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January 2005 Newsletter

Newsletter from Dr. Shunji Tomatsu

January 7, 2005

Dear Mary, Renee, Stacie, and Joni,

Thank you very much for all contribution to Morquio Project. I really appreciate for your long term commitment.

Overview and Background

The mucopolysaccharidoses are a set of lysosomal storage diseases caused by deficiencies of enzymes required to catabolize glycosaminoglycans (GAGs). As a result, GAGs accumulate in the lysosomes of affected tissues. MPS is a rare disease with an estimated incidence of 1 in 25,000 -50,000 live births. The clinical consequences can vary for each individual patient, but the common pathophysiology is lysosomal accumulation of GAG molecules leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction. MPS is characterized by GAG accumulation in the respiratory tract, heart, liver, spleen, leptomeninges, bones, joints, oropharynx, head, neck, and central nervous system. Oropharyngeal and respiratory deposition of GAGs leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and tracheomalacia. This obstructive anatomy and physiology leads to sleep apnea and airway obstruction. Deposition of GAGs in the heart, liver, and spleen leads to organomegaly, and cardiac valves are affected as well. The bone and joint involvement leads to severe skeletal deformities and limitations of joint mobility. In severe cases, central nervous system involvement leads to mental retardation and progressive neurologic decline. Invariably, these diseases are associated with profound and disabling morbidity as well as very early mortality. Many of these diseases are associated with death in infancy or early childhood.

The MPS and ML are theoretically amenable to therapy by exogenously supplied enzymes. The modest success in altering the course of some MPS by bone marrow transplant suggests that enzyme from the donor bone marrow can reduce the storage of GAGs. Moreover, a new treatment approach, namely enzyme replacement therapy (ERT), has been developed and clinically tried to MPS I, II and VI patients. ERT in patients with MPS is expected to offer the possibility of a safe and efficacious approach for the treatment of this disease without a donor of bone marrow. As you may know it already, ERT for MPS I patients has been approved in USA and Europe. Most MPS I patients have had a lot of benefits with dramatic clinical improvements by ERT. Clinical trials of enzyme replacement therapy (ERT) on MPS II and VI are now in progress in USA and Europe. Without doubt, once these treatments are to be successful and to be approved, most affected children will get a great benefit. While many MPS I, II, and VI patients are now treated by ERT, no clinical trial on MPS IVA has been excecuted. As far as our knowledge, MPS IVA should be one of the potential candidate although so far there is no expectation to get an immediate clinical trial because of the lack of the partner company.

We also heard that the drug companies for MPS II and VI would submit applications for marketing approval in both the United States and Europe in 2005. Why no clinical trials on MPS IVA has been done is now a serious issue. We speculate several reasons as follows. 1. It is not cost-benefit for the company because of the low incidence of the patients, 2. The drug must be delivered efficiently to the bon (bone-targeting system), 3. The lobby activity to the drug companies not enough to convince importance of ERT for Morquio. If those factors are main, we have to work together on resolving such issues. It is a critical moment to introduce ERT drug on Morquio patients as quick as possible since many children suffered from Morquio have been handicapped and have to get surgical treatments. The affected children must be treated properly. I anticipate that you as well as I myself could play an important role on this movement. In these circumstances, it is our mission to intensify the necessity of ERT drug for Morquio to the public and companies through any chance and to appeal importance of development of the drug. In these circumstances, our broad goals are to ultimately promote the excecution of the clinical trial of ERT on behalf of Morquio patients and families and to widely promote public and professional awareness, and significantly increasing participation of this movement by regions. I would like to propose the folloing action program to achieve these goals, supported by MPS families, pharmacetutical companies, professionals, and facilities.

1. Contact the pharmacetutical companies as many as possible through using any channel.

Currently, I contact the following companies; BioMarin, Genzyme, Japan Chemical Research, Eli Lilly, and TKT. I visit Japan in the end of this month to see the possibility of the clinical trial by Japanese companies. After returning, I also contact the above US companies as well. However, please also contact any pharmacetutical companies that you may know and please let me know if you have any chance. I am very happy to make a presentation at such companies.

2. Accomplish the preclinical trial of ERT on Morquio mice.

Currently our group has finished three months preclinical trial on Morquio micemodel and is summarizing data in details. We feel stll it is necessary to have a long term experiment on Morquio mice model like over 6 months to conclude our results although the preliminary data are encuraging us. I am very pleased to hear from all of you that you will have the fundraisng party and family meeting at your own site this year as well. These strong supports encourage us a lot since the US government support is quite limited at this point. Please let me know the schedule once the date is assigned.

3. Produce the educational monograph and CD for MPS IVA.

I am now working very hard to make an educational CD first and then monograph since many families, the companies, or even physicians do not know about Morquio. Such educational instruments should provide a proper message for the management and treatment of Morquio children. We may also distribute such educational intruments to the local community and the drug companies who have Morquio children. In this way, the local community and the companies will recognize the issues on Morquio and should understand the affected children well. I would like to finish these educational CD and monograph by the end of this year as quick as possible. Please cooperate to give me some X-ray pictures and clinical pictures listed in.

4. Make the network among the local Morquio families.

Since we really need a lot of help from each Morquio family, it will be ideal to have a good network in each state or region. In this way, we work and unite together toward our goals.

Thank you again for your kind cooperation. I hope that we will solve the above issues in this 2005 year.

Most sincerely,

Shunji Tomatsu


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