Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients

The specific aim of this Phase I/II study is to assess the safety of intravenous administered Morpholino oligomer directed against exon 51 (AVI-4658 PMO).

Primary outcome is safety, tolerability and dose selection for future studies.

Inclusion Criteria:

1. Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent.
2. Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate.
3. Is male and between the ages of ≥ 5 years and ≤ 15 years.
4. Has a muscle biopsy analysis showing < 5% revertant fibres present at baseline.
5. DNA sequencing of the candidate's dystrophin exon 51 confirms that no DNA polymorphisms are present that could compromise PMO duplex formation or there is confirmation of in vitro dystrophin production after AVI-4658 exposure to fibroblast or myoblast in vitro cultures.
6. Intact right and left bicep muscles or alternative arm muscle group.
7. Is able to walk independently at least 25 meters.
8. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen.
9. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD.
10. The parent(s) or legal guardian and Subject have undergone counselling about the expectations of this protocol and agree to participate.
11. The parent(s) or legal guardian and Subject intend to comply with all study evaluations and return for all study activities.

Exclusion Criteria:

1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation.
2. Known antibodies to dystrophin.
3. Lacks intact right and left bicep muscles or alternative arm muscle group.
4. A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockcroft and Gault Formula.
5. A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening of <25% based on echocardiography (ECHO)during screening.
6. A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen.
7. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol.
8. Any known immune deficiency or autoimmune disease.
9. A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry.
10. Receipt of pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz., growth hormone, anabolic steroids).
11. Surgery within 3 months of study entry or planned for anytime during the duration of the study.
12. Another clinically significant illness at time of study entry.
13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances,recent significant emotional loss, and/or history of depressive or anxiety disorder that might interfere with protocol compliance.
14. Use of any experimental treatments, has participated in any DMD interventional clinical trial within 4 weeks of study entry or participated in the AVI-4658-33 intramuscular (i.m.) trial.