Morquio A disease (mucopolysaccharidosis IVA;MPS IVA) is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of N-acetyl-galactosamine-6-sulfate sulfatase (GALNS). Undegraded keratin sulfate (KS) will be accumulated especially in bone, leading to systemic skeletal dysplasia. Since the PI and co-investigators started Morquio A research over 20 years ago, purification of GALNS, cloning of human GALNS cDNA, cloning of human genomic gene, identification of common mutations, cloning of mouse gene, tertiary structure of GALNS, establishment of Morquio A murine models, KS assay by ELISA, Educational CD for Morquio, recombinant human GALNS produced in CHO, KS assay by tandem mass spectrometry, development of International Morquio Registry, the first attempt of ERT on Morquio A knock-out mouse, and growth chart for Morquio A patients were achieved. We have published over 50 peer-review articles on Morquio A. Seven patents related to therapy and diagnosis were applied and/or issued. We are developing new innovative enzyme replacement therapy (ERT) to target bone for Morquio A. Meanwhile, repeated administration of the enzyme could induce an undesirable immune response. 50-90% patients with LSDs administered intravenously raised antibody against infused enzyme. Immune response to ERT in LSDs has been widely reported and presented as one of the major complications of treatment. Goals: The immediate carrier goal is to develop """"""""oral tolerance"""""""" for immune response to ERT of LSDs, in particular, Morquio A disease. The long-term carrier goal is to optimize current ERT regimen and to change efficacy of ERT for LSDs with more feasibility. We will aim: 1) to establish an oral tolerance protocol to the human recombinant GALNS in Morquio A mice;2) to compare the efficacy of ERT between the tolerized and non-tolerized Morquio A mice. Research Plan: For suppressing the immune response to ERT, a novel oral tolerance protocol will be designed by administering synthetic GALNS peptides orally. Induction of oral tolerance with synthetic GALNS peptides will be investigated by a multiple low-dose feeding regimen in a Morquio A knock-out mouse. After induction of oral tolerance against GALNS, we will perform ERT on Morquio A mouse to assess improvement of pathological lesions. The experimental plan is 1) synthetic GALNS peptides will be made, 2) oral tolerance is induced by a multiple low-dose feeding regimen of synthetic GALNS peptides in Morquio A mouse, 3) the inhibition of an inflammatory response will be measured by the increment of regulatory T cell populations by flow cytometry, 4) the presence or absence of antibodies against GALNS will be measured, 5) Morquio A mice will be treated by ERT, and 6) we assess the immunological tolerance by measuring antibodies and assessing pathological improvement..To accomplish the proposed aims will resolve one of unmet challenges in current ERT and could change efficacy of the therapy dramatically.
Morquio A disease is a rare disorder caused by a deficiency of one of lysosomal enzymes, leading to accumulation of a sugar of chain mainly in bone, and showing systemic skeletal disease with short stature, prominent chest, spinal cord compression, knock-knee, and loose joints. Recent advanced technology has led to development of so-called """"""""enzyme replacement therapy"""""""" to make up for the deficient enzyme. To avoid immunological reaction against infused enzyme and resultant unwanted side effect is urgently demanded, therefore, we will develop novel immunological tolerance method to the infused enzyme by oral administration of synthetic peptide for the enzyme.
| Kubaski, Francyne; Kecskemethy, Heidi H; Harcke, H Theodore et al. (2016) Bone mineral density in mucopolysaccharidosis IVB. Mol Genet Metab Rep 8:80-84 |
| Kecskemethy, Heidi H; Kubaski, Francyne; Harcke, H T et al. (2016) Bone mineral density in MPS IV A (Morquio syndrome type A). Mol Genet Metab 117:144-9 |
| Rowan, Daniel J; Tomatsu, Shunji; Grubb, Jeffrey H et al. (2013) Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII. J Inherit Metab Dis 36:235-46 |
| Tomatsu, Shunji; Mackenzie, William G; Theroux, Mary C et al. (2012) Current and emerging treatments and surgical interventions for Morquio A syndrome: a review. Res Rep Endocr Disord 2012:65-77 |
