Liam's Fund for Duchenne Muscular Dystrophy
Bad News About Exon Skipping
Copied below is an email that I received recently from Dr. Aartsma-Rus. I had written to her after doing some research online about exon skipping, when I happened upon a Web page where it describes her work in this area:
In reading through this DMD Genetic Therapy Group page on LUMC's website, it describes applicability of exon skipping for DMD mutations, including those in which skipping a single exon is not sufficient to restore the open reading frame. It mentions that she has indeed confirmed the applicability of double exon skipping in cultured cells from a patient with a deletion of exons 46-50, which is the same as our son's.
Needless to say, this was very exciting news for us. Due to Liam's age, I believe he could have a much brighter future ahead of him if he were able to receive this treatment as soon as possible, so I reached out to her in hopes that she could provide us with some information on how that might need to happen. Unfortunately, this was her response:
I am sorry to hear about your son and the impact of DMD in your family.
Liam's mutation is relatively common and indeed would need double exon skipping to restore the genetic code. Double exon skipping is possible in cultured cells. However, translating it into the human situation is far more complex than for single exon skipping. The reason for this is the fact that both exons need to be skipped. In cultured cells it is possible to just add compounds for exon 45 skipping and exon 51 skipping at very high doses. However, in living organisms one is limited because of toxicity and feasibility. The doses currently used in humans for single exon skipping are probably at the top of what is safe (for one of the chemistries) and what is feasible (for the other chemistry - this is has to do with solubility of the compounds). These doses only lead to minor levels of skipping a single exon. When two exons need to be skipped, most likely a higher dose of each individual exon skipping compound is needed (because you need to target both exons in the same transcript, e.g. if 10% of the transcript are targeted by each exon skipping compound, only 1% of the transcripts are targeted by both compounds, so you get a dilution of the effect - since you would be dosing at half the optimal dose, it might even be worse...).
Hopefully additonal studies in animals will be done to sort this out in the future. Multiple things are possible, e.g. having more efficient exon skipping compounds, or finding a way of dosing that is optimal for double exon skipping, but still feasible and tolerable. However, this would require a lot more work, so in the near future in all likelihood double exon skipping will not be done for humans.
I am sorry to be the bearer of this dissapointing news. Please note that there are other therapeutic approaches in development that would apply to all patients regardless of their mutation. Hopefully one or more of these will work out. Also note that the exon skipping field is still working on double exon skipping - we just have come to the realisation that it is a lot more trickier than we initially thought.
Starting on Steroids
Liam's neuromuscular doctor at St. Louis Children's Hospital, Dr. Pestronk, is starting Liam on a regimen of steroids soon, so that hopefully he can retain some muscle strength in his legs that will help him walk longer. He'll only be taking them on the weekends as irritability is a known side effect that might make him difficult to work with in school if he were taking them during the week.
Unfortunately, there is still no word on progress for exon skipping drugs that would help with his mutation of deletion of exons 46-50 (he would need a duplication exon skipping compound that would skip both exons 45 & 51). We are still hopeful that there will be promising news on this in the upcoming months or years.
We're hoping that those reading this will continue to donate money to organizations like PPMD and http://CureDuchenne.org, who are supporting the efforts of doctors like Dr. Kevin Flanigan at Nationwide Children's Hospital in Columbus, OH, who are working to solve this problem right now. Thank you!
Liam started walking on the same day he turned 17 months old! Let's hope he never loses that ability. Please donate to PPMD!
Liam is one week old today, and he's doing great. I just wanted to post the link to our photo album where we will be adding more and more photos of our adorable new family member in the days, weeks, months, and years to come.
If you think this page contains objectionable content, please inform the system administrator.