Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy
Condition: Duchenne Muscular Dystrophy
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne
Study type: Interventional
Phase: Phase 1/Phase 2

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 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.

        -  Group 1 (3 patients) will receive intramuscular administration of a low concentration of
           study drug (extensor digitorum brevis muscle, EDB) and will undergo a muscle biopsy
           between days 14 and 28 after intramuscular (IM) administration of the AVI-4658.

        -  Group 2 (3 patients) will undergo an identical procedure but receiving an intermediate
           dose of the AVI-4658.

        -  Group 3 (3 patients) will be recruited to receive the highest dose of the AVI-4658 but
           only if the results in the first 2 cohort of patients show a lack of efficacy of the
           lower doses. Up to an additional 3 subjects may be enrolled in cohorts 1 or 2, should
           cohort 3 not be enrolled.

      Screening

        -  A physical examination, including body weight, height, arm span, neuromuscular
           examination and vital signs (blood pressure, pulse, respiration, and temperature).

        -  Neuropsychiatric assessment of both subject and the family.

        -  Molecular genetic on blood sample and dystrophin analysis of original muscle biopsy
           obtained at diagnosis.

        -  Muscle MRI scans of lower limbs to assess the preservation of the muscle to be targeted
           with the injection of AON.

        -  Biochemical (blood) and urine investigation to include standard biochemistry and
           haematology (full blood count; coagulation screen; liver function test; serum Ig;
           protein electrophoresis; inflammatory markers; creatinine kinase; gamma glutamyl
           transferase; urine biochemistry).

        -  Cardiovascular assessments: ECG and heart echocardiogram.

        -  Pulmonary assessments: Forced vital capacity, overnight oxygen saturation monitoring.

        -  Skin biopsy for MyoD-transfection.

      Procedure

        -  The muscle to be used is the extensor digitorum brevis, a foot muscle with very little
           function in children with mobility difficulties.

        -  Local injection will be performed directly through the skin using a combined
           EMG-delivery needle. While the procedure could be performed under local anaesthetic;
           where possible, it will be performed under general anaesthetic in order to reduce
           distress to the subject. A skin tattoo featuring a 1 cm x 1 cm grid with 2 lines in
           between to divide it in 9 smaller squares will be used to mark the site of the injection
           precisely and for a subsequent muscle biopsy.

        -  The total volume of each injection will be 100 μL containing the AVI-4658. Nine
           injections will be performed at 3 mm intervals inside the 1 cm2 grid tattoo. The depth
           of the injection will be carefully recorded.

      Observation

        -  Patients will be closely monitored within the clinical research facility by designated
           nursing staff educated in the trial protocol and with experience in similar Phase I/II
           studies.

        -  The clinical research facility has close access to intensive care unit facilities in the
           event of an unforeseen adverse reaction.

      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:

        1. Prof Francesco Muntoni, Dr. Jennifer Morgan. Dubowitz Neuromuscular Centre, Department
           of Paediatrics, Imperial College Hammersmith Hospital Campus, Du Cane Road London W12
           ONN

        2. Prof Dominic Wells; Dr Kim Wells. Gene Targeting Group, Department of Cellular and
           Molecular Neuroscience Division of Neuroscience and Mental Health, Imperial College,
           Charing Cross Campus, St. Dunstan's Road, London W6 8RP

        3. Prof George Dickson; Dr Ian Graham. Gene Therapy Laboratory, Centre for Biomedical
           Sciences, Royal Holloway - University of London, Egham

        4. Dr Matthew Wood. Department of Physiology, Anatomy and Genetics, South Parks Road,Oxford
           OX1 3QX, United Kingdom (UK).

        5. Professor Steve Wilton. Experimental Molecular Medicine Group, Centre for Neuromuscular
           and Neurological Disorders, University of Western Australia

      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
    

Intervention name(s): AVI-4658 (PMO)
Intervention type(s): Drug
Intervention description(s): morpholino antisense oligonucleotide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Duchenne muscular dystrophy;; antisense oligonucleotides;; gene restoration;; deletion