a>. J Hum Genet. 2020 Jul;65(7):557-567. doi: 10.1038/s10038-020-0744- 8. PMID: 32277174<br></li></ol> | | | <img alt="Shunji Tomatsu headshot" src="/Images%20Bios/tomatsu-portrait.jpg" style="BORDER:0px solid;" /> | |
