Clinical Trial: Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: Restoring Dystrophin Expression in Duchenne Muscular Dystrophy: A Phase I/II Clinical Trial Using AVI-4658
Brief Summary:
Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense therapy with the use of antisense oligonucleotides (AON) has the potential to restore effectively the production of dystrophin, the defective protein, in >70% of DMD. This could result in increased life expectancy through improved muscle survival and function. Recent scientific research has demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. Having demonstrated proof-of-principle in human cell culture and animal model studies, we now intend to determine efficacy and safety of this approach to induce dystrophin exon skipping in children with DMD.
The specific aim of this phase I/II study is to assess efficacy (dystrophin production) and safety of intramuscular administered morpholino oligomer directed against exon 51 (AVI-4658 PMO). We are performing parallel preclinical studies to develop methods of systemic delivery that will be necessary for future phase II/III clinical studies.
Detailed Summary:
Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy affecting 1 in every 3500 live male births. The disease is characterised by severe muscle wasting and weakness, which becomes clinically evident between the ages of 3 to 5 years. Affected individuals stop walking by 12 years of age and usually do not survive beyond the age of 20 unless ventilated. In general DMD is caused by mutations that disrupt the reading frame thus leading to a failure to express dystrophin.
Recent scientific research has led to the belief that DMD may be treated by correcting the genetic error in the dystrophin gene which causes DMD. Most children with DMD have a deletion, i.e., a mutation which removes part of the dystrophin gene. A novel technique using antisense technology to skip a specific exon and bypass faulty genetic material, thus allowing production of functional dystrophin to be produced, has been developed.These antisense oligonucleotides (AON) target and bypass faulty genetic material and allow production of functional protein.This has been successfully demonstrated in cultured human DMD cells and in mouse and canine DMD models.The restored production of dystrophin is predicted to reduce muscle pathology significantly.
In the early part of the study we compared different antisense oligomers chemical modification and concluded that the morpholino backbone is significantly superior when administered to skeletal muscle compared to a number of other types of antisense.
The aim of this phase I/II clinical study is to assess efficacy and safety of AVI-4658, a morpholino antisense directed against exon 51, in DMD individuals with deletions which would benefit from skipping exon 51.
The proposed work is presented in 4
Sponsor: Imperial College London
Current Primary Outcome: safety [ Time Frame: days 1, 3, 14-28, 30, 60, 120 ]
Original Primary Outcome: • Efficacy will be demonstrated by the production of dystrophin in a muscle that otherwise would not be able to produce dystrophin.
Current Secondary Outcome:
- Efficacy of induced skipping of exon 51 in the treated EDB muscle, in at least two of the three subjects per group. [ Time Frame: 3 - 4 weeks ]
- Restoration of dystrophin protein expression both by immunocytochemistry and Western blot analysis [ Time Frame: 3-4 weeks ]
Original Secondary Outcome: • Secondary endpoints will be the pattern of muscle MRI involvement and muscle volume of the treated muscle versus the controlateral untreated muscle.
Information By: Imperial College London
Dates:
Date Received: September 8, 2005
Date Started: October 2007
Date Completion:
Last Updated: February 22, 2010
Last Verified: February 2010
