Back to the Drawing Board

Or to the lab, rather.  This morning the Duchenne community was dealt a pretty crushing blow.  Prosensa/GSK's Phase III trial of the exon 51 skipping drug, Drisapersen, failed to meet it's end points.  What that means is that the boys on the drug showed no significant statistical improvements over the boys in the placebo group. 

If you are completely lost, read Building a Bridge Part 1 and part 2.

What this means for Pro044, the version of Drisapersen that is supposed to help Little, is still unknown at this time.  The Phase III trial for that one was slated to start next fall.  I don't know if they will go forward with it or not.  I do know that they have discontinued dosing any of the boys in the 51 trial and are looking into it more to see if there may be a subset of boys who benefitted more than others.

It was with a very heavy heart that I read the news on Facebook today.  This was the drug that most of us had pinned our hopes on.  I know that it wasn't going to be a cure, but I had really hoped that it would be the drug that improved Little's quality of life.  Worst case, the drug is abandoned all together ~ best case, they can reformulate it and start new trials. 

There is still a similar drug out there in trials called Eteplirsen, by Sarepta Therapeutics.  It is also an exon skipping drug targeted at 51.  I am holding out some hope that this one fares better than Drisapersen.  If so, then hopefully they will add in a formula targeted at the exon Little needs skipped but for right now, it is not on their list.

Although I am saddened by the failure of the drug trial, I am not defeated.   When Little was diagnosed in 2011, we had the bomb dropped on us right then.  Duchenne was introduced to us as an absolutely fatal, not even a treatment to help him slow it down, take your kid home and love him while you have him disease.  So I already come from a place of quiet, reserved hope while still preparing for a life where no drug is viable in time for Little.  Push along and do what I can to make sure his days are the best they can be, trusting in God to take care of him until the Duchenne sends him Home.  Crossing my fingers that one of these labs unlocks the key to reversing muscle waste while still planning on the timeline of deterioration that Duchenne has always followed for every single one of its victims.  Cautious optimism, if you will.  I've always known that even if this drug did work, that it might not be available in time for my son.  This may have been the biggest and brightest hope for a long term therapy for Andrew and the others, but it certainly isn't the only thing out there.  There are many more drugs on the horizon, more labs working on research, and more people aware of this disease than ever before.    I've got my fingers crossed for Halo for one.    Halo is working on HT-100, a drug that is intended to promote healthy muscle regeneration, diminish inflammation and the resulting damage to muscle, and decrease the scar tissue that forms in the muscles of children with DMD.  Less scar tissue = more flexibility and less pain.  Yes, please.  As Parent Project Muscular Dystrophy (PPMD) said today, "We have lost a battle, not the war".

I know some of you are thinking "How can she still trust in God to take care of her son when He let this drug fail?  She sure thanked Him for the discovery of the drug - where is He now?"  Well, it's simple.  Its called faith.  I have faith that God will take care of Andrew because he said He would. 
"For I know the plans I have made for you" declared the Lord.  "Plans to prosper you, and not to harm you,  plans to give you hope, and a future.  Then you will call on me and  come and pray to me, and I will listen to you.  You will seek me and find me, when you seek me with all your heart."  Jeremiah 29: 11-13
I still believe that the discovery of exon skipping therapies will be a gateway to curing all sorts of genetic disorders.  Maybe not Duchenne, and that's okay.  Disappointing, but okay.  And maybe a drug therapy won't come at all during Little's lifetime, and that's okay, too.  Again, disappointing, but as always, not my will but Thine. 

I leave you with the hymn that always pops into my head during times like this ~ times of let down,   times of dashed hope.  Times where the future looks dark and scary and I feel helpless to save Andrew from his broken genes.  Times when I need to remind myself that this life is temporary and what is waiting for us on the other side is full of grace and mercy. 

When peace, like a river, attendeth my way, when sorrows like sea billows roll; whatever my lot, Thou hast taught me to say, it is well, it is well with my soul.

Though Satan should buffett, though trials should come, let this blest assurance control, that  Christ has regarded my helpless estate and hath shed His own blood for my soul.

It is well with my soul.
 

Building a Bridge (part 2)

I've learned more about exon skipping and which one will be right for Little.  Turns out skipping 45 is NOT the way to go after all.  Why it didn't occur to me that it would be pointless to skip an exon that was already deleted is beyond me.  I had the right idea with my sweet sweet drawings, by building a bridge over the missing chunk, but I need to elongate that bridge a little.  I was pointed to a website by another DMD mom, Stacy, that gave me a better understanding of how the exons communicate and how to know which ones to target with the drug therapy.  Thank you, Stacy!  I took that knowledge with me to the meeting with Mr. Mendell at NCH last week and talked with him further and he confirmed that I have the right grasp on it.

So here are some new (boring) diagrams, courtesy of (and by that, I mean plagiarized from) the Prosensa website.

This first one is a mock up of all of the exons that carry dystrophin through the body.   The exons have been given shapes as a way of illustrating which exons communicate with which other exons.  Check out the way the shapes are angled.  Like a jigsaw puzzle, only the pieces that match into each other fit together.  Get it?  Check out #s 1,2,&3 - see how 1 fits into 2 and 2 fits into 3?  Well info can flow from 1 to 2, then 2 to 3.  Check out #s 17 & 18.  See how they match end to end?  That's how the communication of dystrophin information flows all the way from 1 to 79 in you and me (people without DMD)

When one of those pieces is missing and the 2 exons on either side of the hole don't match up, you get a boy like Little.  This picture is Prosensa's version of the train falling through the hole in the track.  Mine had a little screaming stick figure in the front of the train as it plummeted into the darkness....this one is just more blocks. pbbbbbbbbbbbt

See how with exon 45 gone, 44 and 46 can't communicate?  This is called an out of frame deletion on exon 45, the clinical term for Andrew's specific mutation.

Now, check out the shapes of the exons nearby.  What needs to happen now, is for that bridge to be built from one over to the next one with matching parts.  Look at the end of  43.  It matches exactly to 46.  So if we skip exon 44, we can connect 43 to 46 with our little drug bridge.

This is actually fantastic news, bc PRO44 trials have been going on in the UK for a while now and they are already in phase 1 here through Prosensa.  So - just as exciting as when I thought PRO45 was the one we wanted!

And what else is exciting about this?  Check out Little's deletion chart again.  We already saw that 43 and 46 can match up, but look at 44 and 47.  Another match!  So skipping exon 46 and building our bridge from 44 to 47 could also be an option one day!

We're still very much in a good place with waiting on these drugs to become available and I'm still incredibly excited about the new exons that are in the Prosensa/GSK line up.  Bit by bit, God is letting these scientists chip away at Duchenne.  I believe that one day our boys will be living with, not dying from a diagnosis of Duchenne.  One day, a mother will get that phone call from her son's geneticist and he won't be giving her the news with tears streaming down his face and sobs choking his voice.  He'll be able to tell her with a reassuring tone that her son will get better.

This will be it for a week or so, I've got some stuff on my plate that will prevent me from blogging (like my borther's wedding!!!!!!!!!!!!!!!!!!!!!!!!).  But as always, thank you for keeping up with us and we'll be back before you know it.  You can still catch be at LITTLEfeedback@hotmail.com in the mean time.

And now it's time for our Little's Leaguer of the week, my 50th subscribed reader, Dannadannadanndannadannadanna ooops, sorry Lady, seem to have gotten a little Hicks stuck on my keyboard.

Danna Gentry!

You have no idea how hard it was not to use a picture of you in your sweet 6th grade side pony tail.