GenMed lab mom

This Weekend, November 7th - the CINRG Fall Meeting

noreply@blogger.com (Marie) — Thu, 05 Nov 2009 02:15:00 +0000

Just a quick note - this weekend the Cooperative International Neuromuscular Research Group based out of Children's National Medical Center - and the clinical arm of the Research Center for Genetic Medicine - is having their third annual meeting here in DC.

Coordinators, docs, and physical therapists from all over the world will be here.

I am excited because some of my favorite people will be here, Carrie Miceli and Stan Nelson from UCLA, many of the Foundation to Eradicate Duchenne group like Joel Wood, and my dear friends, Tina and Dan Carson. Annie Kennedy from MDA will be here as well. Katie Bushby and Nick Catlin will be here from the UK and foundation leaders, Debra Miller and Pat Furlong from cureDuchenne and Parent Project plus George Vella from Charley's fund will join us. Of course Bob Leshner and Avital Cnaan from CNMC and Lakshmi from India. Although it is a CINRG meeting, Eric Hoffman, as the head of GenMed, of which CINRG is the clinical branch, will be here to lend his support.

The agenda includes the Natural History study, strength testing measures, cardiac drug trial plans, duchenne mutation data comparisons, non-hormonal steroid drug development, various aspects of exon-skipping, and updates from our friends 'across the pond'.

There is a treatment goal in sight and as it unfolds, I am more and more impressed by the duchenne community coming together from around the world, making it happen with compassion and good-will.

Enough said.

Morpholinos 101: An Introduction

noreply@blogger.com (Marie) — Wed, 07 Oct 2009 04:07:00 +0000

Dear Friends,

I want to take a brief moment to introduce my guest blogger today, Jon Moulton. Jon works for Gene Tools. Below, he gives a brief biography but here is what he doesn't say is:

he is a friend of duchenne parents
actively involved in education scientists as well as amateurs like me! Wow! I understand so much more now!
a scientists of the finest caliber
a caring and compassionate human being.

Jon, thank you for this wonderful insight into morpholinos and duchenne dystrophy. After reading this post, I think we should name you Morpholino Man!
____________________________________________________________________

This is an introduction to Morpholino antisense oligos, with notes on their potential application in treatment of Duchenne muscular dystrophy (DMD). Toward the bottom I'll include some links to other places on the web which have more information about Morpholinos.

My name is Jon Moulton, I'm a Ph.D. biologist and a former adjunct professor, and about 10 years ago I leapt from the bottom rung of the professorial ladder to work for Dr. Jim Summerton at Gene Tools LLC. Gene Tools is an Oregon company that manufactures Morpholinos for the research reagent market. Most of our custom-sequence Morpholino oligos go to academic labs worldwide for research.

Morpholinos have genetic bases identical to those of DNA connected to a synthetic, non-natural backbone. The backbone contains morpholine rings, which is where the name Morpholino oligo comes from. Usually a Morpholino oligo is about 25 bases in length and can be described by a base sequence, like:

CCTCTTACCTCAGTTACAATTTATA.

Morpholinos are called antisense oligos because they are typically designed to be complementary to mRNA (an mRNA sequence is called a "sense" sequence) so that they stick to the complementary part of the mRNA, binding A to T and C to G just like in a DNA helix (the DNA strands are also called the sense and antisense strands).

DMD is caused by mutations in the dystrophin gene. Morpholino oligos appear promising as therapeutics for DMD. Morpholinos can be used to alter RNA and RNA determines the structure of proteins (more about that below). The amazing thing about using a Morpholino oligo as therapy for a genetic disease is that the Morpholino is treating the disease by altering the mutated form of the RNA so that it codes for a protein that functions better. That is, the Morpholino treats the disease instead of treating the symptoms. If Morpholinos are approved to treatment of DMD, many more human genetic diseases may be treatable by changing the sequence of the Morpholino oligo so it targets different locations on human RNA.

Morpholino antisense oligos from AVI BioPharma Inc. are currently in clinical trial for Duchenne muscular dystrophy in England. Prior to this trial, preclinical data was gathered from Morpholino experiments with cell cultures, mice, and dogs. The oligos used in DMD-targeted experiments change how pre-mRNA is spliced. The oligos for the clinical trials are used to excise exons from the RNA in order to change the reading frame of sequence downstream of the excision.

I suppose I'd better explain "reading frame". RNA bases are used to specify the order of amino acids in proteins. Proteins are basically strings of amino acids, and the order of the amino acids determines the shape of the protein and how it will function. Three bases of RNA are translated into one amino acid; the three-base groups are called codons. This means that a string of RNA bases can be interpreted several ways by the protein-making machinery of the cell, depending on which RNA base it starts reading from, because this leads to reading different codons.

The RNA sequence:

TTCGACCGTACCGGGTGTA,

can be divided up into codons three ways; each leads to a different amino acid sequence, depending which of the three reading frames is chosen. I ignored the partial codons at the ends.

[TTC] [GAC] [CGT] [ACC] [GGG] [TGT] [A
would make:

- Phenylalanine - Aspartic acid - Arginine - Threonine - Glycine - Cystine -

T] [TCG] [ACC] [GTA] [CCG] [GGT] [GTA]
would make:

- Serine - Threonine - Valine - Proline - Glycine - Valine -

TT] [CGA] [CCG] [TAC] [CGG] [GTG] [TA
would make:

- Arginine - Proline - Tyrosine - Arginine - Valine -

Consider what would happen if you inserted a base halfway along one of these sequences. That would change the reading frame of the sequence to the right (since codons are always three bases, the edges of the codons would move over by one base). This base insertion is one way a mutation can cause a frameshift. Bases can also be deleted and cause a frameshift. If the string of amino acids is part of a functional protein and a change in the RNA causes all the sequence to the right of the change to become different amino acids, there is a good chance that the protein would no longer function.

Many DMD-causing mutations result in altered reading frames and the exon-skipping oligos are intended to restore the "healthy" reading frame to the dystrophin mRNA by removing an exon which has a number of bases that is not evenly divisible by three, changing the reading frame "downstream" (the cellular machinery that translates RNA into protein starts at one end of the RNA, called the upstream (or 5') end, and moves toward the downstream (or 3') end). Treatment with an exon-skipping oligo produces a modified form of dystrophin which, it is hoped, will retain most of the function of the dystrophin of a healthy individual. So far no data have been published showing functional improvement as a result of administration of exon-skipping Morpholinos into humans. There are several kinds of oligos that work by a mechanism similar to Morpholinos. These are called "steric blocking" oligos, and include peptide nucleic acids (PNA), locked nucleic acids (LNA) and 2'-O-methyl phosphorothioate oligos. Another company, Prosensa B.V., has clinical trials ongoing for DMD using 2'-O-methyl phosphorothioate oligos and are using a similar exon-skipping approach to restore the healthy reading frame in the dystrophin protein.

Morpholinos can knockdown gene function more effectively and with less off-target gene modulation than many other methods, such as siRNA and the older phosphorothioate oligos. This has led to their use in developmental biology (the field that used to be called embryology), for which the oligos are injected into eggs or early zygotes to learn the function of genes in development of an organism. The combination of good efficacy and good specificity (less off-target gene modulation) have made Morpholinos the standard gene knockdown reagent injected into zebrafish or Xenopus (clawed frog) embryos to probe gene function in development.

The function of a Morpholino depends on where on an RNA it is targeted. Morpholinos can block translation, modify splicing or block micro-RNA maturation and function. More exotic applications, like blocking ribozyme activity or triggering translational frameshifts, have also been explored. A challenge for any antisense oligo is getting the oligo into the cells where it can function.

Developmental biologists microinject Morpholinos right into the cytosol of a cell, into the egg or early zygote. This won't work for medical applications, such as treatment of a DMD patient, because practially you can't microinject into every cell where the oligo effect is needed. In most organisms, injecting Morpholino oligos into the bloodstream isn't useful because the oligos don't cross the cell membranes. They do, however, filter through the kidney and so you end up with expensive urine -- but no useful biological effects. DMD may be a special case, as dystrophic muscle is leakier than healthy muscle. Morpholinos have been shown in dogs to enter leaky muscle cells from the blood, but the doses required for good activity were pretty large.

Companies working with Morpholinos have been trying to develop modifications of the oligos (broadly called "delivery moieties") to help them enter cells from the bloodstream. Likely the two solutions that have been developed enter cells as they endocytose (form little sacks from their outer membrane and bring these sacks, with their contents, into the inside of the cell) and then the delivery moieties help the oligos escape from the endosomes (the little sacks). AVI BioPharma Inc. has developed what they call a PPMO (peptide-conjugated phosphorodiamidate Morpholino oligo) which does enter cells from the blood -- my wife, Dr. Hong Moulton, is the inventor of the PPMO (proud husband!). Gene Tools developed a system that has some structural similarities to the PPMO (Dr. Yongfu Li of Gene Tools invented the Vivo-Morpholino); both the PPMO and our Vivo-Morpholinos have guanidinium groups in their delivery moieties, and it is these groups that are thought to interact with the membrane of an endosome and make it leaky. Because the dose required of a PPMO or a Vivo-Morpholino is much lower than the dose required of an unmodified Morpholino to reach the same level of cellular activity, I expect that the most effective treatments for human genetic diseases will be developed using these or similar delivery-enabled oligos.

Here is a recent review that I wrote with Dr. Shan Jiang of Gene Tools describing the PPMO and Vivo-Morpholino. The references in this paper provide a good path into the recent DMD literature using Morpholinos. This is open-access, you don't have to pay to view the paper. Just follow this link and then click on the PDF link on that page.

PPMO and Vivo-Morpholino Review
Moulton JD, Jiang S. Gene Knockdowns in Adult Animals: PPMOs and Vivo-Morpholinos. Molecules. 2009 Mar 25;14(3):1304-23.

Here's the Gene Tools website:

Gene Tools
This site is loaded with information about using Morpholinos for research.

If you'd rather hear about Morpholinos than read about them, here are some mp3 files discussing Morpholinos:

Morpholino discussions

Here's the searchable online Morpholino publication database I maintain at Gene Tools:

Morpholino publication database

Here's AVI BioPharma:

Here is a link to the clinical trial page for the Morpholino trial underway in England:

Francesco Muntoni's UK Morpholino Clinical Trial link

Here is the Wikipedia page for Morpholino oligos:

Morpholino Wikipedia page

Here is my blog, where I post notes about new Morpholino publications and whatever else I want (yes, it really is on MySpace):

Jon Moulton's blog

I tweet new Morpholino citations as I find them in the scientific literature:

Morpholino Tweet

If anyone reading this is filled with the desire to start doing Morpholino experiments, you might start here:

Build-your-own Morpholino Experiments

Thanks for coming along for this tour of Morpholino technology. Morpholinos are doing many useful things for biological research -- their application to DMD starts Morpholinos down the path to realizing their potential as therapeutics for genetic and viral diseases. The best outcome will be if the oligos help some boys and their families who deserve real hope and improved health.

Men over 40 with duchenne

noreply@blogger.com (Marie) — Sat, 20 Jun 2009 13:47:00 +0000

Now you can join the likes of Mark Twain and say: "The report of my death is an exaggeration." There are over 400 men with duchenne muscular dystrophy over 40. Who are you?

What do you have to say for yourselves? Where are you 'oh miracles of the living'?

I'm thinking about writing a piece on you, your lives and philosophy but first I have to find you. To that end please take the survey below - send this link to your friends, your friend's friends, and anyone who might be able to answer the call!

If you know of someone who doesn't have a computer and would like to participate, please feel free to send me their contact information.

Click Here to take survey

A Poem for Uncle Petey

noreply@blogger.com (Marie) — Wed, 08 Apr 2009 20:01:00 +0000

Below is a poem that Petey wrote about his uncle, who died Saturday after battling ALS. Even though there are allusions to family connections - karate kid, movies, Stephen Segal - it's easy to follow. One more note - Uncle Petey was the president of the regional CWA for twenty years or so - hence the 'union' references.

Uncle Petey

I remember that grin
Even when the disease loomed
I knew how it must have grown heavy
But his strength was there
I could see it

I regret not seeing enough of a union man
That a President recognized
And a family grew with
Who dressed up like Dumbledor
And quoted Steven Segal
That danced at a daughters wedding
And honored his beliefs

He is a passed titan
Who is still alive through warm hearts that mourn
That celebrate a man still immortal
Telling stories to us in our minds campfire

Petey was the true American dream man
Hit by something deadly
But never stopped swinging

I'm not a religious man
But I know he would say a prayer now
He would be strong with his big heart
And he still is as we know

So Uncle Petey, I know you're listening
And your still grinning in your Dumbledor hat
Saying "Sweep the leg Johnny"
And watching all the best action movies
Starting a union in the afterlife

No strangers in Bangalore: Muscular Dystrophy Conference

noreply@blogger.com (Marie) — Wed, 25 Mar 2009 14:17:00 +0000

Deb Robbins, Parent Project Australia, reports on the first Asian PP Conference in Bangalore, India. I love her down-to-earth, funny, and wise-beyond way of looking at things.

Over 500 delegates attended the First Asian DMD Conference organized by United Parent Projects Muscular Dystrophy, Health Care Global Foundation and NIMHANS at St John’s Auditorium in Bangalore. Parents also came from Iran, Israel, Sri Lanka, Italy, The Netherlands and France. Stakeholders around the world were able to view the lectures via live streaming organized by Duchenne Parent Project Italy. International spectators were able to send chat questions to be answered by the panels along with those from the conference floor.

This was no local seminar but a national conference boasting an international program. Prof Jean-Claude Kaplan, Dr Annemieke Aartsma, Dr Madhuri Hegde, Debby Schrans for Dr Hendriksen, Dr Raghavendra Rao, Dr Lakshmi Raman and Dr Herve Laouenan explained their research. Dr Rao’s reasons for the suspected value of yoga for Duchenne were particularly innovative. Clinicians included Dr Nathalie Goemans from Belgium, Dr Jes Rahbek from Denmark, Dr John Bach, Dr Karim Wahbi and Prof Douglas Biggar. Though only one therapist presented, 160 practitioners attended Helen Posselt’s workshop.

Everywhere was evidence of dedication –the geneticists in Dr Lakshmi’s lab giving up their leisure time for family fun days and disseminating information to doctors surgeries on weekends. And no problem was any trouble for Dr Rao, the local organizer, to solve.

Particularly inspiring were the calls to rally together to abate the progression of Duchenne for one and for all, by Dr Ajaikumar (HCG), Dr Elizabeth Vroom (Conference Convenor & UPPMD President) and Hafiz Issadeen from Sri Lanka. All presenters urged parents everywhere to be proactive in both care and advocacy. With better care and promising research around the corner, it is more important than ever to plan for longer and more comfortable lives for our children than we could have imagined 15 years ago. The Parent Project Muscular Dystrophy group of India was inaugurated at the end of the two day conference and these core parent advocates networked with presenters and UPPMD stakeholders on the last evening.
In Bangalore as at home, I enjoyed swapping practical care tips and the trials and blessings of life with DMD, with other parents. More than one parent asked me to read specific medical information about their child confusing me for one of the doctors. They were desperate for more information though we’d just sat through hours of presentations. Yet the children and youths running, waddling or wheeling around the auditorium were as serene and ‘wise-eyed’ as Australian, European and American boys confirming my own theories about just who is saving who?

TRAKE STORY

noreply@blogger.com (Marie) — Mon, 23 Mar 2009 03:19:00 +0000

My son, Pete, is 26 years old and now has his own blog (like mom like son!). He gave me permission to reprint one of his posts. It is about his take on getting a trach or trake. See his post below and then click on the title above and it is linked to an Aug 07 post of mine that I wrote about what I was going through at the time ...
_____________________________________________________

Ok, I'm going to spell trake wrong in this blog because the correct spelling does not look right. So if no one has any questions, we can continue.

Before my trake surgery a couple years back, I had the craziest question growing like a tumor on my brain -- will I still be able to sing after this?

Lets take a detour from the story for a moment for some backstory. I started writing and occasionally performing hip-hop lyrics at the age of seventeen. Part way through my sophomore year at St. Andrew's in Laurinburg North Carolina, my lungs were getting weak, too weak. This meant, after a pneumonia and a hospital stay that my out-of-State college career was over.

During this life-transition I made one of another kind. A transition from rap to rock. The band and I both noticed, the Summer leading up to the surgery, that it was getting harder and harder for me to belt out lyrics. Naturally horrified, I thought, with a trake that'll really be it! My singing days were surely numbered.

Or were they?

The recovery after the surgery was hell, taking all of three months of going in and out of the E.R., getting MERSA and a hole in the lining of each lung. I was told two weeks, ha, what a joke! I couldn't talk at first and having a cuffed trake didn't help either. Without explaining it in detail -- cuffed equals no sing, un-cuffed equals sing.

After re-learning how to talk and getting a cuffless trake, I must say that singing has become much easier. So after all the pain and hospital stays, I'd say getting a trake was the best decision I ever made! It saved my life and my voice.

Toshifumi Yokota and exon-skipping in the dystrophic dog

noreply@blogger.com (Marie) — Thu, 19 Mar 2009 03:36:00 +0000

Toshifumi Yokota, a young man with a winsome smile and a bright future, is changing the face of translational research in duchenne dystrophy. Working with the dystrophic dog, he is our morpholino, exon-skipping expert. Toshi, as we call him, is the first author on the recently released Annals of Neurology article that is causing a sensation in the duchenne advocate and science world. This article shows the first multi-exon skip and the first large animal proof of concept (see March 15th blog and CNMC press release for details. See also videos of dogs with and without treatment)

Trekking back and forth between Kodaira, Japan, where his animal research is based and Washington DC, where he does bench work and analyzes data, Toshi is part of the team responsible for making sense of what the morpholino research is telling us. Working at Children’s National here in Washington DC, Toshi has access to the one of the leading scientists in duchenne research today. He is mentored by Eric Hoffman, a member of the original Harvard team that discovered the dystrophin, the mutant gene causing duchenne dystrophy.

Toshi ‘s work is crucial to the future of duchenne dystrophy clinical trials and development of a first treatment for our boys. Among the questions he and the research teams will be answering are:

• What are the optimum number of exons to be skipped at one time?
• The large dose of morpholinos given to the dogs is nontoxic. Can we be assured there will not be a toxic response is the clinical trials?
• How about with petide conjugated or vivo-morpholinos?
• What is the minimum dose necessary to have a therapeutic effect?

Toshi’s mother and father came from Northern Japan and they moved to Tokyo where Toshi grew up. He went to Tokyo University and majored in Zoology. In graduate school, he studied under the mentorship of Dr. Shin’ichi Takeda, MD, PhD. Toshi was eager to work with Dr. Takeda because of his stellar reputation and because his lab was known for its leading edge research work and state of the art equipment.

Toshi met his wife-to-be, Rica, at University over a decade ago. Married last year on Guam, the newlyweds live in Odenton, Maryland.

Exon-skipping in the dystrophic dog - good news

noreply@blogger.com (Marie) — Mon, 16 Mar 2009 03:45:00 +0000

Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs

Good news in duchenne research. An Annals of Neurology article released March 13th shows that exon-skipping with morpholinos rescues “dystrophin expression to therapeutic levels” in the duchenne dystrophy dog (on-line 2009). It also shows that multiple exons can be skipped systemically. Toshifumi Yokota (pictured above) in Eric Hoffman’s lab and fellow scientists across the globe eked out meticulously researched findings in this seminal work.

The research reported by this study was a collaborative effort by Eric Hoffman’s Research Center for Genetic Medicine Lab, Children’s National Medical Center in Washington DC, Qi Lu’s McColl-Lockwood Laboratory in North Carolina and Shin'ichi Takeda’s Department of Molecular Therapy, in Japan.

The duchenne dog study shows that:

• Multiple-exons (three) had to be skipped in order to compensate for the deletion in the duchenne dog.
• Doses were 120-200 mg/kg delivered weekly or bi-weekly for 7 to 11 doses. (A similar dose will likely be required to be effective in clinical trials.)
• Intravenous morpholino cocktail showed no toxicity.
• The dogs treated with morpholino therapy ran faster than they did before the treatment while their untreated litter-mates ran slower.
• 26% increase in dystrophin expression levels in average compared to normal animals.

Please see the CNMC press release and the Annals of Neurology article itself for more information about the study.

Contributors donated millions to make this research possible. All I can say is, Thank you! Thank you! Thank you! The contributors include:

Foundation to Eradicate Duchenne (FED; www.DuchenneMD.org),
Department of Defense CDMRP program
Jain Foundation
Crystal Ball of Virginia Beach (Muscular Dystrophy Association
USA),
National Institute of Child Health and Human Development of NIH

These are not faceless organizations I look at this list of contributors and I see the Woods, the Heils and the Carsons from FED. I see Plavi Mittal from the Jain Foundation. And I see Linda Jarvis and her family from the Crystal Ball sponsored by the Muscular Dystrophy Association. Most are volunteers. They work, they take care of a son with muscular dystrophy, and then they make millions for muscular dystrophy research. And they do it for the same reason I put out this blog. We do it for our boys; James, Alex, Mark, Brian and Pete.

Qi Lu's Lab demonstrates the potential of Vivo-Morpholinos to treat duchenne dystrophy

noreply@blogger.com (Marie) — Wed, 11 Mar 2009 03:01:00 +0000

In a new Molecular Therapeutics on-line advance publication released this week, Qi Lu's lab reported the potential of Vivo-Morpholino to treat duchenne dystrophy. Qi Long Lu, Director of the McCool-Lockwood Laboratory for Muscular Dystrophy Research and one of the world's leading experts on exon-skipping with morpholinos, explained the significance of his research:

"Antisense therapy has been demonstrated with great potential to treat majority of DMD. One of the most critical factors for a successful treatment of DMD is the delivery efficiency of the antisense oligonucelotides to body-wide muscles.

Unmodified Morpholino oligomers can restore functional amount of dystrophin protein in skeletal muscles, but with limited ability to do so in heart. Using Morpholino modified with a peptide improves dystrophin expression significantly, basut peptides could cause immune response and potentially prevent long-term use in patients.

Therefore, in this study, the Morpholino is modified with a non-peptide polymer (Vivo-Morpholino) to reduce the risk of immune response and to achieve improved delivery. The results demonstrate that use of the polymer achieves very high efficiency in dystrophin expression both in skeletal and heart muscles. Further long term efficacy study will be required before the same modification can be considered for clinic trial to treat DMD."

An abbreviated abstract and link to the full abstract are found below.

Wu B, Li YF, Morcos PA, Doran TJ, Lu PJ and Lu QL. Octa-guanidine Morpholino Restores Dystrophin Expression in Cardiac and Skeletal Muscles and Ameliorates Pathology in Dystrophic mdx Mice. Mol. Ther. advance online publication, March 10, 2009

Dystrophin exon 23 carries a nonsense mutation in the mdx mouse. Using a Morpholino oligo targeting an exon 23 splice junction can cause the splice machinery to skip exon 23, allowing translation of functional dystrophin with an internal deletion; however, unmodified Morpholinos enter cells poorly and large doses must be used to achieve splice modification in the mouse tissues. Coupling a Morpholino to a guanidinium dendrimer moiety makes a Vivo-Morpholino. When injected into the blood the Vivo-Morpholino circulates through the organism and enter cells, altering splicing and producing functional dystrophin.

Today at the White House - A Victory for Stem Cell Research and My Brother-in-Law, Pete

noreply@blogger.com (Marie) — Tue, 10 Mar 2009 00:26:00 +0000

Here is something a little different from my usual blogs.

Today, with the Executive Order I am about to sign, we will bring the change that so many scientists and researchers; doctors and innovators; patients and loved ones have hoped for, and fought for, these past eight years: we will lift the ban on federal funding for promising embryonic stem cell research. We will vigorously support scientists who pursue this research. And we will aim for America to lead the world in the discoveries it one day may yield.
Barak Obama, March 9, 2009 (White House Blog)

Today, President Barak Obama signed an executive order ending the ban on stem cell research. This is good news for research, the entire world, and especially people like my brother-in-law, Pete, who along with my sister, Terry, were at the White House today to see it happen. At the White House! How awesome is that?

Pete has Amyotrophic Lateral Sclerosis, diagnosed over two years ago. And ever since then he has fought for stem cell research funding. As he told me once, he talked to anybody and everybody who would listen. He was a one-man campaign for stem cell research in ALS.

The National Institutes of Health (NIH) plans to award $10.4 billion in stimulus funding to research in general to be spent over the next two years. At this time I don’t know how much of it will go to stem cell research but, with support from the President of the United States, it will be substantial.

These pictures are from my sister, Terry. She says the above picture of Barak Obama is really a picture of him shaking hands with Pete, but there was only room for one of them in the picture…

.

A Birthday Worth Celebrating

noreply@blogger.com (Marie) — Sat, 21 Feb 2009 21:08:00 +0000

I was roaming around the web here and there and came across another blog: Living With DMD - Not The End. (Links here and on my side bar.) Chris Webb, a fellow, who's been blogging for a while, has dmd. He turned 41 yesterday.

There was no way to email him to say 'Hi - What's Up?' So I thought I'd say 'Happy Birthday' with a blog :)!

So, Chris Webb from Boston, 'Happy 41st Birthday. May your year be one great adventure.'

AVI BioPharma Announces Treatment of First Patient in Systemic Clinical Trial of AVI-4658 for Treatment of Duchenne Muscular Dystrophy

noreply@blogger.com (Marie) — Thu, 19 Feb 2009 18:34:00 +0000

Another scoop from Jon! Thanks Jon.

Click here to see the Press Release from AVI BioPharma.

Parents, be aware that this trial is in the United Kingdom and the dose is homeopathic. See ClinicalTrials.gov for trial details.

AVI BIOPHARMA NEW EXON SKIPPING CLINICAL TRIAL

noreply@blogger.com (Marie) — Tue, 17 Feb 2009 20:39:00 +0000

Hello Folks

And thanks to Jon for the news! I'm trying to get more information and will post as quickly as I can.

Here is a News tidbit and the link.

News...

AVI BioPharma has started a clinical trial of their AVI-4658 Morpholino oligo targeted to block splicing of exon 51 in the human Dystrophin transcript. This is an experimental therapeutic for some mutations causing Duchenne muscular dystrophy, designed to restore the reading frame and ameliorate the effects of a frame-shifting mutation. This is a systemic study involving intravenous injection of an unmodified Morpholino (note: Morpholinos are also called PMO, an acronym for phosphorodiamidate Morpholino oligomer).

ClinicalTrials.gov

GenMed's Extended Family

noreply@blogger.com (Marie) — Wed, 28 Jan 2009 21:28:00 +0000

I'd like to share a story with you that Ruth Hoffman sent to me recently. Ruth is Eric's wife, mother of twelve, head of Candlelighters, a Children's Cancer Foundation, and, now, Hope's grandmother. It is an article about her daughter, Naomi and granddaughter, Hope.

Naomi is amazing enough, someone who makes you believe in miracles. But wait until you meet Hope.

Hope's Story

A duchenne moment

noreply@blogger.com (Marie) — Wed, 28 Jan 2009 17:59:00 +0000

Want to hear a good pick-up line? Read on.

When Nicole, Mary, and Petey were in grade school, it was our custom to celebrate good report cards. On one occasion, even though it was a school night, I treated them to a special dinner in Georgetown.

The name of the restaurant eludes me but we had pieaya and it was exotic and the children were excited to be feted, celebrated.

It must have been nine o'clock by the time we were done eating. The area was deserted but for two men who were talking and laughing across the street. The glow of their cigarettes brightened and dimmed. Seeing them, I felt a momentary sense of unease but shook it off.

Both girls wanted to hold Petey’s hand. One took the left, the other the right and we crossed, the children right behind me.

Now, Petey was still walking but he was unsteady on his feet so we made slow progress. We were in the middle of the road when I saw headlights from an approaching car.

“Quick, Quick!” I warned them.

That’s when Petey fell. The girls tugged on his arms, trying to stand him up. I turned around, scooped him up, and the four of us, Petey, my two daughters, and me, ran to the other side safely, laughing all the way.

The two men, witnesses to our pandemonium, were just feet away. One of them turned to the other and said, “So that’s how you pick up beautiful girls. I’ll have to try it next time!”

What could have been a moment of ‘oh, no, another duchenne fiasco’ became a laugh shared, a moment put in a good light, and the kindess of strangers.

We drove home.

[Well, I didn’t say it was a pick-up line you could use!]

Quick Correction of my January 21st post from Toshifumi Yokota

noreply@blogger.com (Marie) — Thu, 22 Jan 2009 16:35:00 +0000

Thank you, Toshifumi for your email correction of my last post.

Toshi said that potentially multi-skipping of ex45-55 can treat approximately 60% of boys with duchenne with dystrophin deletions.

We theorize up to 80-90% patients total can be treated by multi-exon skipping.

Antisense Oligonucleotide: An Exon-Skipping Review

noreply@blogger.com (Marie) — Wed, 21 Jan 2009 16:37:00 +0000

The Achieves of Neurology published a review on exon-skipping therapy in duchenne dystrophy: “A Renaissance for Antisense Oligonucleotide Drugs in Neurology.” (Yokota et al, Jan 2009). Along with the review the authors look ahead to AO production, toxicity studies and “challenges to … drug regulatory attitudes”. This is a collaborative effort of the Hoffman Lab in DC, Lu’s lab in NC and Takeda’s lab in Japan.

The review discusses what we know so far and addresses key therapeutic points.

• How duchenne happens. Dystrophin is the missing gene that causes duchenne, Normally the gene makes DNA, which makes mRNA, and that makes a protein. Some of the gene’s exons are missing or otherwise broken, which halts the protein making process, leaving the muscle without protection that comes from dystrophin.

• How exon skipping works. Exon skipping fixes the break made by the missing exons using a designer small molecule drug, called an antisense oligonucleotide or AO. This molecule attaches itself to the dystrophin gene, making a bridge over the broken place and restoring dystrophin function.

• Skipping multiple exons? In other words, it changes a duchenne mutation (broken dystrophin falls apart) into a becker mutation. The authors make a case for skipping multiple exons at one time because animal trials show this works as well and in some cases better than a single exon. Plus multiple exon skipping would provide a treatment for up to 60 percent of boys with duchenne.

• Knowing what exons to skip. Science must be sure to pick the right exon or exons to skip since some beckers are as destructive as duchenne.

• Which drug is the right one? The authors point out that there are several exon-skipping drugs out there with good preliminary results and that clinical trials are the way to find what approach or approaches work.

• Personalized medicine calls for new approaches. Animals with duchenne have exon hot spots that are different from humans. And giving healthy individuals exons they don’t need is potentially damaging and should be avoided. The review suggests that exon skipping is so individual that the only way researchers and physicians can know if it works and what exons exactly to give is by testing it, starting with small contained doses in the people that need it, our boys.

• The FDA. One of the final hurdles is FDA drug approval. Conventional drug approval does not apply in exon skipping since it is unique to each child.

My humble opinion: Although I am not a scientist, I am a parent and have a stake in what happens, whether it helps my son or not. I thought over a year ago that clinical trials would be underway in the United States soon. They have not begun. And even though we have gained information in the meantime, we would know so much more if clinical trials were underway. Government officials, foundation leaders, scientists, and Biopharmas need to be open with parents about what’s going on, what are the sticking points, and how we can help.

A small tale: GenMed Lap Dog

noreply@blogger.com (Marie) — Wed, 14 Jan 2009 00:41:00 +0000

The animals that live in our house have it pretty good. There’s Sadie, a dog with doe-like eyes, who loves, loves, loves my husband. They walk all over Prince Georges County together. My daughter, Mary, found her as a tick-covered pup wandering the streets of Arizona and brought her home to us. Then there is Pippen the cat, named after the Tolkien character, not the basketball player. He’s fearless. Dogs walk right up to him and I swear he looks bored.

Then there is Tommy. Tommy is a yappy, little bit of a dog who thinks I’m his mother. But from the first day he came to live with us, Petey has been the love of his life.

Gerry from work fosters small, poodle-ish dogs picked up by animal rescue. Tommy is one of the dogs she fostered. When he came to us he weighed four pounds and was, we guessed, about seven years old. His coat was shaved to the skin from head to tail. He walked right up to me, put his little butt down and bent his right foreleg up; something I’ve come to recognize as Tommy’s way of saying pick me up.

When he’s insistent about getting picked up, he speeds round and round in circles and simultaneously jumps up and down, like he just found out the best news in the world. The first time I saw this performance, Tommy had walked into Petey’s room. I put him on Petey’s bed and from then on, where Petey was, Tom was sure to be.

Tommy has a few minor social issues. He doesn’t like cats and he doesn’t like dogs. Oh, and he barks at everyone coming in the door, any door, and everyone going out … any door.

At times, he trusts no one with Petey, not even me. Like when we get him up in the morning. While Petey gets washed up and his clothes on, Tommy moans and complains, sounding as sad a sack as that old Hanna Barbara character, Droopy Dog. And when we put Petey up in the hoyer lift to move him between bed and wheelchair, Tom goes bananas. He barks, runs in circles, and gets a look of total fear on his face. It’s like he’s shouting at us, “No! No! You’re hurting him! You’re going to drop him! Put him down!” You would think he’d get used to it but he never does.

Tom has been with us over two years now. He weighs almost 6 pounds. He’s pretty happy and trusts that this is his home now. He’s also the perfect dog for Petey. Tom likes to stay put, as long as it’s wherever Petey is. Petey likes it that way too.

2009: Nine new year's resolutions for the muscular dystrophy community

noreply@blogger.com (Marie) — Thu, 01 Jan 2009 15:05:00 +0000

In the world of muscular dystrophy, medical personnel, researchers, and parents are a team. But there is a much larger team to be plugged into, the world of advocacy, funding, and awareness. Here are a few resolutions to make this year the best 2009 that it can be.

1. Parents and affected adults: Muscular Dystrophy affects body, mind and soul... Life works best when balanced so exercise all three.

2. Funding. Funding. Funding: Fund raise, leverage and appropriate funds for muscular dystrophy research. Everything from pennies to dollars to big donor checks are fair game and all make a difference.

3 Put everything we've got, including the kitchen sink, into research: basic, translational and clinical. We need more clinical trial-ready drugs.

4. Biopharmas; Prosensa, PTC, AVI and the like: be ready to push forward with clinical trials. We are 100% behind you and need you to be 100% behind your products. Parents, scientists, foundations, and government agencies offer help and guidance whenever possible.

5. FDA keep us on the right track for each and every stage of clinical research study development and trials.

6. NIH, MDA, Parent Project, and all: Make sure you're funding research that gives you the most bang for your bucks. No status quo funding!

7. Researchers, Biopharmas; funding agencies: Shave off every possible second in making viable muscular dystrophy treatments available.

8. Make a media sensation! the more muscular dystrophy is in the public eye, the better our chances of moving to viable clinical trials.

9. If you believe; pray.

Christmas, soul breathing and Health Care Community Discussion

noreply@blogger.com (Marie) — Fri, 26 Dec 2008 18:42:00 +0000

If you had been at my house on Christmas, you would have seen a beautiful tree; really the best we've had. And, although we agreed not to buy gifts this year (Peter, me, and the children, all grown), we all gave each other a little something. The perfect size.

I had a revelation. Over the years I've always said that each of us has their own hardships to deal with but somewhere in the back of my mind I didn't quite believe that the heartaches of others were quite as heart-achey as mine. A son with duchenne dystrophy is, after all, an overwhelming and constant loss. And while my opinion had shifted during these past few years, I still held on to a piece of it.

That changed.

This Christmas at one gathering, almost everyone was dealing with a tragedy or tragedy in the making. One person with ALS was trying to decide whether or not to get a tracheostomy because he would soon not be able to breath on his own. One woman, younger than me, had been dealing with diabetes for years, undergone amputations, and was now living in a nursing home. Someone else was in constant pain from a back problem. Each family had its own problem. It's a good perspective on life.

_______________________________________

Today I was back at work.

I returned my son's 24 hour heart monitor to cardiology. While I was there I passed the chapel and decided to stop in. As the world whirled away outside the door, I sat in silence, reading a self-guided Christmas service left behind amid the Koran, the Old Testament and a Hindu text of some sort. It was soul breathing, kind of like bringing the peace of Christmas back to work with me.
_______________________________________

Today, Children's held a Health Care Community Discussion in response to a request from the Obama Transition Team. My contribution was about the cost of health care and coordination of services. There were other suggestions and two stick out:

modeling the country's health care plan on the Oregon Health Plan, which covers everyone who lives there and
imposing a penalty on insurance companies who deny a service that is later found to be covered.

Bottom line: it's exciting to think that I might be part of a much needed change.

The Happiest of Holidays and the Merriest of Christmases

noreply@blogger.com (Marie) — Fri, 19 Dec 2008 02:30:00 +0000

Dear All,

As Christmas approaches and excitement fills the air, I take time to reflect how much good there is in my life.

First, my husband! My beautiful granddaughter will be here to celebrate her first Christmas. All my children will be home for the holidays. They are all healthy - especially Petey, who just saw Drs. Leshner and Spurney earlier

today. He's got a good heart (I knew that!) and his lungs pass muster.

My Christmas wish; my Christmas prayer: that exon-skipping clinical trials will begin here in the new year.

The Blessings of the Season to one and all.

Give and Take

noreply@blogger.com (Marie) — Wed, 17 Dec 2008 04:07:00 +0000

Trevor, one of our guys with Duchenne, died December 15th. He was 16 years old and his heart and his lungs just gave out. His mom, Barb, is in my heart and prayers.

Duchenne is unrelenting.

On the give side of things, another man with Duchenne (does anyone know him? Let me know) is traveling across the continent to California to live in warmer environs. He's Mike Oliveri, 24, with muscular dystrophy, a gutsy man. Here is the link to his story, "Risking it All"

Vacation Week and Petra Kaufmann's Seminar

noreply@blogger.com (Marie) — Wed, 10 Dec 2008 00:11:00 +0000

I'm taking the week off to catch up on my home life: read, write, visit with my granddaughter, Emma, and make Christmas cookies!

I've been doing bits and pieces of work-work that needed taking care of but also went in to Children's today to hear Petra Kaufmann, who is here this week to give a seminar and to interview for the position of Director of clinical research and MDA clinic.

By the time she finished her lecture, I was sold.

At first I was thinking - shouldn't she be talking about duchenne and how she would handle the research we're trying to put forward - ie - exon skipping and the like? But as she advanced her ideas and what she has learned in the past eight years at Columbia University, I saw the wisdom of her approach.

She spoke about what she knew - SMA and ALS and the 'how-to's' of research.

It turns out she knows a lot about research - design, outcome measures, the FDA and other things like working with small populations in rare diseases. These are the kinds of things she would have to contend with working with duchenne.

She addressed the most important ingredient of all in her research planning/calculations/deliberations - the patients and families.

Clinical research is a two-way street, she said. Work with patient groups, attend patient focused meetings, make participation in research something that can fit into our lives.

I liked her.

Tomorrow - cookies and Emma!

Answer to Jon and what's up

noreply@blogger.com (Marie) — Tue, 09 Dec 2008 14:54:00 +0000

Jon and everybody who's still around after my hiatus ....

sorry for my incommunicado-ness. I've been under the weather - mostly not doing well emotionally - although better each day.

Petey is amazing.

He's doing his band thing - sans drummer for the time being. Petey's the singer/songwriter. His songs, 'a la rebel', are visual masterpieces. And I'm not saying that just because I'm his mother :).

I want them to record something, but Petey keeps putting it off and, without the drummer, it would be kind of tough. I do have a couple of his old numbers from before this band.

He attracts the most wonderful people.

Kristine, his girlfriend, is coming back at the beginning of January. It's their first Christmas. She's perfect for him. I mean pretty kitty and skulls. They are such a sweet couple...

His friends are awesome - especially Jason and Eric. And they're always around. Sometimes I feel like Wendy and the 'lost boys', which is just the opposite of what it used to be...

When his sisters, Nicole and Mary, were little, I was surrounded by all girls - and Petey. Even when I was the B&G Club soccer coach for their team - there were boys but at least as many girls who were just as good as the boys.

Petey, of course, was the mascot. :)

He had his own team - but in the beginning, he was too young so he tagged along with us. His team spirit came out in some peculiar ways (That thing with the other team's water cooler - he must have been put up to it by older co-conspirator...)

Life moves forward.

Next week, he has an appointment with Chris Spurney and Robert Leshner, heart and body tune-ups. Fortunately, he's been pretty much bug-free so far. I'm the one that's sick - I've got some kind of stomach bug thing and am staying as far away from him as possible.

Big Peter - had a birthday yesterday and did his usual man and dog against nature thing - on the Eastern shore. On Sunday, we had the kids over (with baby Emma) for a birthday dinner and we went to the church Christmas concert. Two groups took the cake: the girls' choir from Seton HS - brought tears to my eyes - and this hilarious group of scientists from NASA. Emma was precious. Petey didn't go - too cold so he and Jason stayed home.

As for the Cold Habor exon-skipping thing - it included AVI, us, Genzyme, Parent Project, Steve Wilton, the Aussie, and I'm not sure who else.

The consensus is to push forward, plan for clinical trials and hopefully, using a large enough dose of exons, prove proof of concept to the FDA. So far, dose has been woefully under strength to prove much of anything. Until that is addressed, what they have to show the FDA is inadequate.

PARENT PROJECT CONFERENCE 2008 A HUGE SUCCESS

noreply@blogger.com (Marie) — Mon, 28 Jul 2008 03:42:00 +0000

It was the middle of the Friday afternoon session and I was searching for a place to plug in my laptop. You know how no one likes to sit in the front of the room? Well, all the desks up there were empty – except one where scattered notebooks and papers marked out someone’s territory. This was, of course, right beside the one empty power receptacle. I sat down anyway. Hopefully, whoever they were, they wouldn’t mind.

They didn’t. And while Jeff Chamberlain, champion of gene therapy, talked about exons and virus delivery shuttles for dystrophin, the missing gene in duchenne dystrophy, we introduced ourselves. They were Wendy and her husband, Brad, this was their first Parent Project Conference and my fourth, and I felt like I was coming home.

At this Parent Project conference, as in years past, parents of boys with duchenne met with researchers who will someday, hopefully soon, find a treatment for our sons. We network, learn about advocacy with Congress, NIH, and the FDA and how to care for the bodies, minds and souls of our boys. And when our boys become men, like my Pete, we learn to turn that care over to them.

Wendy and Brad were studying what looked like a lab report, similar to the one Pete got a few months ago when a lab rechecked his dystrophin gene deletion at exons 48 to 52.

As for exons, after ‘how old is your son’, the next question duchenne parents ask each other is, ‘what’s his deletion?’ So I asked and Wendy held up the report with a look of embarrassed perplexity. These reports are not a bit parent friendly. Wendy said they didn’t know and had been trying to figure it out.

“May I?” I asked and looked over the report.

Their son, Juan, was five and had been diagnosed just weeks ago. After the doctor told them Juan had duchenne muscular dystrophy, after the stunned silence of having the light in your heart darkened, he asked them to leave - his next appointment was waiting. Questions? He suggested they try the web – it has all the latest information about research and care.

Did I think their son could qualify for the PTC-124 clinical trials? Of all the trials for duchenne dystrophy the PTC trial is the most advanced. When it becomes available, it will help 10 – 15% of the boys with duchenne who have misplaced stop codons – a message in their dystrophin gene that tells the protein making machinery to stop too early, before the protein is made. Juan’s deletion spanned exons 48 – 51- not a stop codon.

One of the big surprises of the conference was the announcement that Genzyme was investing $100,000,000 in PTC and PTC-124. Obviously, they think it’s a winner too.

Besides meeting new friends like Wendy and Brad, I saw some dear old ones. Some of my favorite people, the Gapko’s from Wisconsin and Adele and Jason Abramowitz from Maryland, were there and we got the chance to go out to dinner together. I felt strangely empty-armed but free. No Pete to feed, get into bed, scratch itches, bathroom – I felt exhilarated and at the same time, I felt guilty for feeling so good.

I met a few ‘legends’ in the duchenne community; Wil Verheyen, father to Wilson, Canadian, and retired member of a foundation that supports duchenne research, and Nick Catlin, of actionduchenne fame. Deb Miller from CureDuchenne, and Tracy and Ben Seckler from Charley’s Fund were there. Big Pharma was there in record numbers: AVI, Prosensa, and PTC, who each have candidate therapeutics in clinical trials. Other industry representatives were there as well. And MDA.

MDA Vice President of Advocacy, Anne Kennedy, Head of Research, Sharon Hesterlee, and Chairman of the Board of Directors, Dr. Rodney Howell, were at the conference. I was thrilled to see the two giants of the duchenne community, Parent Project and the Muscular Dystrophy Association, working together. Such a partnership will guarantee the shortest time to a treatment.

Pat Furlong, President and Founder of Parent Project graciously gave me time in her busy schedule to talk about the Foundation and how far the group has come. We both learned a lot since those early days in Tennessee with the failed myoblast transfer therapy we held so much hope for.

Pat spoke about the first conference in Florida, how Parent Project has blossomed over the years and now this conference has grown to include over 400 participants, with 7 staff members running the show. The conference was so packed with information and the food was so good, it was a remarkable bargain. Pat said that subsidizing the cost of the conference so that more parents could attend was Parent Project money well spent.

The highlight of the conference came for me on the last day, when a panel of five young men with muscular dystrophy took to the stage and spoke candidly about their lives and their disease. Jacob Gapko is a PhD student in library science, whose dissertation project includes a bibliography of duchenne literature. Pat Mosechen is a counselor and middle school teacher and all around comedian (Seriously, he could go into the business). Jason Abramowitz is a sports enthusiast who plays soccer and hockey in wheelchair leagues all over the country. Conrad Reynoldsen is a congressional aide in California, who talked about his job and how he made it work. And Josh Wenheld, who’s critically acclaimed book, “Worth the Ride” was a hot item at the conference, regaled us with the business side of writing a book. My son would have fit right in!

Thank you guys. You showed us that you are not duchenne. You are not a wheelchair. You chose making your lives work. You’re blazing a trial.