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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.
Full description
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 sections detailing the main approaches.
Study design
This dose escalation IM trial will involve of up to 9 subjects, subdivided in three groups, of three subjects each. Patients in group 1 will be recruited sequentially whilst patients in groups 2 and 3 will be recruited serially.
Screening
Procedure
Observation
Follow-up Day 2 - Patients will be discharged. Prior to discharge, a brief physical examination and systems review will be performed.
Day 3 - A further brief physical examination and systems review including examination of the injection sites and reporting of any reactions. This examination can be performed at the local surgery or at the hospital of the referring clinician.
Days 5, 7 - Contact with the subject and inquire as to current status.
Day 14 to 28 - The subject is admitted to hospital. Perform systems assessment (physical examination), body weight and vital signs. Blood and urine biochemistry will be repeated then as well as open biopsies of both injected muscles will be performed under general or local anaesthetic.
Day 30 - Contact with the subject and inquiry as to current status.
Day 60 - Contact the subject and inquiry as to current status.
Day 120 - (Final Visit at the hospital where the study drug was administered). A brief physical examination and systems review will be performed.
MDEX Consortium.
The PRECLINICAL studies were performed by the following groups, who are all members of the MDEX consortium:
Additional CLINICAL SUPPORT other than the Study officials will be provided by:
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Hospital Campus, Du Cane Road, W12ONN: Prof Caroline Sewry; Dr. Maria Kinali; Dr Virginia Arechavala; Dr Lucy Feng
Department of Surgery, St Mary's Hospital Trust, Imperial College Praed Street, London, W2 1NY: Mr David Hunt
DNA Laboratory, Genetics Centre, 5th Floor Guy's Tower, Guy's Hospital London SE1 9RT: Dr Steve Abbs
Academic Unit of Child and Adolescent Psychiatry, Division of Neuroscience and Mental Health, Imperial College, St Mary's Campus, Norfolk Place, Paddington,London, W2 1PG: Professor Elena Garralda
MDEX Study coordinator:
Dr K Ganeshaguru, Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, W12ONN, k.ganeshaguru@imperial.ac.uk
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7 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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