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2005 Morquio Research

Dr. Tomatsu's Research Team


Letter from Dr. Tamasu


Dear Morquio Patients and Families,

RE: The meetings of Morquio families and annual follow-up survey for 2005 year

A Happy Holiday!!!

We hope that all Morquio families are very well in this holiday season.

My name is Shunji Tomatsu, who has been working on Morquio Research for these 19 years to develop a new drug, so-called, enzyme replacement therapy (ERT). I am also a chief medical adviser of International Morquio Organization (IMO) organized by Carol Ann Foundation (President Mary Smith, AZ). I have been working with Mary Smith and other Morquio families on behalf of Morquio children. I would like to thank you for all Morquio families and local communities to support and encourage our research on Morquio through the 2004 year. Especially, I have met a lot of lovely Morquio families through this 2004 year at many meetings. Since one Louisiana family (Lantier Family) and IMO have begun this Morquio family event in Oct, 2003, we have three Morquio family events at this 2004 year. Each host family performed the formidable preparation and efforts to hold each family meeting as well as the fundraising party. Lewis family in LA in May, Little family in NY in July, and Waters family in GA in Oct hosted each meeting with the tireless work. I was so impressed with these meetings since all Morquio families dedicated themselves to hold such a meeting. I talked and discussed with each Morquio family on any related issues. In the end I have had a lot of Morquio Families as a friend. I really thank each host family and Mary Smith for the great success and am very pleased to hear that The Bennett foundation (GA) and The Jacob Randall Foundation (FL) for Morquio children have been also established following Carol Ann Foundation.

Surprisingly, many Morquio families gathered to attend each meeting even from Indonesia. We also appreciate a lot of support from Austrian, German, Italian, and Japanese MPS societies for the funding and the questionnaire. Without those aids from the non-profit organizations, our movement for Morquio Project shall not have been forwarded at any inch. I have already heard that several Morquio families are willing to hold next Morquio Family meeting and fundraising party next year. I hope many families, physicians (experts), community will join this event on behalf of Morquio children. Over 300 Morquio families are now joining and playing a part of role to expand the Morquio Society and to improve of a quality of life for each affected child. Without coming together, nothing has happened. We have to work together to establish a new drug to improve the quality of life of Morquio children. Please check the web site (www.morquio.com) to get more information for the meeting periodically. We are currently developing the drug delivery system to the bone for Morquio patients.

Meanwhile, we have now over 300 Morquio patients in our international registry program as you may know well. We have to follow up clinical status of each Morquio child. This is an annual follow-up study. I really appreciate your kind cooperation on the annual follow-up talk with us. This annual survey is quite important to know the progression of the disease as well as current status of your child. Please kindly cooperate on behalf of your child. To renewal your information, you can answer again the questionnaire through web site www.morquio.com or e-mail to me directly, or download from this site at  AnnualQuestionnaire.doc.   Especially, please keep and update the medical record annually to evaluate the condition. If you can send the current height and weight with the current age and growth chart, I can evaluate your child's status in comparison with the age-matched control population and affected children. We would like to also investigate some specimen from each patient to know the clinical condition of each patient. We recently established keratan sulfate (KS) assay system. As you know well, KS is the storage material for Morquio patients causing the bone dysplasia and the key substrate to evaluate the condition of the progression of the disease.

If possible, I would like to have some specimen to assay KS from blood and urine. The best way is as follows: Please kindly send specimens (urine and blood) from your child and parents who want be tested. This is free of charge since International Morquio Organization (www.morquio.com), The Bennett foundation (GA)  and The Jacob Randall Foundation (FL)  are supporting this purpose. The tests will be accomplished within a couple of weeks and results will be returned to you or your primary physician if you want.

1. Peripheral blood sample (5ml) for KS assay Extract the peripheral blood sample (5ml) in the syringe and transfer into the tube including EDTA (anticoagulant material). Make sure the lid of the content is tightly closed and send them at ambient temperature by overnight express.

2. Urine sample for KS which accumulated in the Morquio patient 5-10 ml in the Falcon tube and ship at ambient temperature by overnight express as well as blood sample. If you have any questions, please let me know. Of course, all those information should be kept confidential and there is no obligation to follow all procedures. If you have sent the specimen alreday to us and have not received the results yet, please let me know it. I will check it up immediately. Please call me or e-mail to me if you have any Morquio related question.

Again thank you very much for your support for our activity. I am very thrilled to see you again at next Morquio family meeting. Finally, I put the questionnaire and the background of Morquio research and future plan in this letter. If you can not understand what we are doing, please let me know without any hesitation. Please send the questionnaire back at your earliest convenience. One questionnaire is called "the Annual Questionnaire" and is used for every year.

I believe the 2005 year will be the best year for all Morquio families and our Morquio research project. Again, have a nice holiday and happy new year!

Sincerely,

Tomatsu Shunji MD PhD
Department of Pediatrics, Saint Louis University,
Pediatric Research Institute
3662 Park Ave. St. Louis MO 63110-2512
Phone: 314-577-5623 ext. 6213
Fax: 314-577-5398
E-mail: tomatsus@slu.edu


P.S. Again, please send me the latest height and weight with the date of birth and current age immediately to assess the condition!!! I have also attached the growth chart by PDF file (girls and boys). Please fill in annual growth of your child and send it to me by e-mail, fax, or mail at your earliest convenience. Please put measured values of the weight and height as much as possible in the graph of growth chart.

Background of Morquio Research

I. Summary of Morquio and its research:

Morquio syndrome (mucopolysaccharidosis IV: MPS IV) is an autosomal recessive disease classified in the group of mucopolysaccharide storage diseases. Two forms are recognized, type A and type B. MPS IVA is characterized by the absence of the enzyme N-acetylgalactosamine 6-sulfate sulfatase (GALNS). MPS IVB results from deficiency of the enzyme ߭galactosidase. Both types excretes keratan sulfate (KS) in urine. In 1929, Morquio, a pediatrician in Uruguay, described cases of Morquio syndrome. In 1952, Brante isolated the stored mucopolysaccharides in Morquio patients. In 1976, the enzyme deficiency in MPS IVA (GALNS deficiency) was identified. Shortly thereafter, the enzyme deficiency in MPS IVB was described (߭galactosidase deficiency). Historically, MPS IVA was considered to have more severe manifestations than MPS IVB. However, with the ability to differentiate between types A and B by enzyme analysis, variability in clinical expression in both groups becomes apparent. MPS IV causes skeletal dysplasia through excessive storage of KS. The unique clinical manifestations of this disorder are attributable to the restricted tissue distribution of KS (corneas and cartilage), in contrast to the much wider distribution of dermatan sulfate (DS) and heparan sulfate (HS). The ELISA-sandwich assay by a monoclonal antibody specific to KS has been developed. It was found that blood and urine KS level varied with age and clinical severity, indicating that the new assay for KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IV. The broad range of clinical phenotypes seen in MPS IVA is presumed to be the result of many different GALNS mutations. The isolation and characterization of the full-length cDNA encoding the human GALNS protein and genomic sequence (Tomatsu et al., 1991; Nakashima et al., 1994) have facilitated investigations into the molecular genetic heterogeneity in MPS IVA. GALNS is a member of the sulfatase gene family of which 13 sulfatase genes in human have been cloned. All sulfatase gene products are closely related, showing 20-35% similarity at the amino acid level. C79 residue of human GALNS is conserved among all sulfatase proteins from many species. Characterization of sulfatase proteins by structural analysis and homology comparisons suggested C79 as an active site residue (Bond et al., 1997; Sukegawa et al., 2000). The post-translational modification of the highly conserved cysteine residue is required for generating catalytically active sulfatases (Schmidt et al., 1995). Recently, three different MPS IVA model mice have been established (Tomatsu et al 2003; unpublished data). Clinical manifestations in the affected mice are milder than those in human patients. Only palliative measures are currently available for treatment of patients with MPS IV. Potential strategies, which are currently at different levels of development, include enzyme replacement, gene therapy, and allogenic bone marrow transplantation in which engrafted cells provide the normal enzyme. Those treatments are expected to have dramatic improvements in visceral organs but little or no improvements in bone since the enzymes are not delivered to the bone effectively. In this context, it is still a challenge to maximize the clinical efficacy to the bones, especially to systematic bone disease, MPS IV.

II. Toward development of advanced treatment on MPS IVA: establishment of enzyme replacement therapy

The broad goal of our research is to develop enzyme replacement therapy for mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome). In the next year, we will test the newly-designed drug delivery system (DDS) to the bone by using an acidic amino acid oligopeptide as a drug carrier. Modifying the drug to be delivered to the bone more specifically is noteworthy since it will enhance the drug effectiveness and to reduce the secondary side effects. The small acidic peptide is tagged to the substance (drug) and the tagged drug is tested to evaluate whether it is delivered to the bone compared to the untagged drug. This DDS is applied to a large molecule, enzyme, to digest sugar chains (mucopolysaccharides). This protein is used for enzyme replacement therapy (ERT) to compensate for the enzyme deficient in MPS IVA. We will test the oligopeptide-tagged enzyme on MPS IVA model mouse, which has clinical similarity to human patients. By infusing the deficient enzyme into the model mouse weekly for several months, the clinical improvements will be assessed compared to the untagged enzyme. The results of pre-clinical trials on both mice models will guide us in developing adequate assessment of effectiveness of this novel bone-targeting strategy, and provide information required to design human trials. Establishment of a bone-targeting therapy will help us broad our applications to other bone-related disorders.

III. The pharmaceutical company

We are looking for the partner company now to work with to execute the clinical trial. This is one of the primary goal now. If you have any suggested company, please let me know!

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