Splice modification to restore functional dystrophin synthesis in Duchenne muscular dystrophy

Steve D Wilton, Susan Fletcher
Current Pharmaceutical Design 2010, 16 (8): 988-1001
In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending splice-switching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of "fusion therapies", including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"