MD-CARE REAUTHORIZATION BILL OF 2008: TELL YOUR MEMBERS OF CONGRESS TO SIGN ON

H. R. 5265/S. 2618 -- Paul D. Wellstone Muscular Dystrophy Community Assistance, Research and Education Amendments of 2008

Parents call or write your Senators and Representative and ask them to support the MD CARE Reauthorization Bill of 2008. Please click on these links to find out who your members of congress are and where to write to them.

Below are some important facts about the 2001 MD-CARE Act and what is being proposed for 2008.

Congress enacted the Muscular Dystrophy Community Assistance, Research and Education Amendments of 2001 (MD-CARE Act) to coordinate and focus federal research on muscular dystrophy, to develop therapies, and to develop epidemiologic data. The House of Representatives approved the MD-CARE Act without opposition; the Senate approved the legislation by unanimous consent; and President George W. Bush signed the bill into law (Public Law 107-84) on December 18, 2001.

The 2001 MD CARE Act has provided critical authority and direction for MD research:

• Six cooperative MD research Centers of Excellence were established by the National Institutes of Health (NIH). The centers work individually and collaboratively. Each has both basic and clinical research projects, and one or more core facilities to support them. Centers must also make core resources or services available to the national muscular dystrophy research community.


• The public-private Muscular Dystrophy Coordinating Committee, established under the bill, has worked to expand, intensify, and coordinate research activities related to muscular dystrophy.


• The MD STARnet (the Muscular Dystrophy Surveillance Tracking and Research Network) is a data collection and surveillance mechanism aimed at epidemiological research and is overseen by the Centers for Disease Control (CDC).

To build upon the progress made by the MD-CARE Act, reauthorization bills were introduced on February 8, 2008 by Congressmen Eliot Engel (D-NY) and Michael Burgess (R-TX) [H.R. 5265] and by Senators Amy Klobuchar (D-MN) and Johnny Isakson (R-GA) [S. 2618]. These reauthorization bills would:

• Expand the number of NIH institutes involved to include the National Heart, Lung, Blood Institute.

• Officially name the Centers of Excellence, the Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers.


• Emphasize the need for an enhanced clinical and translational research infrastructure, as promising therapies emerge.


• Ensure MD STARnet data is regularly updated to reflect patients’ changing conditions over time and includes tracking of health outcomes. CDC is required to report annually to Congress on the status of data collection.


• Direct the CDC to disseminate care considerations for the muscular dystrophies.


• Direct the Agency for Healthcare Research and Quality (AHRQ) to work with medical and patient organizations to develop standards of care for Duchenne and Becker muscular dystrophy, and to replicate the methods used in developing these care considerations to include other muscular dystrophies.
  

GGT: a test for liver disease in boys with duchenne

In speaking with other parents, too many times I have heard of doctors performing liver biopsies to find out what was wrong with their boys before coming up with the diagnosis of duchenne dystrophy.

This happens because levels of Aspartate aminotransferase (AST) and Alanine transaminase (ALT) enzymes routinely tested for in blood work, are elevated in liver disease and duchenne dystrophy. Doctors often check for liver disease, not duchenne dystrophy, first.

But what if, instead of a biopsy, there was a blood test to rule out liver problems? That is what Jerry Mendell and his team developed at Nationwide Children’s Hospital in Columbus, Ohio.

Dr. Mendell’s team tested gamma-glutamyl transferase (GGT), a liver enzyme in 20 healthy volunteers and 28 walking and non-walking boys with duchenne. A portion of them were on Deflazacourt. The study showed that GGT, almost exclusively found in the liver, is a reliable test for liver damage.

Recently, I emailed Dr. Mendell to ask him about GGT. Here is his response.

“We routinely use this assay [GGT] in all of our clinical trials. We decided to do this study because some investigators challenged its validity. The study shows that GGT does not vary with CK or activity and should be used as a test for liver toxicity in DMD, as well as other muscle diseases.

So many of the kids come in having had liver biopsies because their docs were not aware of an alternative way to exclude liver disease when AST and ALT are elevated. “

The study, “Fidelity of Gamma-Glutamyl Transferase (GGT) in Differentiating Skeletal Muscle From Liver Damage” by Rosales, Chu, Shilling, Wall, Pastores, and Mendell was published in the Journal of Child Neurology on March 19, 2008 (epub ahead of print)

Uncle Pete

Every now and then I get a bright idea - like to ask Pete Catucci if I can put his Caring Bridge page on my blog.

Pete and I have a silly joke thing going: he calls me Aunt Marie. I call him Uncle Pete. We don't know why but it's funny. He's my brother-in-law.

In February 2007 he found out he has ALS. I think the whole world was stunned. Pete Catucci, who could run a five minute mile, who was captain and star of Coach John Thompson's pre-Geogetown, St. Anthony's High School basketball team. Has ALS.

Pete's a busy man. Vice-President of the Communications Workers of America, golfer, and schmoozer par excellence. He's always got something going. And so it was hit or miss whether or not he would show up at family gatherings. At one such event a few years back, I was going in my front door with Petey, my son, when Pete and my sister Terry, his wife, were coming up the walk. My son, Petey, turned to me deadpan and said, "The beast ... is out."

I like that story. It's so Pete. It's so Petey.

The other day in an email exchange, Pete reminded me that I was one of the first ones to come to see him after his diagnosis. I remember the house was full of people. Pete paced from room to room frenetically talking, talking, talking.

Sitting in the kitchen with my sister, Terry, felt strangely familiar, as though it was twenty years earlier and I was finding out all over again that Petey had duchenne muscular dystrophy.

How do any of us handle all this?

Uncle Pete, I hope you like your journal on my page.

Love,

Aunt Marie

Tell the Department of Education: We Need Medical Rehab for Neuromuscular Diseases

The National Institute on Disability and Rehabilitation Research (NIDRR) within the Department of Education is shifting their priorities from medical rehabilitation research to vocational rehabilitation research. This is especially true for neuromuscular disease medical rehabilitation research.

The only neuromuscular disease research and training in NIDRR goes to the Rehabilitation Research and Training Center (RRTC) in Neuromuscular Diseases with total funding of $4,000,000 over a five year period ending November 30, 2008.

March 19th, today, there will be what is essentially a no-notice public outreach meeting in Washington DC, with webcasts at sites throughout the country.

I will be at the Washington DC site. If you'd like to join me at the Washington DC site from 1:00 to 5:00PM, please contact Donna Nangle at Donna.nangle@ed.gov.
and let her know you will be attending and would like to say something. She will give you public hearing location address, which was not listed. It may be at the Department of Education:

Donna Nangle
U.S. Department of Education
400 Maryland Avenue, SW.
Room 6029
Potomac Center Plaza
Washington, DC 20202-2700

If you cannot join me and would like to do something, write to NIDRR to let them know that we still need neuromuscular disease medical rehabilitation research.

NIDRR is pretty much cutting out future medical rehabilitation research, including some important programs for muscular dystrophy research. And this change in focus was done without consideration of the MD Care Act 2001 provision that institutes coordinate their programs through the Muscular Dystrophy Coordinating Committee (MDCC).


If you are interested in participating in Washington DC, please contact Donna Nangle at Donna.nangle@ed.gov.

Ms. Nangle is in charge of public participation.


Can't get there tomorrow - or, not in Washington DC and want to participate?

Go to NIDRR's web site. There is a toll-free number, videoconference centers information and mailing address and email address for written input, which will be accepted until March 31, 2008.

Below is a summary I wrote up based on information I received from Erik Henricson of UC Davis about the event and why it's important. If you would like to receive the document I got from Erik, email me at genmedlabmom@gmail.com and I'll be happy to send you the entire document.

ACTION ALERT: Federal Government Completely Eliminates

All Funding for Rehabilitation Research in Neuromuscular Diseases.

Since 1983, National Institute on Disability and Rehabilitation Research (NIDRR), in the Department of Education, Office of Special Education and Rehabilitation Services (OSERS), has been the only federal agency to fund medical rehabilitation research for people with neuromuscular diseases(NMDs) including muscular dystrophies.

NIDRR recently reported that they would not hold a competition to re-fund the Rehabilitation Research and Training Center (RRTC) in Neuromuscular Diseases ($4,000,000 for the period 2003-2008) (This is the Center where Erik Henricson works). They said they wanted to make NIDRR’s resources available for new work (ie, vocational rehab work).

NIDRR’s decision to eliminate neuromuscular diseases from its research and training portfolio:

• Is unfair to people with muscular dystrophies and other neuromuscular diseases. NIDRR is making up 44% of its mandated 1.747% reduction by completely eliminating Neuromuscular Disease research rather than distributing this reduction across all programs and activities as required by the Consolidated Appropriations Act of 2008 (H.R. 2764).

• Runs contrary to the MD Care Act of 2001, which calls for more funding and federally supported efforts in rehabilitation and training that is related to muscular dystrophies. The Muscular Dystrophy Coordinating Committee (MDCC) was established by Congress in P.L. 107-84 to coordinate NIH, CDC, and Department of Education to work together.

• NIDRR is required to tie accomplishments to money spent and is ignoring the fact that Neuromuscular Disease Rehab research has had more than four times the number of accomplishments per dollar spent compared to the average of all NIDRR health and function centers, and exemplary performance on all other performance review criteria established by NIDRR.

• Rewrote the final priorities that changed NIDRR’s research agenda without allowing for public notice and comments as required.
  

• Will stop the largest international multi-center natural history trial in Duchenne muscular dystrophy (NIFD). This trial was described as one of the greatest research needs in the MDCC Action Plan.
  

ACTIONS RECOMMENDED:

• Immediate congressional inquiry into the decision by NIDRR to eliminate their entire research and training portfolio related to neuromuscular diseases with emphasis on the:

• the impact of this decision on persons with neuromuscular diseases;

• lack of transparency and public comment;
  

• lack of consideration of prior productivity and impacts of centers being cut.

• Reinstatement of Priority 12: “Enhancing the Health and Wellness of Individuals with Neuromuscular Diseases” in similar form to that written in the Federal Register from August 31, 2007 (Federal Register, vol. 72, No. 169, pp. 50528-50529).
  

• Create legislation to mandate that NIDRR fund a Rehabilitation Research and Training Center in Neuromuscular Diseases (other legislation has recently mandated NIDRR to allocate a greater proportion of its fixed budget for traumatic brain injury model systems).

• Fund Rehab medicine research projects for muscular dystrophy under NIH (e.g. National Center for Medical Rehabilitation Research within NICHD). Priorities should be consistent with the MDCC Muscular Dystrophy Research and Education Plan for the National Institutes of Health.

Help find a cure for John John Boom and all boys with Duchenne

Help find a cure

John John Boom

Duchenne Muscular Dystrophy

WHAT: Potomac River Run - ½ Marathon

WHEN: May 4th, 2008 Start time: 7:00

COURSE: Belle Haven to Mount Vernon and back

CHARITY: Foundation to Eradicate Duchenne (FED) – Team John John Boom

HOW YOU CAN HELP:

1. Contribute directly – go to the FOUNDATION TO ERADICATE DUCHENNE donation page.
2. Sign up to run with Team John John Boom it’s only 13.1 miles!
3. Contribute a service (dinner, dry cleaning, gift card) – we’ll auction it and get you a new customer
4. Host a fund raiser (i.e. at a happy hour, at the yoga studio) – some % of proceeds get donated
5. Post this letter in your business
6. Forward to your friends, relatives and business associates
7. Support the Potomac River Run on May 4th

John

“John John Boom” Morrison is a spunky little 5-year old with amazing personality and character. Unfortunately, in September 2006 during a routine pediatric doctor's appointment at Walter Reed Army Medical Center this little man was diagnosed with a debilitative fatal disease called Duchenne Muscular Dystrophy (DMD) that presently remains incurable.

Duchenne Muscular Dystrophy

DMD is the world’s number one genetic disease, impacting one in every 3,000 boys born throughout the world. There is no cure for DMD and it is always fatal. In fact, 90% of afflicted boys do not live to celebrate their 20th birthdays. The mission of the Foundation to Eradicate Duchenne (FED) is to fund research for treatments and ultimately a cure for this devastating disease. Our goal is to help this generation of DMD boys. We know we can do it – but we need your help.

The Foundation to Eradicate Duchenne is a 501 c3 nonprofit organization founded in 2002 by Joel and Dana Wood, of Alexandria, when they found out in their son, James, was diagnosed with DMD.

FED raises critical research funds that are “mainlined” directly to the world's only clinical trials network for DMD that works collaboratively with scientists all over the world on aggressive cutting edge therapies for DMD.

For Your Generosity: We will have a sponsorship poster and handout at the race, we will mention all sponsors in an ad in the local paper, we will email all participants and supporters the names of the sponsors, and we’ll encourage everyone to patronize you over others.

All sponsorships over $500 will have their name on the back of our Team Race Shirt.


You may donate on-line to the team “John John Boom” or to an individual runner on the team at:

Foundation to Eradicate Duchenne donation page

or

Make Checks Payable to: Foundation to Eradicate Duchenne, Inc.
EIN# 71 0874241

Mail To: Foundation to Eradicate Duchenne, Inc.
P.O. Box 2371
Alexandria, VA 22301

If you would rather give in some other way, contact Pete O’Dell, 703-519-0188 or pete.odell@swanisland.net.


Through your commitment to FEET for FED Team “John John Boom”, through your love, and prayers, and, yes, dollars ... you are giving him hope.

From the bottom of our hearts, thank you.

Sincerely,

Pete O’Dell, Team “John John Boom”, and the Foundation to Eradicate Duchenne

Thank you blog and meeting guests

Family and friends

Thanks to the many people who stopped by the blog: Folks from Kenya and Ghana in Africa, Germany, Italy, Greece, Hungary, Czech Republic, Romania, and Norway, and Columbia, Brazil, Argentina, and Peru in South America. And of course, thank you to the folks from the US and all over for your visits.

Meeting and celebration guests

I'm glad I had a chance to meet our clinical trials network guests last weekend. It was great to see so many of you again and to meet all the new participants as well.

I especially would like to say hello to our kind visitors from Japan. Our friend, Dr. Shin’ichi Takeda, was there from the National Center of Neurology and Psychiatry (NCNP), along with Drs. Aoki, Kato, Komaki, Miyoshi, Nakamura, Sato and Shinozaki.

Arigato.

I also want to say hello to all the moms who attended the 20th Anniversary celebration; Tina, who I love dearly, Carolyn, my angel, Nikki, a new friend, and Dana and Monica, who do so much for duchenne research. Donna, who is not a mom but a bright spot in Mike’s life (I hope your trip home was uneventful!) Also my old friends, Grace and Deb and Ping. And finally Janet, who came from so far away and made my night because she was there.

Also thank you to MDA for the celebration itself! Annie, Katie, Sharon, Christine, and Sarah, you guys are wonderful!

GenMed Lab Mom

A Mother Copes ... Lives ... Loves

Here is Anneliese, today's guest blogger, with her family. And though she is the photographer, she uses a timer to put herself in the picture. She is the one with her arm leaning against her son's wheelchair. Anneliese and her family live in Oregon.

Raymon, Anneliese's sixteen year old son who has duchenne, with his nephew.

People can assume I am coping with life, with living with a child with Duchenne Muscular Dystrophy, and coping well. Often they do. But they don't see me at home crying or fretting do they? That isn't exactly how I appear when I am at church or the grocery store. They see me when things are fine, or when I wear my facade.

How do I cope? What do I do? I guess my best answer is that I don't cope well.

When my son was younger I coped differently. I coped by making a lot of physical therapy appointments, occupational therapy appointments, the bi-yearly clinics, and IEP meetings with the schools. I researched everything, found internet support groups, and got my hopes up about that illusive cure.

He got AFO's and eventually his first manual chair and we adapted fairly easily because it was safer and easier. When he got his first power chair we rejoiced at his new freedom and he was excited!

Thirteen years have passed since his diagnosis. What works for him and me now is different than what seemed to be working for us when he was younger. After years of doing all we thought we were supposed to do, we found ourselves unhappy and stressed. He was stressed and I was stressed. We had to evaluate things and decided to minimize things as much as possible, and find our comfort level.


How do I cope now? I'm still not sure I actually do cope but if I had to tell you how I would say: I cope by pretending every day that my son is normal and life with a hoyer lift, shower chair, and wheelchair, lifting his arms to hug me, and drinking through a straw is normal.

I cope by not dwelling on the DMD and part of how we do that I suppose is by eliminating any doctor appointments that aren't absolutely necessary. We check in with a PT and OT once a year. We do cardio and pulmonary exams every six months. Most wheelchair adjustments I do myself or we do with the provider we bought the chair from. I read the current research when I feel that I have some strength to deal with the face of DMD. I don't have much hope for my son but I certainly hold out hope of better treatment for the younger boys.

We homeschool. He and I are much happier. I've also found a fantastic support group for homeschoolers of disabled children. These changes have helped him be a much happier person and also more social. That helps me cope.

Raymon and I find humor helps in many of our situations. For example, we laugh at those urinal mishaps we call "splash mountain" .

How do I cope with the depression I still get and the anxiety? I have been taking more walks alone, even if only for ten minutes, and I often bring along my camera. I've taken up photography though I am by no means skilled yet, although I am far from an amateur. I do enjoy the process of learning.

The camera has given me a view of the world that reminds me how wonderful the world is, how beautiful life is, and how peaceful it can be. I find that when I am busy taking pictures I am not focusing on anything but what is in the camera's viewfinder. This is how I get my brain to shut off the negatives, for a short time at least.

I joined an online photography forum, which has given me another outlet for some social time without leaving home. This helps me not feel as "stuck" at home.

However, some days it does hit me that life really isn't "normal" and is much too much work for someone who's just too tired. Those days are usually brought on by other life events piling up rather than the DMD itself.

Raymon is the youngest of four and life can get hairy and busy with other family needs too. My husband is also batteling his own health demons.

Some days I feel like I am living on top of a bomb that I've been told will blow up, devastating my house and life, but that I am not able to dismantle it, nor can I predict when it will blow. I'm told I must keep living, trying to live in the moment and day, and ignore that one day the inevitable will happen...that bomb will blow!

I have to remind myself to breathe now and then, and that breathing is enough. My mother recently told me, "Since a freight train is heading your way, trouble is coming....you should not spend your days rushing to meet it. It will arrive on it's own time without your help." She's right.
Now, where did I put my walking shoes and camera?


Anneliese

Anneliese's photography

Beauty in the eye of the beholder

A squirrel peeks out from among the leaves




deer twins



fly among the flowers

Anneliese's sanctuary

a flower's beauty




A wood duck among the pines





The turtle escapes





A fence and an old shoe

Advocacy Conference Review from February 10, 2008 by Adele Abramowitz

Adele Abramowitz attended the Parent Project Conference in Washington DC last month. Adele's 22 year old son, Jason, who also attended the conference, has Duchenne Muscular Dystrophy. The following is her report on the weekend's events.

March 3, 2008

On February 10. 2008, I attended the Parent Project Muscular Dystrophy Advocacy conference held in Washington DC.

For those who are unfamiliar with this, each year representative from many states come to DC to talk to their Senators and Congressman about either signing on to a specific piece of legislation to either create, or increase funding to NIH specifically for DMD research.

BACKGROUND:

Back in February, 2001, PPMD, along with MDA went to DC and testified in front of a subcommittee to have the MD Care Act passed. In December 2001, President Bush signed this into law. Passing this very important bill paved the way for DMD specific funding from NIH (National Institute of Health, CDC (Center for Disease Control) and believe it or not, the DoD (Department of Defense).

Much has happened over the past 5 years to further research into DMD. Funding has gone from $12.6 million to $38.7 in 2004. Currently, the budget has been hold steady at around $47 million for the past 3 years (FY 2007, 2008 and 2009). In the last years we asked for money to start a registry.

PRESENT INITIATIVES

Registry

Up till now, there is no data being collected and examined on DMD. No one really knows how many people are living with DMD and how many of those are living to 20’s 30's and 40’s. Did they die of lung or heart problems? Did they have a deletion or duplication? What exons are involved? We now have the start of a registry, which will help everyone, doctors, researchers, parents and the people with DMD. See DuchenneConnect.

Standards of Care

PPMD and MDA are working to get the all important “Standards of Care” going, without which, getting good care from your doctor or local hospital, help in getting specific equipment approved from your insurance company and other benefits would be very hard. Please see American Thoracic Society's, Respiratory Care of the Patient with Duchenne Muscular Dystrophy for a standard of care of respiratory management.

Re-authorization

This year, we had really only one “ask”. The MD Care Act is up for re-authorization. The Bill is only good for 5 (five) years, so every five years we have to get it reauthorized. We asked each of our Senators and Congressmen to co-sign the Re-authorization. So far, we have many names, but as of 2 weeks ago, not enough to get it passed.

Presentations

Also in attendance we had a Mr. Tim Cote from the FDA. He is the Director of Orphan Product Development. His was a very interesting presentation. Also, Dr. Lee Sweeny, a big name in DMD research. You see him listed in the Quest Magazine quite often.


Great Turnout

Over all, I think we had a great turnout. Many states were represented, but not all. It was good seeing people who I talk to on many of the groups, renewing old friendships, meeting new people.

You can still help!

I know many of the families either can’t get away or afford making this trip, but each person can help out by writing letters to you Senators and Congressman about you, your sons and will they support what PPMD is asking for in the current year. These people were elected by the people, may not have been you in particular, but they are suppose to be YOUR representative in the government. Writing them and asking them to support something you find very importation to you and your family is your right and responsibility. To find out who you should contact in Washington, follow the instructions on the Officials page on the Congress.org website.

Recent strides in research have been made possible by the efforts of PPMD.

This year, as well as last year, Jason made the trip with me. We live about 40 minutes for Capitol Hill, so this is an easy one for us. I just wish it would not snow or get icy each time we go. We have a great time.

Pictures from the 20th Anniversary of the Discovery of Dystrophin Celebration

My thanks to Tina Carson and her husband, Dan, for the pictures because most of mine didn't turn out too well.

The Honorees: Michel Koenig, Anthony Monoco, Lou Kunkel (the boss!) and Eric Hoffman

Eric Hoffman, accepting his award

Here are the moms! Nikki, Tina, Dana, and Michelle.




More moms! Marie (that's me!), Tina, and Nikki




And yet more moms! Nikki, Tina and Carolyn

A day of meetings and an evening of celebration

We did it! Yesterday’s meetings and dinner were successful on many levels.

The six review meetings, with the main focus being the clinical trials network, accomplished the goals we had set for them. GenMed scientists, collaborators and clinicians discussed measurement of clinical endpoints and potential treatments, including exon skipping (Toshifumi Yokota), modified morpholinos (Qi Lu), nf Kappa B modifiers (Yi-Wen Chen), and high throughput drug screening (Carrie Micelli and Stan Nelson).

The main thrust of the potential treatments, including nonhormonal steriods, combination therapy, and exon skipping were discussed in previous posts.

We topped it off with the MDA 20th anniversary of the discovery of dystrophin celebration. Families poured in for the reception and dinner that evening; even the weather cooperated. The research atrium, overlooking the reservoir and the Capitol beyond, was festively decorated with candles, flowers, pictures and balloons and full to overflowing with people.

We came from all over. Researchers, clinicians, different muscular dystrophy foundations, organizations, and parents and children came together to celebrate the discovery that got us where we are today; on the verge of a treatment.

It was a night to honor Lou Kunkel, Michel Koenig, Anthony Monaco, and Eric Hoffman, the Boston team that 20 years ago discovered the dystrophin gene, which is absent in boys with duchenne muscular dystrophy. This was the first time in over a decade that the team had come together.

My daughter is an artist and made sculptures that were presented to the honorees. The sculpture is of her brother's hands, duchenne hands, unraveling a strand of DNA.

Along with the honorees and MDA, we parents claim a piece of the discovery we honored that night. Without parents and the sacrifice made, that advancement and all the others would not have happened.

Combination Therapy targets multiple pathways for synergistic results

Have you ever seen a biochemical pathway diagram? It is filled with lines, arrows, squiggles and jellybeans (yes – jellybeans!) on either side of a cushy-looking surface representing a cell wall. Pathways are the way our bodies change one substance into another – like food into energy or a gene into a protein. They are automatic steps our bodies take to make those changes happen.

These pathway changes affect your genes, which turn off and on to a greater or lesser degree in response to the changes.

There are a whole bunch of pathways such as the regeneration pathway, inflammatory pathway, nf KAPPA B pathway, calcium pathway, and the TGF-beta pathway.

In duchenne dystrophy these pathways go majorly out of whack and change considerably from what is normal.

Our lab does research to find out how genes turn on and off, measured by gene chips, which we then use to analyze what is happening along these pathways. This research is based on the idea that if you bring pathways that are out of balance back into balance, you can exert control on the disease process that make duchenne so deadly.

Clinical trials of different drugs have tried to do just that. For the most part such trials in duchenne dystrophy have been a disappointment. Historically, drugs that worked well with the mdx mouse made a poor showing with our boys.

So we thought, instead of using one drug to change one pathway, what if we hit several pathways at one time?

This approach has borne results in other diseases including HIV and malaria. In either case, no single drug worked well but a combination of drugs targeting the different pathways of these diseases made a big difference, enough to turn deadly killers into a livable disease.

That’s what scientists from GenMed want to do. They believe that approaching several pathways at once will have a synergistic effect and hopefully avoid the same kind of disappointing results from the one-drug trials.

Yesterday at the CINRG Review meeting, Susan Sparks, an MD, PhD from the Wellstone Muscular Dystrophy Center within GenMed, proposed a combination of three to five drugs to work on different pathways that she believes may have synergistic effects and help control the disease process that makes duchenne so deadly.

Her idea is to see how this drug combination affects the mdx mouse and, if it proves successful, to continue towards clinical trials.

Dr. Sparks proposed a combination therapy study with 10 groups of mdx mice to test drugs a combination of up to five drugs.

She chose drugs that affect the different pathways that go out of whack with duchenne. These drugs are proven safe via the FDA in children age six and up and are known to interact safely with each other.

Below are some of the drugs she proposed for the study:

• prednisone – corticosteroid – inflammatory pathway

• losartin - angiotensin II – effects TGF b pathway

• cromolyn – mast cell stabilizer – nf Kappa b pathway

• erythromycin – affects the extracellular matrix and fibrosis – regeneration pathway.

The mdx mouse study would be followed by clinical trials. This would begin with ten patients, six years or older with duchenne. What drugs would be involved will depend on the success of the mouse study. Since the drugs are already approved for use in children over the age of six, the approval process to go to clinical trials would be shortened.

Susan’s proposal was enthusiastically received – hopefully this will translate into a quick beginning for combination therapy.

'But keep the pathway open

Your home is at the end.'

From God’s Garden by Robert Frost

Exon Skipping and Clinical Trials

I found out yesterday that if I want a lot more visitors to my blog, I should write for the finance community. On purpose.

Yesterday, I was thrilled to see the number of visitors climb to twice what it had ever been in the past. Then I noticed many of the visitors were from 'Yahoo financial' and the like, drawn by my mention of drug companies and clinical trials.

I took the page down, changed some words and added a disclaimer. No more writing for the finance types.

Here is my original post sans speculative wording....

What parent of a kid with duchenne diagnosed in the recent past does not know their dystrophin gene mutation? Not only do parents know the mutation but chances are they know what exon or exons need to be skipped to put dystrophin back ‘in-frame’, and hopefully make strong and healthy muscles.

Here at GenMed, as we swing into the last few days before the CINRG annual meeting, we are looking at data sets and statistical analysis to put the finishing touches on the clinical trials we will propose as the best therapy for our kids. Exon skipping rises to the top.

Building on the success and knowledge afforded us by the Dutch clinical trials and the knowledge to be gained from the study now underway at Imperial College London, we will make several recommendations for CINRG sites to consider. CINRG and the Research Center for Genetic Medicine will be proposing targeting specific exons that we believe are the best candidates.

Exon 45 is one candidate.

In “Potential of oligonucleotide-mediated exon-skipping therapy for Duchenne muscular dystrophy”, authors Yokota, Pistilli, Duddy and Nagaraju from our Center analyzed the 313 DMD patients with exon deletions from the Leiden database reported from the United States.

In duchenne dystrophy, an exon deleted or duplicated causes an ‘out of frame’ deletion, a gene that will make no protein. The idea behind exon skipping is to restore the reading frame but even then according to Toshifumi and friends, this may not fix the problem. The disease may be just as bad. The authors then make a compelling case for multiple exon skipping.

The rationale for multiple exon skipping is based on the observation that some large chunks of the central rod domain can be skipped to form a mild version of the disease. They made a good case for exons 45 – 55.

The 45 – 55 region could be treated as one drug, requiring only a single toxicology study. Skipping this region could be responsible for fixing up to 63% of the deletions that cause duchenne.

A major drawback of exon skipping is AONs inaccessibility to heart and diaphragm muscle. Qi Long Lu, PhD, one of our DoD program project scientists from McKool-Lockwood Laboratory for Muscular Dystrophy in Charlotte North Carolina has been working on a solution. He used a peptide, which, attached to a morpholino, will target the diaphragm and heart.

Studies with the mdx mouse show no toxicity problems with low doses of the peptide-attached morpholino and he is working to improve the performance. I don’t know what plan we will end up with.

But I would say if we are to work our way from exon 45 to the 45 – 55 region, where we can do the most good in a single region, we will need to sit down at the table with the FDA and soon.

As Eric Hoffman, Director of the Center said in his stunning New England Journal of Medicine editorial dated December 27th: the “realization of this hope [of a treatment] might benefit from approval of dystrophin antisense sequences as a class of drugs. This approval would be the first for the FDA but the promise of personalized molecular medicine might justify such a change in approach”.

Carvedilol Review

Christopher Spurney, MD, is an Assistant Professor of Pediatrics, Division of Cardiology, Children’s National Medical Center, Washington, DC. He is
a researcher in duchenne dystrophy and my son, Petey's, cardiologist.

I recently asked Chris about a beta-blocker, carvedilol. I wanted to know whether carvedilol could be prescribed for duchenne dystrophy.

Here is Chris’ email response:

"For the field of pediatric cardiology, a major study looking at the use of carvedilol in pediatric heart failure patients was just published with disappointing results – carvedilol did not improve heart function compared to placebo in heart failure patients. However, the study included many different populations of heart failure, including those with single ventricle physiology, into the analysis. This study would need to be repeated with more emphasis on separating the different etiologies [types] of heart failure for a better understanding of the effects of carvedilol. There have been many adult studies which have shown beneficial effects of carvedilol in adult heart failure so we are hopeful as a field, but further studies are required to better answer the question."

To get the complete picture, below are a few useful links.

The first is a brief summary describing cardiac problems in duchenne muscular dystrophy from "Journey of Love", an MDA publication.

The second is a link to download a document that I found on the Parent Project website. It is called Survival in Duchenne Muscular Dystrophy: Improvements in live expectancy since 1967 and the impact of home nocturnal ventilation by Eagle et al, Neuromuscular Disorders, December 2002. This article found at: http://www.parentprojectmd.org/site/PageServer?pagename=nws_index, speaks about coordinating pulmonary and cardiac care.

The third is a link to the preliminary results of a study published in JAMA on carvedilol in children, "Carvedilol for Children and Adolescents with Heart Failure."

Finally, the fourth link is a to clinicaltrials.gov, which describes an ongoing study in Japan, involving carvedilol and duchenne dystrophy.

A little more editing and the blog about CINRG clinical trial proposals in exon skipping and combination therapies will be published.

Cheers!
GenMed Lab Mom