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.
Posts
7 comments:
Is the dose so high because they are skipping 3 exons here? Also, do they have preclinical work completed for skipping only one exon?
In the UK trail skipping 51 using PMOs they have 3 mg/kg in the highest dose and they (Les Hudson suggested this during their latest conference call) expect to see the therapeutic range close to that. Now, we would expect to see lower dose levels with PPMOs, but they are a lot higher in this paper. Does anyone have an idea why?
Ofelia
Never mind my earlier question. I just noticed that they used PMOs. That explains the dose difference b/w the AVI's work with PPMOs and this work.
Ofelia
Hey Ofelia - could you explain for folks the difference between PPMOs and PMOs - good catch by the way.
I think Jon can explain it a lot better! So Jon, please help me. :-)
I think we can say that bare Morpholinos (PMOs) work fine in the heart, the challenge is delivering them into the cells which was not accomplished so far. It is possible that by using techniques like ultrasound the bare Morpholinos might be introduced into cardiac cells, but I don't think that this method was well-explored.
The delivery into the cells is a serious challenge and the Morpholino-peptide conjugates (PPMOs) are designed to overcome delivery into the heart cells. In a multi-author paper (Jon's wife being the 2nd author) "Effective rescue of dystrophin improves cardiac function in dystropin-deficient mice by a modified morpholino oligomer" they prove not only that dystrophin expression was achieved in the heart using PPMOs but also the dose level was a lot lower (30 mg/kg at biweekly intervals if I remember correctly) and the dystrophin expression in the skeletal muscle was a lot higher than the percent obtained using PMOs. Also, PPMOs can be administered subcutaneous as opposed to IV. There is yet to be proven that the toxicity with PPMOs is low (as low as with using PMOs), so far the preclinical results look good.
Is Dr. Hoffman’s group also using PPMOs? For some reason I was under that impression.
Ah... Now I understand the difference! In the dogs we are using bare morpholinos, peptide morpholinos and soon we will use vivo morpholinos.
Hi Marie,
How long until the PPMO results will be ready for public?
The dose using PMOs is so high (120-200 mg/kg), it's scary! Not to mention the heart...Jeff Chamberlain from Univ of Washington has proven that in the mice treated with PMOs the heart problems started much earlier (b/c of the improvement in the skeletal muscles).
Thanks,
Ofelia
Dear Ofelia - Jeff's conclusion is right. As Terry Partridge puts it, "The heart is likely to suffer more if improvements in body muscle strength lead to more activity. I would guess that PPMOs would have to go through standard toxicity studies but that experience with PMOs might be used to argue against the need to do this with each individual sequence". Cheers!
Marie
Post a Comment