Research on MMD1

Just thought I'd share the "good" news about research on MMD1. Not a thrilling read but informative.


MMD1: Synthetic 'H' Molecules Lock Up Toxic Repeats
Scientists have developed synthetic compounds that reduce the harmful effects of MMD1-associated expansions of RNA in cellular models of the disease

Molecules with "H" sections divided by "spacer" sections can block the effects of expanded CUG RNA repeats in cell culture systems designed to model type 1 myotonic dystrophy.
Article Highlights:
Researchers have developed bis-benzimidazole-based nH-4 compounds that can interrupt the interactions between expanded RNA and cellular proteins in cells with the type of genetic defect that causes type 1 myotonic dystrophy.
Cells treated with the nH-4 compounds showed fewer harmful RNA-protein clumps, improved splicing of genetic instructions, and increased synthesis of a desirable protein compared to untreated cells.
The new compounds add to the toolkit of researchers developing strategies for type 1 and type 2 myotonic dystrophy.
BY MARGARET WAHL ON FEBRUARY 23, 2012 - 3:45PM



Small, laboratory-designed molecules can make a big difference in cells carrying the genetic defect that causes type 1 myotonic dystrophy (DM1, or MMD1), researchers have found.

Matthew Disney, Ph.D. (Photo courtesy: Scripps Research Institute)
The findings add to the therapeutic options being explored in MMD1, all of which target extra genetic material that interferes with the usual functioning of nerve and muscle cells in this disease.
MDA research grantee Matthew Disney, an associate professor in the Department of Chemistry at the Scripps Research Institute in Jupiter, Fla. ("Scripps Florida"), with colleagues there and at the University of Rochester (N.Y.), announced the findings online Feb. 14, 2012, in ACS Chemical Biology.
"Our group is centrally focused on answering fundamental questions about what types of drugs bind to what types of the genetic material known as RNA," Disney says.
"Our answers to this question so far have led us to target the MMD1 RNA with small molecules. We think this approach may be broadly applicable not only to MMD1 RNA but also to other RNA sequences that contribute to disease."
Expanded DNA and RNA root cause of MMD1

The underlying cause of MMD1 is an expanded section of the DNA sequence "CTG" (for cytosine, thymine, guanine) in a gene known as DMPK on chromosome 19. Normally, there are from three to 37 copies of this DNA "triplet repeat," while in MMD1, there can be hundreds or even thousands of such repeats.
When the DNA is converted to RNA (a normal cellular process), the expanded triplet repeats become "CUG" (for cytosine, uracil, guanine) instead of CTG.
Hundreds to thousands of extra CUG repeats in the RNA build up in the nuclei of nerve and muscle cells in MMD1, forming clumps of RNA and protein and disrupting cellular processes. These CUG repeat expansions have several effects:
The clumps they form, in conjunction with proteins, are probably harmful to cellular functions in and of themselves.
The extra CUG repeats stick to various cellular proteins, particularly one called MBNL1, trapping them and keeping them from doing their usual and important jobs.
The larger-than-normal pieces of RNA, containing the CUG repeat expansion, can't exit the nucleus, a necessary step for the RNA to be used for synthesis of the DMPK protein. Therefore, this protein is deficient in MMD1.
'H' compounds improved cellular functioning

The laboratory-synthesized compounds created by Disney's group consist of multiple copies of a bis-benzimidazole molecule, abbreviated as "H," separated by varying numbers of spacing modules, indicated by the numbers 2, 3 and 4. Each H component binds to a CUG repeat, with the spacers in between helping them to do so.
The nH-4 compounds, with varying number of H molecules and four spacer modules between each one, performed the best, improving the functioning of cells in a culture dish that had CUG repeat expansions. In summary, the nH-4 compounds:
disrupted the clumps of RNA and protein in cell nuclei;
improved a celluar process called splicing, probably by freeing the MBNL1 protein, a splicing protein, from its entrapment by CUG repeats; and
allowed RNA previously trapped in the nucleus to leave the nucleus and be used for protein synthesis.
Findings add to strategies to disrupt expanded RNA

The new findings add to previous experimental strategies developed to inhibit the effects of CUG repeat expansions in MMD1-affected cells.
In July 2009, researchers announced that a molecule known as CAG25 could perform this role in mice with an MMD1-like disease. CAG25 is an antisense oligonucleotide, a type of molecule that scientists are using experimentally to block, destroy or change genetic instructions in a variety of diseases.
In October 2009, MDA-supported researchers announced that a small molecule known as pentamidine could serve this function in mice with a disease resembling MMD1.
Other emerging strategies to treat MMD1 and type 2 myotonic dystrophy (DM2, or MMD2) were presented in December 2011 at the MDA-supported 8th International Myotonic Dystrophy Consortium. MMD2 is a similar disease to MMD1, but it's caused by an RNA repeat expansion on chromosome 3.
Learn more

To read more about MMD drug development by Disney's group, see Scripps Research Scientists Create Potent Molecules Aimed at Treating Muscular Dystrophy. This Feb. 22, 2012, news release from the Florida campus of the Scripps Research Institute refers to the findings published Feb. 14, 2012 (summarized above), as well as to the findings of Disney and others reported Feb. 2, 2012 ("Design of a Bioactive Small Molecule," referenced below).
Disney and colleagues have published the following other papers on drug development for MMD1 and MMD2:
Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2 provides a summary of a scientific paper published in ACS Chemical Biology, April 6, 2009.
The Role of Flexbility in the Rational Design of Modularly Assembled Ligands Targeting the RNAs that Cause the Myotonic Dystrophies summarizes a scientific paper published in ChemBioChem, Feb. 15, 2010.
Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA Via an RNA Motif-Ligand Database & Chemical Similarity Searching is a summary of a scientific paper published in the Journal of the American Chemical Society on Feb. 2, 2012; this paper includes some promising experiments in a mouse model of MMD1 as well as in cells.

Coco the horse

Full Body Motion Analysis

Ayaaaaaaaaaaaaaah

Scream of relief, of elation, of agony, don't know which one fits. I am so so so tired of dealing with insurance companies, you cannot even imagine what I have to go through. It is endless boondoggling and befuddling agony.
I am pretty good at it though, and yet despite it not being my true calling, I have a real knack for it, for being an advocate, for fighting the system, for dealing with all this nonsense.

I am now fighting claims that date back to July 2011!

The amount I am fighting for is: 1380 dollars.

I know it is not a huge amount, but it is the principle. We pay insurance every month, and they need to give us back what is due!

So they needed the W-9 form, which was faxed three times, but they were unable to process it because they were lacking sufficient information. Now they need the license number, and it has taken them 8 months to tell me that they are unable to process my request. Welcome to the Kafka Land of Special Needs!

Today, I am proud of myself, I told the woman behind the phone that I gave her One week to process the darn W-9 form or I would have to go up the ladder to the California State Insurance Commission, to see what they can do to help us....Let there be blood...

Anyway, I feel stressed out, what else is new?

Last week we went up to Shriners for Zoé to undergo a "Full Body Motion Analysis", the ladies in charge of the study were wonderful, warm, caring and understanding, like all the people at Shriners for that matter.
They needed to put a lot of little camera probes on Zoé's body and for it to work took a lot of of ingenuity and patience.
We played princess, we played Simon Says:"Walk in a straight line without stopping..." imagine my Zoé, the constant butterfly standing still while they calibered the cameras?
We came up with the idea that the metal plate she was standing on was Jasmine and Aladdin's carpet, then, she had to walk straight and without stopping once.
I used the tempting "Chocolate ice-cream" carrot, so she would do as she was told...
The ladies were about to give up, and I was devastated, for I wanted the study done, in the end we managed!
Zoé then got to see her body in 3-D, as little connected dots walking forward, backwards, etc.
She loved it.
We now have a baseline to see how Zoé's body is structurally speaking, which muscles she fires and which ones she doesn't use.
We will see the neurologist in May for an update.

As far as school goes, Zoé still needs to work on settling down. I don't know whether it is because she is in pain or uncomfortable sitting down, but she is constantly moving around the classroom, fidgeting, etc. Is that typical of Steinert (MMD) or not, I don't know.

On the poop front, nothing much. my constant frustration, and sadness. But what can I do?
I have tried everything: the reward, the sticker chart, TV, Videos, etc. To no avail. I just have to let go.
Zoé keeps telling me that she'll be "clean" when she is 5. We shall see, but 5 seems so far away. But she has incredible volition, so I wouldn't be surprised if on her 5th birthday, she'll decide to be potty trained!

As far as other therapies go:
Speech, had to be changed, for Zoé suddenly became bored. So now they make it slightly more interactive instead of having her repeat 50 times bilabial words.
Swim therapy is back in session and Zoé loves it.
Horse therapies are also terrific.
Physical therapy: Zoé has made tremendous progress, she can now step down from sidewalks.
OT: we need to work on dressing, which Zoé doesn't do that well, because she's used to me doing it all. I have to learn to let her do it, but when we are in a rush, it's easier for me to run around the house, making a hot lunch, packing her lunch bag, dressing her, brushing her teeth. I think we'd need an hour and a half if she were to do it all by herself.

As far as social skills go, we are going to have Zoé assessed by a developmental specialist, for she lacks social skills. She told her French teachers that she "prefers to stay with adults in the classroom at recess because kids are boring!!" She also has a hard time remembering names of friends, but if you gave her 55 princesses she'd know their names by heart within minutes!
Zoé has an incredible memory, but I think it is truly selective: songs, letters, cards, etc.
voila for now, dear readers.

Make a Muscle! 2012 Walk

To all the wonderful people who are committed to help find a cure, we send our warmest thoughts! We are proud to be part of this wonderful family.
Zoé and Sarah

Mama's Pride

Hi Sarah,
I am a SNAP swimmer (I help in the Friday 6pmclasses); Nancy tuned me into your blog last semester and I am truly touched by your posts. I think they are beautifully written and get to the heart of parenting a child with special needs. I am a graduate student pursuing a masters in Rehabilitation Counseling and I have found your blog very helpful learning about MMD. I am doing a presentation on Muscular Dystrophy in one of my classes and was wondering if I could use some of the quotes in your blog. I would omit any identifying information to ensure your and Zoe's confidentiality. I would understand if you did not want me to share these quotes as it is personal information.
Either way, thank you for writing. Looking forward to SNAP starting this week! GOOO SNAP
Best, J. H.
(I want to preserve her identity)

Hi J,
I feel truly honored to know that you want to use my blog to illustrate your presentation.
Please feel free to use it as much as you want.
I am curious which quotes you want to use.
Thanks you for reading the blog!
Looking forward to seeing you in the water this semester.
Best,
Sarah


Hi Sarah,
Thanks for letting me quote your blog. I've pasted the quotes I plan
to use at the end of the email. I mainly chose quotes that dealt with
issues of navigating our broken medical system, increasing
independence with the help of accommodations, and adjustment to
disability. I think the quotes add a nice personal touch to the
presentation when so many students get bogged down in medical terms.
Thanks again for your help!
Best, J.


“I have learned how much strength it takes to care for a child
with special needs, and how it's okay to not always be okay. To hold
grudges against yourself won't help, to look at the glass half full
and not half empty is better. It's a challenge, but it now gives true
meaning to my life.”

“Tomorrow is "Clinic", we are going to see Dr. [P], the woman who
decides how far [my daughter] has come, if her goals have been met
both physically and cognitively, if she can still benefit from
California Children Services (CCS), if the services rendered will be
reduced or not. It's going to be nerve wracking to see how [her]
"case" will be handled. These clinics are quick and to the point, but
should be an open place to communicate and I need to advocate for
[her].”

“For the first time she walked into PIP with her walker, and she was
sooooo proud of herself, being independent, down the hall, into the
playroom, and into her classroom.”

I am soooo proud to share this! I had to post it.

A Haunting Story

I have been meaning to write lately and got caught up in the everyday whirlwindish quality of our life.

I have to share the article I just read in The New York Times magazine dating back to the February 5th issue of the paper.

The article haunts me.

It is the story of survival of the mother of a special needs child name Iyal, who was affected by FAS also known as Fetal Alcohol syndrome. The side effects of this terrible diagnosis are multifaceted and variable. For the most part, Iyal born in Russia and adopted by a family in Atlanta, Georgia, had to endure and will have to endure a plethora of symptoms ranging from: "being intellectually impaired, and at high risk for a range of secondary disabilities, including poor judgement, impulsive behavior, social isolation, limited academic achievement, unemployment, drug and alcohol abuse, imprisonment, mental-health problems including suicidal ideation, inability to love independently and inappropriate sexual behavior."

For his parents, no medications nor therapies can help, nothing is deemed effective

After months and years of being part of the "universe of special-needs families, Donnie, Iyal's mom put aside her production carreer. Friends of theirs wondered what their lives would have been like if they hadn't adopted Iyal. His parents couldn't even fathom the idea of dissolving the adoption. On the contrary, they said they "couldn't bear imagining their son growing up without them."
"we fell in love with our son." still Donnie admits: "staying in love has been trickier. People with brain injuries aren't able to reciprocate love in the ways you expect. You're struggling with this cluster of emotions toward your child -- love, but also anger, bewilderment, resentment, frustration and yearning."

There is no real outcome to this story, for Iyal's parents and Iyal himself are faced with a never ending journey, the last resort his mother found was a service dog agency placing autism assistance dogs with children.

I was amazed to read how sensitive dogs can be, Iyal curls up under his dog's paw in order to "come to self-mood regulation". Specially trained dogs can even anticipate mood swings or tantrum, as if they had a sixth sense. They bring so much to these kids for unlike their peers, they hold no grudge, no judgement. " The absolutely nonjudgemental responses from animals are especially important to children." The latter can let their guards down. "The performance anxiety this child may feel all the time is absent when he's with his dog. Suddenly he's relaxed he's with a peer who doesn't criticize him."

A dog can not only bring comfort, it is also an ice breaker, it can increase social interaction. The dog will not cure Iyal, because despite being an amazing service dog, he is a dog. yet, he can "mitigate the disability."


I am in awe when I read about Donnie's hardships, how much she has to endure.
But I also welcome her to the wonderful circle of special moms.

Iyal's dog is named Chancer. "Chancer doesn't know that Iyal is cognitively impaired. What he knows is that Iyal is his boy. Chancer loves Iyal in a perfect way, with an unconditional love beyond what even the family can offer him. Chancer never feels disappointed in Iyal or embarrassed by Iyal. Beyond cognitive ability or disability, beyond predictions of a bright future or a dismal one, on a field of grass and hard-packed dirt, between the playground and the baseball diamond, you can see them sometimes, the two of them, running, laughing their heads off, sharing a moment of enormous happiness, just a boy and his dog."

I had to share this most inspiring story. I feel that dogs can help anyone, or cats for that matter, or horses. Animals are amazing.
When Zoé rides her horse this Friday, I will look at Sweet Pea in a different way. With a new set of lenses.

I welcome any thoughts or ideas or comments on the blog, as you know, for it is what brings it to life.