H.O.P.E. Duchenne MD
Volume 2, Issue 2
Spring 2002
Helping Our Parents Explain Duchenne MD
Research News
Dr. Steve Wilton is a researcher at the
Australian Neuromuscular Research
Institute. Dr. Wilton’s work centers
around Exon Skipping. The following
article was written by Dr. Wilton as an
explanation of Exon skipping.
Kids for Kids Project cast member
Ali Stoker with the Mesick boys at
the 2001 Parent Project Muscular
Dystrophy annual conference.
Inside this issue:
Research News
1
Research News (cont)
Conference News
2
Focus On Fundraising
What’s New
Awareness Week
3
Advocacy News
News From the Lab
4
Spring Ahead
with S.T.I.R.
5
What is Dystrophin
6
THE BAD AND OLD DOG ATE THE FAT CAT END
At the gene level, the instructions in the exons
would be broken up by introns:
(THEiiiiiiiiiiiiBADiiiiiiiiiiANDOLDiiiiiiiiiiiii DOGAiiiiiiiiiiiiT
ETHEFATiiiiiiiiiiiiCATEND
The role of the genetic instructions (order of A,
C,G and T) is to eventually make a protein, such
as dystrophin. The genetic instructions for the
dystrophin gene consist of about 14,000
bases spanning almost 2,400,000 letters (A,C,G,
T). Another way of looking at this is that the
dystrophin "instruction manual" is huge but the
important instructions are only a very minor part
(14,000 out of 2,400,000).
Once splicing has occurred, all the instructions
are joined together to give the final message
shown above.
The 14,000 letters of instructions are arranged
in 79 "chapters" (exons) and the rest of the
2,386,000 letters could be regarded as
"advertising junk" (introns) which is then thrown
away. The process where the exons are joined
together and the introns are removed is called
splicing and it is here that our antisense therapy
is directed.
The gene would look like :
THEiiiiiiiiiiiiBADiiiiiiiiiiENDOLDiiiiiiiiiiiii DOGAiiiiiiiiiiiiTE
THEFATiiiiiiiiiiii CATEND
Apart from the very beginning and the end of the
14,000 letters of instructions, about 11,000
letters are arranged in 3 letter words (codons).
Each codon represents an amino acid (protein
building block). If the genetic instructions are
corrupted (change to a premature stop signal)
then the protein machinery cannot make the
normal protein.
In DMD, a more common defect is a deletion of
one (or more) of the exons can disrupt the
reading frame so the wrong set of 3 letters are
read. This may be clearer in the following
example.
It is difficult to come up with an interesting
sentence of 3 letter words using a,c,g,t so I will
use the entire alphabet. The final genetic
instructions are in capitals and the intronic
(advertising junk) is shown as a lower case "i".
Final genetic message once the advertising junk
has been removed:
If there has been a spelling error during copying
of the dystrophin gene eg the A from AND is
changed to an E you get an early stop signal.
END rather than AND (remember we are
talking about changing 1 letter out of 2,400,000).
So the final message would be THE BAD END.
This is the type of message that would result in a
DMD mutation. Instructions for the end of the
gene cannot be read.
Our type of work is looking at "re-arranging" the
way a muscle cell joins the instructions
together so that the defective exon is
removed:
THEiiiiiiiiiiiiBADiiiiiiiiii^^ENDOLD^^
iiiiiiiiiiiiiiDOGAiiiiiiiiii iiTETHEFATiiiiiiiiiiii
CATEND
where ^ represents our antisense drugs that
prevent the cell from recognizing the ENDOLD
exon.
The antisense induced message would now be:
THE BAD DOG ATE THE FAT CAT END
Not the same matchless prose but still much
better than THE BAD END.
Page 2
Research News (Cont.)
The dystrophin gene consists of 79 exons and we know that many
of these can be removed without seriously compromising the functionality of the gene product.
I mentioned earlier that the most common type of DMD mutation
is a deletion of 1 or more exons that disrupt the reading frame
(iiiiDOGAiii) deletion:
\
/
\ /
THEiiiiiiiiiiiiBADiiiiiiiiiiANDOLDiiiiiiiiiiiiiiiiiiiTETHEFAT
iiiiiiiiiiiiiCATEND
The deleted message would now be read as:
THE BAD AND OLD TET HEF ATC ATE ND
You can see how the message has been corrupted. The wrong set
of letters is read in blocks of 3. Another example of a DMD type
of mutation.
Dr Steve Wilton
Senior Research Scientist
Australian Neuromuscular Research Institute
Parent Project Muscular Dystrophy’s
Inaugural Duchenne MD Awareness Week...
The Inaugural Parent Project Muscular Dystrophy Duchenne MD
Awareness Week took place February 11-17, 2002. For the first
time in history our boys had a voice of awareness that reached
around the globe.
H.O.P.E. Duchenne MD
Conference June 27th-30th, 2002
Bridging The Gap in Duchenne MD, Parent
Project Muscular Dystrophy’s 8th Annual Conference will
bridge the gap between families and scientists. It will merge
mere ideas with research strategies and span the distance
between knowing about Duchenne MD and understanding
Duchenne MD. We will discuss issues related to Research,
Treatment and Hope so you can make informed decisions.
What better place than Pittsburgh, PA, the “city of bridges” to
host this conference and bring together top scientists and
researchers, leading medical professionals, physicians, and
expert counselors in a powerful and informative forum.
This year’s conference will be held at The Hilton in Pittsburgh,
PA from June 27th –30th, 2002 and will be structured differently
than previous conferences. We will offer more breakout
sessions, more time for open Question and Answer
discussions with Scientists and presenters, and additional
half-day, Pre-Conference Workshops.
This year we have almost doubled the amount of time
dedicated to panel discussions and question and answer
sessions. We want to make sure that you have the
opportunity to speak directly with the scientists and
presenters and feel comfortable with the answers you receive.
Sometimes we all feel like we are on a road to nowhere - or
even worse, heading down a frighteningly predictable road.
Please join Parent Project Muscular Dystrophy this year for an
educationally enlightening conference that will offer you the
latest information regarding Duchenne MD so you feel
empowered to make better decisions for your son and
your family.
Families and friends across the country and around the world participated in this Duchenne MD Awareness Week by hosting fundraisers, participating in letter writing campaigns and sending out
press releases and letters to the editor.
In London 200 blue balloons were released at a rally in Trafalgar
Square. In Michigan, Nathan Hurwitz arrived at school on Valentine's Day to see his entire first grade class dressed completely in
blue and yellow. In New York City the Kids for Kids Project performed a cabaret evening to kick off the week. On February 14th ,
the one year anniversary of the introduction of the DMD Care
Act, Senator Collins made a floor speech in Congress. And far
away Australia, the Dusty Brandom Fellowship was awarded to Dr.
Steve Wilton’s lab.
The Inaugural Parent Project Muscular Dystrophy Duchenne MD
Awareness Week was quite successful, generating awareness
around the globe as well as generating over $75,000 for our boys.
Thank you to all those who participated. Next year will be even
bigger and better.
The Parent Project Muscular Dystrophy Annual
Conference Brochure is now available.
For your copy of this year’s Conference
Information Brochure or registration form,
please call 1-(800)-714 - KIDS or visit our website
at www.ParentProjectMD.org
Volume 2, Issue 2
Page 3
Focus on Fundraising...
Parent Project Muscular Dystrophy is a national nonprofit
organization that survives largely on Grassroots fundraisers
held across the country. Whether they be golf tournaments,
dinner dances, bike rides, etc., these fundraisers enable Parent
Project Muscular Dystrophy to allocate money for research,
education and advocacy. Each event is special and
empowering.
This month, Parent Project Muscular
Dystrophy’s Focus on Fundraising
centers around three bike ride fundraisers
that are being held across the country
during approximately the same time. These
courageous and determined people will
pedal their way across the country in hopes of raising funding
and awareness of Duchenne MD.
The first ride, Bike Ride for Muscular Dystrophy is being
organized by Whalen Kuller of Gainesville, Florida. This ride
will begin in Gainesville, FL and end in Pittsburgh, PA on June
27, 2002, the day the 2002 PPMD Annual Conference begins.
This 914.9 mile journey is not the first for Whalen. You can
read more about Whalen’s ride at http://plaza.ufl.edu/wkuller/
Hulda’s ride will begin in San Francisco, CA and end in
Portsmouth, NH. She will average 80 miles per day to make
a total of 3,800 miles. You can learn more about Hulda’s
ride at www.abbike.com/country.html
Why do these people pedal their way across the country?
Because they can. Because they are using the strength of
their muscles to strengthen the muscles of boys around the
world.
All three of these rides need the support of families across
the country. These individuals are not only riding for their
sons, but they are riding for your sons. They are pedaling
their bikes hard and fast, turning the wheels quickly so that
our sons may one day not need the wheels of a wheelchair.
If you would like to sponsor a rider, help out along the
routes, or make a donation to any of these events, please
call 212-262-6433 or visit our website at
www.ParentProjectMD.org
Another very driven parent participating in a bike ride this
spring is Board Member Chris Schiavo. Every year Chris and
Susan Schiavo hold a large dinner-dance fundraiser as well as
other smaller fundraisers, but this is their first cross country
ride.. The journey called The TransAmerica Trail will begin in
Astoria, OR and end in Virginia Beach, VA. Chris will be riding
the approximate 4,200 mile trail in honor of Chris and Susan’s
son Michael and all boys diagnosed with Duchenne MD. You
can read more about this cross country trip at www.
adventurecycling.org/routes/transam.cfm
And lastly, Hulda Grin will be riding in the Cross Country
Challenge bike ride June 8th-July 30. Hulda is not a parent of a
boy diagnosed with Duchenne MD. Rather she is a friend.. .
Someone who recognizes the battle that our boys fight.
What’s New
E-Mail Alerts– Parent
Project Muscular Dystrophy is now using a database system that |allows us to
email updates on current events such as
breaking research news, advocacy news
and Parent Project Muscular Dystrophy
news. If you are interested in joining
this list serve– or if your email address
is out of date with us, please forward
your email address to Kimberly at
[email protected] .
Newsletter News– Parent Project
Muscular Dystrophy is happy with the
positive response our quarterly Newsletter
has created. Parent Project Muscular
Dystrophy is committed to bringing you up
to date information related to Duchenne
and Becker MD. We are very happy to
offer you this newsletter at no cost—and
we appreciate the many people who send
in donations for the newsletter which helps
to offset the printing and shipping costs.
Please feel free to also send along
comments or suggestions about the
newsletter. Your feedback is appreciated!
Ribbons– Parent Project Muscular Dystrophy now has awareness ribbons available for your fundraisers. These yellow
and blue ribbons keep the awareness going and are wonderful items to handout
at your event.
The Kids for Kids Project -continues
to expand its outreach program teaching
inclusion through music. To purchase
the CD– A GENERATION FOR
CHANGE please call 1-800-714-KIDS or
visit our website at
www.TheKidsForKidsProject.org
Page 4
H.O.P.E. Duchenne MD
Advocacy Update...
Advocacy Update...
Help us make sure the letter and intent of the MD
CARE Act is fully implemented and funded.
Congressional Calendar for 2002
Last December, President George W. Bush signed into law
the Muscular Dystrophy Community Assistance, Research and
Education (MD CARE) Act. This is a bill that Parent Project
Muscular Dystrophy wrote, found Congressional sponsors for,
and lobbied successfully through advocates like you until
Congress passed the bill and the President signed it into law.
The MD CARE Act provides important authority and
direction to intensify, expand and coordinate federal research
into Duchenne and other muscular dystrophies. Specifically,
the Act addresses three primary areas:
January 23
February 18 - 22
March 25 - April 5
May 27 - 31
July 1 – 5
July 26
August 2
September 3
September 16
October 4
November 5
Congress reconvenes
Winter District Work Period
Spring District Work Period
Memorial Day District Work Period
Independence Day District Work Period
Summer Recess Begins - House
Summer Recess Begins - Senate
Return from Summer Recess
Congress Not In Session - Yom Kippur
Targeted Adjournment Date
General Elections
1. It authorizes Centers of Excellence in muscular dystrophy
research at the National Institutes of Health (NIH).
News from the Lab...
2. It establishes an inter-agency coordinating council at the
U.S. Department of Health and Human Services to include the
NIH and the Centers for Disease Control and Prevention
(CDC) among others. The Act also calls for the development
of a national research plan to coordinate MD research.
News from the lab of Marie-Terese Little
3. It authorizes the CDC to initiate data collection,
surveillance and epidemiological research specific to muscular
dystrophy and authorizes the agency to enhance its education
of health care providers in diagnosis and treatment.
These activities, and others underway, are part of the Parent
project Muscular Dystrophy's efforts to put federal support
for Duchenne research on a par with disorders of similar
prevalence and severity.
So now that the MD CARE Act is law, what's next on our
advocacy agenda?
This year, Parent Project Muscular Dystrophy is focused on
ensuring full and meaningful implementation of the MD CARE
Act. We are actively working with the NIH and the CDC to
develop the national research plan for Duchenne, develop an
epidemiological program in childhood muscular dystrophy,
establish an effective coordinating committee among federal
agencies, and establish centers of excellence in MD
research. And we are working to ensure that Congress
provides the funding necessary to accomplish these activities.
Are you interested in helping? If so, we can use your
support. Nothing is more potent on Capitol Hill than your
voice as a constituent. If you would like to learn more, please
e-mail please e-mail Sarah Durham at Sarah@bigduckstudio.
com, or Kimberly Galberaith at [email protected].
We hope to hear from you!
Several research groups have shown that adult bonemarrow derived stem cells have the potential to give rise
to non-hematopoietic cells such as endothelial cells and
skeletal muscle. An additional stem cell population in
adult muscle displays a remarkable capacity to
differentiate into hematopoietic cells as well as muscle
following transplantation. In addition, marrow cells
carrying the wild type dystrophin gene restore myofiber
dystrophin expression in the mouse model (mdx) of
DMD. These findings, along with the expertise at the
Fred Hutchinson Cancer Center, Seattle with both in
vitro characterization and manipulation of immature
hematopoietic and muscle cells and in vivo hematopoietic
stem cell transplantation prompt the question whether
adult hematopoietic stem cells (HSCs) or muscle derived
stem cells can be harnessed for therapeutic myogenic
benefits in Duchenne MD. Dr. Little’s team believes that
marrow-derived HSCs are endowed with the capacity to
migrate and home to the muscle in response to specific
myogenic signals and adopt a myogenic fate dictated by
microenvironmental cues from the muscle. They wish to
explore the idea that successful myogenic recruitment,
differentiation, regeneration and maintenance can be
achieved by the systemic delivery of autologous
genetically manipulated allogenic hematopoietic stem
cells when a defined demand is placed on the muscle as is
the case in the large animal model. Very basically, they
are examining the therapeutic potential of systemically
delivering HSCs, believe they will home to muscle in
response to specific signals and provide rescue for
degenerating muscle.
Page 5
S.T.I.R. News...
Ah… it’s spring again. With spring comes warmer
weather, the flowers and trees begin to bloom and
of course its time to “spring ahead” and change our
clocks.
This year as you “spring ahead” won’t you consider putting a
little “spring” into your STIR donation? Many of you already
participate in Parent Project Muscular Dystrophy’s monthly
giving program, STIR. But some of you don’t know what STIR is
or just how valuable it is to the progress of Parent Project
Muscular Dystrophy’s mission. Now is the time to get involved
in S.T.I.R. or if you are already involved, increase your monthly
pledge.
What is S.T.I.R.?
In April 2001 Parent Project Muscular Dystrophy began a
monthly giving campaign called S.T.I.R. (Striving To Impact
Research). To date, S.T.I.R. has approximately 200 participants
and has generated over $70,000!
This program is a simple yet very effective fundraising tool for
Parent Project Muscular Dystrophy. By joining such a campaign
you are helping Parent Project Muscular Dystrophy secure
predictable funds that can be used to further Duchenne MD
efforts.
Parent Project Muscular Dystrophy families and supporters are
encouraged to sign up for this monthly giving campaign by filling
in the S.T.I.R. registration form and either filling in a credit card
number which can be charged each month or by attaching a
voided check. With this information Parent Project Muscular
Dystrophy’s banking system will automatically deduct the
amount you requested each month from your checking account
or charge that amount to the credit card you list.
The automatic debit to your checking account and credit card
account is very safe and secure. The deduction happens on the
H.O.P.E. Duchenne MD
15th of every month and is handled by Parent Project Muscular
Dystrophy’s staff. At the end of the year, you will receive a tax
donation receipt for the total amount given during the year.
Who can join?
Anyone can sign up for S.T.I.R. and feel good about the extra
support they are giving to the Parent Project Muscular Dystrophy
mission. S.T.I.R. is an easy way to make a big difference by joining
forces with others. Consider that this newsletter will be sent
out to approximately 2500 parents and families worldwide. If
each of these 2500 people gave a mere $10 a month Parent
Project Muscular Dystrophy could increase its annual budget by
$250,000– a quarter of a million dollars! Now just imagine if each
of those 2500 people asked just 3 other people to join in… still
only giving $10 a month…. Parent Project Muscular Dystrophy
could increase its annual budget by $1,000,000 dollars. One
million EXTRA dollars to further Duchenne MD efforts.
Do you realize that many people spend more than $10 a month
on coffee? Better yet, imagine the effect if monthly donations
were more than $10 a month, say $25, $30, or $50 a month.
Right now participants in S.T.I.R. give between $10 and $500 a
month. Every donation is so very important.
So how can I join?
It is simple to join and even easier to get others involved. below
you will find S.T.I.R. application form. Please feel free to make
copies of this from to give to friends and family members. Simply
fill in the required fields and mail to
Parent Project Muscular Dystrophy, 1012 North University Blvd.,
Middletown, OH 45042.
Remember…
Every little bit can and does make a difference in the lives of so
many little boys. By joining the S.T.I.R. campaign today you are
helping build a solid foundation of predictable income- you are
helping to STIR things up!
Yes! I want to S.T.I.R. it up! (Parent Project Muscular Dystrophy’s Monthly Giving Campaign)
Name: _____________________________________________________________ Phone: ____________________
Address: ______________________________________________________Email: ____________________
City: _______________________________________________ State: ________ Zip: __________________
Two easy ways to enroll!
!
Credit Card Credit Card# _________________________________________ Exp. ________________
Please debit my credit card monthly (circle amount)
!
$10
$25
$35
$50
$100
______other
Checking Acct. Enclosed is a voided check # _________________ that will register my account.
Please deduct from my checking acct. monthly (circle amount) $10 $25 $35
$50 $100 _______other
Signature: ______________________________________________________________________________
Please mail to: Parent Project Muscular Dystrophy, STIR Campaign 1012 North University Blvd., Middletown, OH 45042
What Does Parent Project Muscular Dystrophy do? : Very simply, we break barriers -scientific, providing
support for collaborative research, medical, promoting the development of Standards of Care, newborn screening,
genotype/phenotype registry; government, aggressive legislative strategy.
For our sons, we support project-based research toward treatment and cure. With advice from our Scientific Advisors, we are a
catalyst, providing start-up funding for high risk/high impact research. From preliminary data, scientists will secure critical
information to qualify for increased support via Federal funds and/or major foundations and corporations.
For our families, we provide education regarding aggressive care to prolong mobility and extend the lives of children with
Duchenne and Becker as they await treatment.
For our communities and worldwide, we raise awareness for this devastating disease.
In living with Duchenne MD, we have found that our commitment and our goal serve both our sons and ourselves. We refuse to
give into the discouraging prognosis of the disease; we opt for hard work and hope for the present and the future. We are
committed to find treatments and a cure for Duchenne MD, to provide the best possible care and therapies available -- and to be
able to offer our children a sense of integrity and hope while facing truly overwhelming challenges.
1012 North University Blvd.
Middletown, OH 45042
www.ParentProjectMD.org
What is Dystrophin: Duchenne muscular dystrophy is one of the most frequent hereditary diseases of men and mammals.
About one in 3,500 boys, independent of his ethnic background, is born with this disease, which is caused by a mutation or
damage of the Duchenne or dystrophin gene. The dystrophin gene was identified in 1986 on the short arm of the X-chromosome
(Kunkel, Boston) and its structure elucidated shortly afterwards. With 2.6 million base pairs, it is one of the longest genes ever
found: if stretched out, it is 0.84 mm long. Only 0,5% of the base pairs, 13,973, belong to the 79 exons of the gene, that combined
together contain the active coding sequence, the information for the synthesis of different forms of the protein dystrophin. The
transcription of the genetic information of the dystrophin gene into mRNA is under the control of at least five DNA regions, promoters, which govern the splicing process so that a number of different proteins are produced. The main product is the
full-length dystrophin, a very long rod-shaped protein consisting of 3,685 amino acids. It has a molecular weight of 427 kDa
(Kilodaltons), i.e. it is 427,000 times heavier than a hydrogen atom. It is 125 nm (Nanometer = millionth of a millimeter) long; i.e. if
8,000 molecules were put together in a straight line, their overall length would be just one millimeter. Dystrophin is located on the
inside of the muscle cell membranes to which it is anchored through a complex of many other proteins. It is important for the mechanical stability of the cell membrane during muscle contraction. In spite of its importance, only 0.002% of the weight of the
muscle proteins are dystrophin (20 mg per kg muscle!).