Senate Resolution 450

• On your cell phone send a message to 80888.
• In your message box type CUREMPS.
• A message will notify you in less than 30 seconds to confirm your donation to the National MPS Society for $10. Follow the directions and reply by typing YES.
• You will receive another message thanking you on behalf of the National MPS Society for your donation.
• You will be billed for this donation through your mobile carrier such as: Verizon, Sprint, AT&T, etc.
• You may participate in TEXT TO GIVE up to three times a month!
• Email family and friends and share on social media. Help us launch a national effort to support those suffering from MPS and related diseases.

For more information contact Terri Klein at terri@mpssociety.org.

Today we:

• Remember all the children and adults who suffer from MPS and related diseases.
• Think about the children we have lost.
• Think about the doctors and scientists who are dedicated to finding a cure for MPS and related diseases.
• Remember each other and are thankful for the strength and support we both give and receive.

On March 28, 2012, Ultragenyx announced the European Medicines Agency (EMA) granted orphan drug designation for UX003 for the treatment of MPS VII.  See the full press release for more details.

Congratulations to the previous recipients of Continuing Education Scholarships from the National MPS Society! Read more about the 2011 recipients.

The purpose of World Rare Disease Day is to harness the creative energy of the millions of people around the world with rare diseases — as well as that of all the people who care about and assist them — to help others understand certain fundamental issues that need to be addressed.

For more information please visit the US Rare Disease Day website and Global Rare Disease Day website!

26th Annual Family Conference brochure

Registration forms for Annual Family Conference:

• Parents of an individual with MPS or related disease OR Adults with MPS or a related disease
• Friends, relatives and professionals

Registration form for 2nd Annual Finding Our SPIRIT conference

Registration form for 4th Celebrating Your Child’s Life Experience (CYCLE) conference

The Society is pleased to offer scholarships to our conferences. The registration package for the SPIRIT conference includes some travel/hotel funding (see registration form above). However the Annual Family Conference and CYCLE conference require separate applications – see below.

• Annual Family Conference Scholarship Application
• CYCLE conference

1. The support of basic or clinical research for MPS II - One (1) $90,000 two year grant: $45,000 awarded in 2012 and in $45,000 in 2013

2. The support of basic or clinical research for MPS IV - One (1) $80,000 grant: $40,000 awarded in 2012 and $40,000 in 2013

The Society is also offering an MPS III Grand Challenge Grant, to support an MPS III clinical trial, or to study either a therapy or a biomarker that has passed the proof of concept stage but requires further pre-clinical or clinical testing. Biomarkers must be potentially useful in monitoring the therapeutic response in the central nervous system in clinical trials. Proposals for therapies or biomarkers for other MPS and related diseases will be considered, provided they are applicable to MPS III.

• MPS III Grand Challenge Grant with support from Team Sanfilippo - One (1) $235,000 grant: one year

Requirements:

• Three pages maximum:
  • two pages summarizing in a concise manner your specific aims
  • one page preliminary budget
• Do not describe the MPS diseases
• Include your name and institution on the right hand corner of each page

Please e-mail a two-page Letter of Intent summarizing the project and a one-page preliminary budget no later than March 15, 2012 to Barbara Wedehase, Executive Director: barbara@mpssociety.org

Successful candidates will be invited to submit full proposals for a May 1, 2012 deadline; funding will begin July 1, 2012. Grants and fellowships from the National MPS Society are provided to qualified medical researchers for the purpose of promoting medical research in the fields of MPS and related diseases. No institution overhead or other indirect costs will be paid and shall not be included as part of any grant request. There are no restrictions on citizenship, residency or location of research project.

For additional information contact:
Barbara Wedehase, Executive Director
National MPS Society, PO Box 14686, Durham, NC 27709-4686
phone: 919.806.0101
www.mpssociety.org

Click here to become a member!

Your membership brings us another step closer to achieving our goal of ultimately curing the debilitating diseases that affect our families and friends. Together we work to provide support and information to families affected with MPS and related diseases; to increase public and professional awareness of MPS; and most importantly – to further the vital research that adds quality to all our lives.

Become a member to receive benefits and the latest news about the Society, fundraising events, research and more! Sign up online or choose the appropriate membership form below.

• 2012 Membership Form for Families/Friends, Professionals, Foreign and Corporate memberships. Membership dues are listed on the form and can be submitted to the address below. For parents experiencing financial difficulty, please contact Laurie Turner at laurie@mpssociety.org for assistance with membership dues.

• 2012 Membership Form for Adults with MPS or Related Diseases Membership for affected adults in the United States is complementary but must be renewed each year. The form can be mailed to the address below or emailed to laurie@mpssociety.org.

• 2012 Membership Form for Newly Diagnosed Families The Society provides complimentary first year dues for newly diagnosed families living in the United States. Please submit the form to laurie@mpssociety.org or the address below. Visit our New Diagnosis webpage for additional information on beginning your journey with MPS or related diseases.

Please make checks payable to: National MPS Society

Mail to: MPS Annual Membership
PO Box 14686
Durham, NC 27709-4686

Skeletal Dysplasia and MPS Summer Camp Flyer

Skeletal Dysplasia and MPS Summer Camp Application

Frequently Asked Questions

A team of scientists, led by researchers at the University of California, San Diego School of Medicine and Zacharon Pharmaceuticals, have developed a simple, reliable test for identifying biomarkers for mucopolysaccharidoses. The findings are published online January 8 in the journal Nature Chemical Biology. Click here to read the full press release.

Funding for this research came, in part, from the National Institutes of Health, a Kirschstein National Research Service Award and the National MPS Society.

New Year — Renewed Hope

The Boston Park Plaza Hotel & Towers is located in the heart of historic Back Bay and is one of Boston’s most recognized and renowned landmarks. Rich in history, The Boston Park Plaza has distinguished itself with classic elegance and personalized service that continues to attract travelers from all over the world. The hotel is located only three miles from Logan International Airport and only 200 yards from the nation’s first public parks, Boston Common and the Public Garden is easily accessible to shopping along world-renowned Newbury Street, Faneuil Hall Marketplace, the theatre and financial districts and more historic landmarks.

In December 2011, U.S. Representatives Cliff Stearns (R-FL) and Ed Towns (D-NY), two senior members of the Energy and Commerce Committee, introduced bipartisan legislation to help spur the development of treatments for very rare diseases. The Unlocking Lifesaving Treatments for Rare diseases Act of 2012, or ULTRA, H.R. 3737, will improve access to the FDA’s Accelerated Approval process for very rare diseases, provide a more predictable regulatory process, bring down development costs, and spur investment in the development of treatments. Additionally, ULTRA requires the FDA to use the best science available, ensuring treatments are safe and effective and reach patients sooner.

Over 90 organizations have signed on to the letters of support. Click here to see the list and read the letter. Visit CureTheProcess.org for more information.

For more information about the program, including eligibility, and to complete the online application, please visit: www.aldurazyme.com/copay/

You can also call your Genzyme Case Manager directly to learn more about the program and application process at 1-800-745-4447, Option 3

Genzyme Co-Pay Assistance Program flyer (pdf)

See the flyer for more details.  Shire HGT 2012 Copay Announcement

For more information please visit: http://rarediseases.org/docs/clinical-trials/diss-recruitment

• Legislative Advocacy to improve services to families and to increase money for research
• Family Support with conference scholarships, continuing education scholarships, durable medical equipment
• Bereavement programs to support families with desperately needed resources
• Informational resources for the public, the medical community, and the families
• Parent to parent support, to serve the daily needs of the families

Beth Karas, Correspondent, In Session on truTV (formerly Court TV) is the Chair of the National MPS Society 2011 Annual Fund. Beth is the sister of two brothers Joe and Johnathan Karas who passed away from the debiliating effects of Mucolipidosis III, (ML III).  She is honored to be the chair and we are honored to share her story with you.  Beth and the National MPS Society hope that your family will make a difference by making a donation to the 2011 Annual Fund and support our mission and keep the Society strong.

Beth states, “Joe and my younger brother, Jonathan, were born in the 1950s with a rare genetic disease. That diagnosis would not be made, however, until the 1970s. Doctors were baffled in the early years by my brothers’ condition as they searched for a diagnosis. They believed that whatever this mysterious affliction was, it surely had to be sex-linked because my sister and I were disease-free. Regardless, they cautioned my parents against having more children.

Joe and Jon suffered the debilitating effects of ML-III as they aged. They could walk, even run, in their early years but used wheelchairs at the end of their lives. Jonathan was more severely affected than Joseph and spent two years in bed in the 1970s, in a body cast, following two surgeries for his scoliosis. Later, they both had hip replacements as doctors reconstructed their failing bodies.

My brothers learned to live with chronic pain from their stiff joints as they faced an unknown future and a slow decline toward their premature deaths. By their last years, we could only provide palliative care. Jonathan passed away in 1993. He was 34 years old.” Joe passed away in 2001 at the age of 46.

The National MPS Society’s 2011 Annual Fund program is focused on three general areas; (1) where needed most (2) legislative activities and (3) family assistance.  By improving the Society’s capabilities and effectiveness, the two programmatic areas of legislative and family assistance will be strengthened.  The Annual Fund program provides donors the opportunity to give a gift in any of these three areas.
By building the capacity of the Society, proceeds from the Annual Fund raise public awareness, improve advocacy, strengthen the leadership and overall effectiveness of the organization, and expand the Society’s leadership role in public policy formation.

You can make a donation online here.

Or make a check payable to: National MPS Society and send to

National MPS Society
Attn: Annual Fund
P.O. Box 14686
Durham, NC 27709

For more information contact Terri Klein at 919-806-0101 or terri@mpssociety.org.

For contest rules and how to enter, please visit www.rareartist.org/main/contest_rule.

Each Grand Prize winner will also receive an iPod touch.  Winners can use the iPod touch to record a video and share their story about being an artist affected by a rare disease.  The artists’ video stories will be posted on www.RareArtist.org.

Deadline:  Entries must be received by 5 pm PST on Tuesday, January 31, 2012.

The Boston Park Plaza Hotel & Towers is located in the heart of historic Back Bay and is one of Boston’s most recognized and renowned landmarks. Rich in history, The Boston Park Plaza has distinguished itself with classic elegance and personalized service that continues to attract travelers from all over the world. The hotel is located only three miles from Logan International Airport and only 200 yards from the nation’s first public parks, Boston Common and the Public Garden is easily accessible to shopping along world-renowned Newbury Street, Faneuil Hall Marketplace, the theatre and financial districts and more historic landmarks. Save the date to attend this conference which promises to offer all the updates on research, medical care and topics that you’ve requested.

Race Coordinator: Scott Hardin
Host Family: The Holland Family

**Family Pricing, please contact Scott
Hardin directly to order additional
T-shirts if using Family Pricing Option**

Registration 7-8:15am
Time: 5K =8:30am, 1M=9am, Toddler Trot=9:15am

Event flyer (pdf)

Event map (pdf)

Patients Brochure

Illinois Public Act 097-0532

Thanks to our conference scholarship program, many families attended their first conference, and many of those were newly diagnosed families. Knowing how challenging that first conference can be, we offered sessions for the newly diagnosed families in addition to a special welcome dinner. Due to the heat, the planned family outing to the St. Louis Zoo was supplemented last minute with an alternative outing to nearby Aquaport. The pools, lazy river and water slides at Aquaport appealed to those who wanted to relax in a cool setting.

Save the date!

Join us for the Inaugural Annie’s 5K Run
and 1 Mile Walk
in Paducah, Kentucky

Please register onsite on day of event.

8:00 am registration onsite
9:30 am start time

1K Fun Run Registration $13
5K Run Registration $15

We received 33 letters of intent from researchers around the world for the five grants offered in 2011. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 13 researchers.

All grant recipients were awarded $70,000 for the two year grant, with half of the total provided each year. The Society will fund $25,000 to support the Lysosomal Disease Networks NIH grant research goals. The funding is designed for the Neuroimaging Core, which will benefit the four MPS projects. The Society also provides funding for post-doctoral fellows to attend scientific meetings, such as the American Society of Gene and Cell Therapy and the Gordon Conference on Lysosomal Diseases.

MPS II Grant

Vito Ferro, Small molecule chaperons for ERT for MPS II

MPS II is caused by defects in an enzyme called iduronate-2-sulfatase. L Many of these defects result in degradation of the enzyme in cells before it has had a chance to carry out its normal function, thus producing clinical symptoms. MPS II patients may be treated with enzyme replacement therapy in which a synthetic, fully functional enzyme is administered by injection. Unfortunately, the replacement enzyme cannot cross the blood-brain barrier and thus cannot relieve the neurological symptoms associated with severe cases of MPS II. The aims of this project are to develop small molecules for the treatment of MPS II, which unlike enzymes, are capable of crossing the blood-brain barrier and thus may offer relief of neurological symptoms. The small molecules are designed to act as chaperones to protect the defective enzyme from degradation and restore enzyme activity to sufficient levels to relieve symptoms. This approach has shown great promise in other lysosomal storage diseases but has yet to be extended to MPS II. This project will address that situation.

MPS III Grant

Patricia Dickson, Choriod plexus-directed gene therapy as a source of intraventricular NAGLU-IGF2 for MPS IIIB

Animal models of MPS types I, II and IIIA can be treated by providing recombinant enzyme into the fluid surrounding the brain (cerebrospinal fluid). The application of this treatment of IIIB has been hampered by the inability of the missing enzyme, alpha-?-acetylglucosaminidase (NAGLU), to enter cells efficiently. We have created NAGLU tagged with insulin-like growth factor 2 (IGF2) which enters cells effectively using the mannose 6-phosphate receptor. Here, we will deliver NAGLU-IGF2 to the cerebrospinal fluid by using gene therapy in animal models. We will target the part of the brain that makes cerebrospinal fluid (the choroid plexus), to determine whether this will provide a source of NAGLU-IGF2 for the brain. This study will provide proof-of-principle for choroid-plexus directed gene therapy with NAGLU-IGF2 as a potential therapy for MPS III IIIB, to determine whether this approach can deliver enzyme using cerebrospinal fluid without the need for repeated injections.

General Grants

Alberto Auricchio, Gene therapy of MPS VI

Enzyme replacement therapy for MPS VI requires weekly administrations of costly enzyme and has a poor outcome on some of the disease characteristics including bone and cartilage abnormalities. We have recently shown that a single systemic delivery of an adeno-associated viral vector (AAV) encoding the correct copy of the enzyme missing in MPSVI results in: i.sustained expression of the enzyme from liver of MPS VI cats transduced by AAV; ii.significant amelioration of the disease phenotype (including bone and cartilage) in this large model of the disease.

Based on these promising results we are planning a clinical trial to test the safety and efficacy of our approach in MPS VI patients. Towards this goal we propose to:

complete some of the pre-clinical data required for further clinical development

develop bioengineered enzyme molecules with improved secretion or bone uptake which may increase the efficacy of gene therapy and lower the vector doses used in patients.

We believe these data will be instrumental to rapidly move gene therapy for MPS VI from bench to bedside thus overcoming some of the limitations of current therapies. In addition, the results from these studies may improve the cures for other MPS.

Adriana Montano, Role of inflammation in pathogenesis of MPS IVA

Morquio A disease is characterized with the build-up of two specific sugars (chondroitin-6- sulfate and keratan sulfate) in all the body cells, particularly in skeletal tissue. Effects of this build-up on the immune system and the consequences on the cartilage destruction and alterations of bone metabolism in Morquio A disease have not been investigated yet. We will clarify the role of immune system in the pathogenesis of Morquio A disease. We will characterize the immune profile of Morquio A mouse bone and cartilage cells and tissues, as well as Morquio A human cartilage cells. The outcome of this research will enable us to develop better approaches for treatment strategies to stop cartilage degeneration not only in Morquio A but also in other MPS.

Richard Steet, Blockade of cathepsin activity and TGF-beta signaling as a therapeutic approach for LSDs

Understanding the molecular events that cause disease symptoms is an important step in the development of new therapies for many inherited disorders, especially in cases where replacement of the defective gene or enzyme is difficult. In earlier studies, we showed that the cartilage defects in a zebrafish model for ML-II are associated with increased activity of protein-degrading enzymes called cathepsins and excessive TGF-beta signaling. Our most recent work now demonstrates that reducing the activity of one of these enzymes, cathepsin K, results in correction of the cartilage defects in ML-II zebrafish embryos. Using known drugs, we now propose to block the activity of two other cathepsin proteases and to reduce excessive TGF-beta signaling to determine how these molecules impact the onset and progression of disease phenotypes such as impaired development of cartilage and heart valves. Since elevated cathepsin activity is a common feature of many MPS disorders, we believe our results on ML-II will increase our understanding of the disease mechanisms associated with other lysosomal diseases.

Insurance Commissioner Dave Jones and Assembly Member Mike Feuer, joined by Wendy Lazarus, Founder and Co-President of The Children’s Partnership, representing The 100% Campaign held a news conference today at the Children’s Hospital Los Angeles to highlight a critical open-enrollment period for kids’ health insurance that began on January 1, 2011 and ends on March 1.

During the open enrollment period, parents can sign up their children for more affordable health insurance. As a result of President Obama’s federal health care reform plan and AB 2244 by Assembly Member Feuer, children with pre-existing conditions cannot be denied coverage – they also cannot be charged rates that are more than double the rates of healthy kids. Parents of healthy children without insurance should also sign their kids up during this period; otherwise, they may be subject to a 20 percent surcharge on their insurance rates for a full year.

“President Obama’s health care reform plan has and will do much to change the face of health care in America,” Commissioner Jones said. “One of the most important changes that federal health care reform has brought about is allowing for children with pre-existing conditions to attain health coverage. This initial open enrollment window is critical and parents should take full advantage of it by signing their children up for coverage.”

“Under my new law, kids will receive the health care they need, at a price their parents can afford,” said Assembly Member Feuer. “But it’s important that parents act during this open enrollment period to get their kids signed up for health insurance. If they don’t act by March 1, coverage for their kids could be significantly more expensive.”

Assembly Member Feuer authored legislation, AB 2244, that helps to implement this component of federal health care reform in California. The new law, which has been in effect since January 1, gives California children access to affordable care and a healthy future by ensuring that certain children cannot be denied coverage or priced out of the market. It also prohibits insurers that sell individual market policies in California from refusing to sell or renew coverage to children with pre-existing conditions – it also bans insurers from the individual market for five years if they do not sell policies to children.

“The 100% Campaign’s mission is to achieve health care coverage for 100% of California’s children. For years, hundreds of thousands of children have been left out because they have pre-existing health conditions and insurers refused to provide coverage. September 23, 2010 marked the historic end to this practice, and January 1, 2011 marked the first open enrollment period for obtaining insurance under the new law,” said Wendy Lazarus of The 100% Campaign. “We’re pleased to be working with Insurance Commissioner Jones and Assembly Member Feuer, as we urge families to sign up for health care coverage by March 1 – even if they have been turned down in the past. With these new protections, children with conditions such as asthma and diabetes cannot be denied insurance – and families will have the peace of mind to know their children can receive needed care.”

Today’s event also highlighted the availability of a number of important educational resources for parents on how they can obtain health coverage for their children during and after the open enrollment period. Parents are encouraged to check the web site of the California Department of Insurance (CDI) at www.insurance.ca.gov, where they can find fact sheets on how to insure their children. Parents were also encouraged to call CDI’s consumer hotline at 1-800-927-HELP or the state health insurance hotline at 1-888-466-2219 with any questions or concerns. Another important resource is http://finder.healthcare.gov/, a web site created to assist consumers in navigating their options under the Affordable Care Act.

The Time for Action is NOW to secure co-sponsors for Senate resolution designating May 15, 2011 as National MPS Awareness Day. The deadline for co-sponsors is May 11, 2011.

WE NEED YOUR HELP. National MPS Awareness Day is fast approaching. With new senators recently elected, this is a perfect opportunity for them and all our senators on capitol hill to become more familiar with MPS and related diseases and how this disease impacts your family. Senator Lindsey Graham (SC) is again sponsoring this years resolution proclaiming May 15, 2011 as National MPS Awareness Day.

We are asking you, your family and friends to contact both of your United States Senators and ask to speak with their Health Legislative Assistants (HLA). Their contact information is available at www.senate.gov. If you click on the upper right hand corner by your state, you will see their contact information including phone, fax and email addresses.

If calling your two Senators offices, ask to speak with the Health Legislative Assistant (HLA). If you get their voice mail, be prepared to leave your message. We have attached a suggested script for calling, faxing or emailing. Explain to the HLA that you are a constituent and give a brief description of how MPS affects your lives. Let your HLA know the purpose of the resolution is to raise awareness and recognize affected individuals and families and ask for them to co-sponsor this resolution.

If emailing or faxing, address your correspondence to your Senator in care of the Health Legislative Assistant (HLA). You can use the attached sample letter to personalize for your family also explaining how MPS has affected your lives and the purpose of the resolution. Please include the 2010 Senate Resolution in your communications with your Senator.

VERY IMPORTANT: Be sure and have your HLA or Senator contact Senator Lindsey Grahams office and speak to either Colin Allen or Leigh Ellen Gray at 202.224.5972 to sign on as a co-sponsor.

If you have any questions feel free to contact us by reply email or by calling the National MPS Society’s office at 919.806.0101. Please let us know when you have contacted the HLA at your Senator’s offices.

Thank you for your help.

Your voice is a powerful tool in raising awareness for MPS and related diseases.

We received 33 letters of intent from researchers around the world for the five grants offered in 2011. After reviewing those letters, our Scientific Advisory Board review committee requested full grant proposals from 13 researchers.

All grant recipients were awarded $70,000 for the two year grant, with half of the total provided each year. The Society will fund $25,000 to support the Lysosomal Disease Networks NIH grant research goals. The funding is designed for the Neuroimaging Core, which will benefit the four MPS projects. An additional $11,500 has been allocated for a mucolipidosis partnership grant with ISMRD. An $8,000 partnership grant with the Ryan Foundation funded the University of MN project “Longitudinal Studies of Brain Structure and Function: The Effects of Genetic Mutations.” The Society also provides funding for post-doctoral fellows to attend scientific meetings, such as the American Society of Gene and Cell Therapy and the Gordon Conference on Lysosomal Diseases.

MPS II Grant

Vito Ferro

University of Queensland

Brisbane, Queensland ,Australia

Small molecule chaperons for ERT for MPS II

MPS II is caused by defects in an enzyme called iduronate-2-sulfatase. L Many of these defects result in degradation of the enzyme in cells before it has had a chance to carry out its normal function, thus producing clinical symptoms. MPS II patients may be treated with enzyme replacement therapy in which a synthetic, fully functional enzyme is administered by injection. Unfortunately, the replacement enzyme cannot cross the blood-brain barrier and thus cannot relieve the neurological symptoms associated with severe cases of MPS II. The aims of this project are to develop small molecules for the treatment of MPS II, which unlike enzymes, are capable of crossing the blood-brain barrier and thus may offer relief of neurological symptoms. The small molecules are designed to act as chaperones to protect the defective enzyme from degradation and restore enzyme activity to sufficient levels to relieve symptoms. This approach has shown great promise in other lysosomal storage diseases but has yet to be extended to MPS II. This project will address that situation.

MPS III Grant

Patricia Dickson

Los Angeles Biomedical Research Institute at Harbor-UCLA

Torrance, CA

Choriod plexus-directed gene therapy as a source of intraventricular NAGLU-IGF2 for MPS IIIB

Animal models of MPS types I, II and IIIA can be treated by providing recombinant enzyme into the fluid surrounding the brain (cerebrospinal fluid). The application of this treatment of IIIB has been hampered by the inability of the missing enzyme, alpha-?-acetylglucosaminidase (NAGLU), to enter cells efficiently. We have created NAGLU tagged with insulin-like growth factor 2 (IGF2) which enters cells effectively using the mannose 6-phosphate receptor. Here, we will deliver NAGLU-IGF2 to the cerebrospinal fluid by using gene therapy in animal models. We will target the part of the brain that makes cerebrospinal fluid (the choroid plexus), to determine whether this will provide a source of NAGLU-IGF2 for the brain. This study will provide proof-of-principle for choroid-plexus directed gene therapy with NAGLU-IGF2 as a potential therapy for MPS III IIIB, to determine whether this approach can deliver enzyme using cerebrospinal fluid without the need for repeated injections.

General Grants

Alberto Auricchio

Fondazione Telethon

Naples, Italy

Gene therapy of MPS VI

Enzyme replacement therapy for MPS VI requires weekly administrations of costly enzyme and has a poor outcome on some of the disease characteristics including bone and cartilage abnormalities. We have recently shown that a single systemic delivery of an adeno-associated viral vector (AAV) encoding the correct copy of the enzyme missing in MPSVI results in: i.sustained expression of the enzyme from liver of MPS VI cats transduced by AAV; ii.significant amelioration of the disease phenotype (including bone and cartilage) in this large model of the disease.

Based on these promising results we are planning a clinical trial to test the safety and efficacy of our approach in MPS VI patients. Towards this goal we propose to:

• complete some of the pre-clinical data required for further clinical development
• develop bioengineered enzyme molecules with improved secretion or bone uptake which may increase the efficacy of gene therapy and lower the vector doses used in patients.

We believe these data will be instrumental to rapidly move gene therapy for MPS VI from bench to bedside thus overcoming some of the limitations of current therapies. In addition, the results from these studies may improve the cures for other MPS.

Adriana Montano

St. Louis University

St. Louis, MO

Role of inflammation in pathogenesis of MPS IVA

Morquio A disease is characterized with the build-up of two specific sugars (chondroitin-6- sulfate and keratan sulfate) in all the body cells, particularly in skeletal tissue. Effects of this build-up on the immune system and the consequences on the cartilage destruction and alterations of bone metabolism in Morquio A disease have not been investigated yet. We will clarify the role of immune system in the pathogenesis of Morquio A disease. We will characterize the immune profile of Morquio A mouse bone and cartilage cells and tissues, as well as Morquio A human cartilage cells. The outcome of this research will enable us to develop better approaches for treatment strategies to stop cartilage degeneration not only in Morquio A but also in other MPS.

Richard Steet

University of Georgia

Athens, GA

Blockade of cathepsin activity and TGF-beta signaling as a therapeutic approach for LSDs

Understanding the molecular events that cause disease symptoms is an important step in the development of new therapies for many inherited disorders, especially in cases where replacement of the defective gene or enzyme is difficult. In earlier studies, we showed that the cartilage defects in a zebrafish model for ML-II are associated with increased activity of protein-degrading enzymes called cathepsins and excessive TGF-beta signaling. Our most recent work now demonstrates that reducing the activity of one of these enzymes, cathepsin K, results in correction of the cartilage defects in ML-II zebrafish embryos. Using known drugs, we now propose to block the activity of two other cathepsin proteases and to reduce excessive TGF-beta signaling to determine how these molecules impact the onset and progression of disease phenotypes such as impaired development of cartilage and heart valves. Since elevated cathepsin activity is a common feature of many MPS disorders, we believe our results on ML-II will increase our understanding of the disease mechanisms associated with other lysosomal diseases.