The ultimate goal of this project is to develop an antisense oligonucleotide (AO) therapy for Duchenne muscular dystrophy (DMD). Antisense oligonucleotides (AOs) can be used to reduce the severity of DMD by removing specific exons during pre-mRNA splicing, to either by-pass nonsense mutations or restore the reading frame around dystrophin genomic deletions. As a result of the treatment, dystrophin expression would be restored in dystrophic tissue and DMD patients would theoretically manifest only the milder phenotype of Becker Muscular Dystrophy (BMD). This project will explore the design and delivery of AOs to minimize the consequences of disease-causing dystrophin gene mutations. (1) Animal models of muscular dystrophy will be used to develop treatment regimens and assess therapeutic benefits in vivo. (2) AOs will be designed to target the most amenable splicing motifs at relevant exons in the human dystrophin gene transcript and will be evaluated in cultured human muscle cells. Although this approach cannot permanently correct the primary genetic lesion, we propose that repeated administration, preferably through systemic delivery, should be feasible. AO chemistries or modifications to increase stability and/or uptake, optimized for in vivo induction of exon skipping, will be developed and evaluated. Only periodic administration of AOs should be required to maintain therapeutic levels of induced dystrophin in dystrophic muscle. DMD is a serious disorder for which there is no effective treatment. AOs will not cure this devastating condition, however, AO-based splicing intervention has the potential to reduce the severity of DMD so that treated boys should be able to produce some functional dystrophin. This would be expected to moderate the severity of DMD and improve the quality of life for patients and their families.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044146-04
Application #
7210764
Study Section
Special Emphasis Panel (ZRG1-GRM (04))
Program Officer
Porter, John D
Project Start
2004-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$142,085
Indirect Cost
Name
University of Western Australia
Department
Type
DUNS #
889328519
City
Crawley
State
Country
Australia
Zip Code
6009
Greer, Kane L; Lochm├╝ller, Hanns; Flanigan, Kevin et al. (2014) Targeted exon skipping to correct exon duplications in the dystrophin gene. Mol Ther Nucleic Acids 3:e155
Fletcher, Sue; Meloni, Penny L; Johnsen, Russell D et al. (2013) Antisense suppression of donor splice site mutations in the dystrophin gene transcript. Mol Genet Genomic Med 1:162-73
Moorwood, Catherine; Soni, Neha; Patel, Gopal et al. (2013) A cell-based high-throughput screening assay for posttranscriptional utrophin upregulation. J Biomol Screen 18:400-6
Adkin, Carl F; Meloni, Penelope L; Fletcher, Susan et al. (2012) Multiple exon skipping strategies to by-pass dystrophin mutations. Neuromuscul Disord 22:297-305
Fragall, Clayton T; Adams, Abbie M; Johnsen, Russell D et al. (2011) Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching. BMC Med Genet 12:141
Forrest, Sarah; Meloni, Penny L; Muntoni, Francesco et al. (2010) Personalized exon skipping strategies to address clustered non-deletion dystrophin mutations. Neuromuscul Disord 20:810-6
Fletcher, Sue; Adams, Abbie M; Johnsen, Russell D et al. (2010) Dystrophin isoform induction in vivo by antisense-mediated alternative splicing. Mol Ther 18:1218-23
Mitrpant, Chalermchai; Adams, Abbie M; Meloni, Penny L et al. (2009) Rational design of antisense oligomers to induce dystrophin exon skipping. Mol Ther 17:1418-26
Mitrpant, Chalermchai; Fletcher, Sue; Iversen, Patrick L et al. (2009) By-passing the nonsense mutation in the 4 CV mouse model of muscular dystrophy by induced exon skipping. J Gene Med 11:46-56
Madden, Heidi R; Fletcher, Sue; Davis, Mark R et al. (2009) Characterization of a complex Duchenne muscular dystrophy-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. Hum Mutat 30:22-8

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