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 in human clinical trials.

The aim is to perform a Phase I/II trial in individuals with DMD after having investigated techniques to increase the efficacy and delivery of oligonucleotides. In parallel, further laboratory studies will develop methods of systemic delivery that will be necessary for future Phase II/III trials.

Condition	Intervention	Phase
Duchenne Muscular Dystrophy	Gene Transfer: Antisense Oligonucleotide therapy	Phase I Phase II

Further Study Details: 

Primary Outcomes: • Efficacy will be demonstrated by the production of dystrophin in a muscle that otherwise would not be able to produce dystrophin.
Secondary Outcomes: • Secondary endpoints will be the pattern of muscle MRI involvement and muscle volume of the treated muscle versus the controlateral untreated muscle.
Expected Total Enrollment:  9

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 has been devised which allows to administer antisense oligonucleotides (AON) to dystrophic muscle. These AON target and bypass faulty genetic material and allow production of functional protein.This has been successfully demonstrated in a mouse model and cultured human DMD muscle cells. The restored production of dystrophin is predicted to reduce muscle pathology significantly.

The aim of our study is to perform a Phase I/II clinical trial in DMD individuals. In order to achieve this there is the need to optimise the efficacy and delivery of the AON, and to develop methods of systemic delivery that could be used for future Phase II/III trials.

The proposed work is presented in 4 sections detailing the main approaches. Study design Dose escalation study of 9 patients in three groups • Group 1 (3 patients) will receive intramuscular administration of a low concentration of AON (extensor digitorum brevis muscle, EDB) and will undergo a muscle biopsy after 4 weeks.

• Group 2 (3 patients) will undergo an identical procedure but receiving a higher dose of AON.

• Group 3 (3 patients) will receive whichever concentration of AON gave the best results in either group 1 or 2; however, instead of proceeding with a muscle biopsy after 4 weeks from the injection, in these patients we will perform a muscle biopsy after 8 weeks. This will assess the longevity of the restored dystrophin.

Baseline investigations • Clinical examination. • Molecular genetic on blood sample and dystrophin analysis of muscle biopsy • 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 (FBC; LFT; serum Ig; protein electrophoresis; inflammatory markers; CK; LDH; urine biochemistry).

Procedure • The muscle defined by the preparatory studies will be accessed under local anaesthesia. This muscle will be most likely, 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. 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 the injection will be 1ml containing the AON. Nine injections will be performed at 3 mm intervals inside the 1 cm 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 • Blood and urine biochemistry will be repeated 4 weeks from the local injection.

• MRI scan of the injected muscle will be repeated (at 4 weeks for groups 1 and 2 and group 3 at 2 months).

• Open biopsy of the injected muscle will be performed under local anaesthetic (at 4 weeks for groups 1 and 2 and group 3 at 2 months).

Ages Eligible for Study:  14 Years   -   18 Years,  Genders Eligible for Study:  Male

Criteria

Inclusion Criteria:

1. boys with Duchenne Muscular Dystrophy (DMD) which has been established by either DNA mutation analysis and muscle biopsy.
2. suitable out-of-frame deletion(s).
3. age: over 14 years

Exclusion Criteria:

1. Severe (symptomatic) cardiomyopathy.
2. Severe respiratory insufficiency (requiring nocturnal ventilation)
3. Severe cognitive dysfunction and inability to collaborate with the consent procedure.

Please refer to this study by ClinicalTrials.gov identifier  NCT00159250

Francesco Muntoni, FRCPCH      +442083833295  Ext. 33295    f.muntoni@imperial.ac.uk
Kinali Maria, FRCPCH      + 44 2083833295    m.kinali@imperial.ac.uk

United Kingdom
      Dubowitz Neuromuscular Centre, Hammersmith Hospital, London,  W12 0HS,  United Kingdom
      Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne,  NE1 4LZ,  United Kingdom

Study chairs or principal investigators

Francesco Muntoni, FRCPCH,  Principal Investigator,  Dubowitz neuromuscular Centre, Imperial College London   
Kate Bushby, MRCP,  Study Director,  Institute of Human Genetics, University of Newcastle upon Tyne   
Terence A Partridge, BSc PhD,  Study Director,  MRC Clinical Sciences Centre, Imperial College London   
Graham Ian Ross, BSc PhD,  Study Director,  School of Biological Sciences, Royal Holloway , University of London   
Dominic J Wells, Vet MB PhD,  Study Director,  Division of Neuroscience and Psychology, Imperial College London   
John G Dickson, BSc PhD,  Study Director,  Royal Holloway College, University of London   
Jennifer C Morgan, BsC PhD,  Study Director,  Imperial College London   

Study ID Numbers:  05/MRE12/32
Last Updated:  September 11, 2005
Record first received:  September 8, 2005
ClinicalTrials.gov Identifier:  NCT00159250
Health Authority: United Kingdom: Research Ethics Committee
ClinicalTrials.gov processed this record on 2005-09-13