Dogs with muscular dystrophy, treated with splice-modifying oligos

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Jon Moulton
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Dogs with muscular dystrophy, treated with splice-modifying oligos

The paper cited below describes work in a dog model of Duchenne muscular dystrophy (DMD). One in 3500 male human births have DMD, a devastating congenital disease caused by a non-functioning protein in muscle called dystrophin. Short sections of a synthetic material that resembles nucleic acid can be used to bind intron-exon boundaries in pre-mRNA, redirecting splicing. Many mutations causing DMD are frameshifting mutations, insertions or deletions that shift the boundaries of codons during translation. Redirecting splicing can correct the frameshift by removing an exon to cause a new frameshift so that the mutation and the exon skip cancel each other out and return the sequence downstream to in-frame translation.

Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E. Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs Annals of Neurology 2009 [epub ahead of print] doi 10.1002/ana.21627
Videos of treated and control dystrophic dogs:

Video 1, Non-treated Dystrophic Dog, 7 months old
Video 2, Non-treated Dystrophic Dog, 7 months old
Video 3, Treated Dystrophic Dog, 7 months old, after 5 x Weekly 120 mg/Kg Morpholino oligo cocktail injections.
Video 4, Treated Dystrophic Dog, 4 months old, after 7 × 200 mg/Kg Morpholino oligo cocktail injections.
Video 5, Treated Dystrophic Dog, 7 months old, ater 11 × 120 mg/Kg Morpholino oligo cocktail injections.
NIH press release on Morpholinos for Duchenne muscular dystrophy in a dog model of DMD:
http://www.nih.gov/news/health/mar2009/nichd-16.htm
Children’s National Medical Center press release:
http://www.childrensnational.org/pressroom/NewsReleases/FirstExonSkippingLargeAnimal.aspx

 

Jason King
Jason King's picture
I was at the ESGCT meeting at

I was at the ESGCT meeting at the end of 2006 and George Dickson's lab was reporting that they were about to start clinical trials on DMD. Here's a paper in which they look at the effect of different antisense sequence targets. In the abstract they say that they are at phase I / IIa, and this was in 2007.

Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle.

Arechavala-Gomeza V, Graham IR, Popplewell LJ, Adams AM, Aartsma-Rus A, Kinali M, Morgan JE, van Deutekom JC, Wilton SD, Dickson G, Muntoni F.

Hum Gene Ther. 2007 Sep;18(9):798-810.

Jon Moulton
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There are two competing

There are two competing antisense structural types that are being used in clinical trials to induce exon skipping for DMD. These are:
 
2'-O-methyl phosphorothioate oligos
   In trials by ProSensa B.V.
 
Morpholino oligos (a.k.a. PMO, phoaphorodiamidate morpholino oligomers)
   In trials by AVI BioPharma Inc.
 
There are also two modifications of the Morpholino oligos in use for research but not yet into the clinic. These are the cell-penetrating-peptide linked PMO (PPMO from AVI BioPharma) and the Vivo-Morpholinos from Gene Tools, LLC (I work for this company). These have delivery moieties linked to the Morpholino oligos which help the Morpholinos escape from endosomes.
This has been fascinating development to watch.