A phase I/II clinical trial in Duchenne muscular dystrophy using systemically delivered antisense oligonucleotides
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
We aim to test the therapeutic potential of ‘molecular patches’ (antisense oligonucleotides) administered systemically to reduce the progressive muscle degeneration and weakness of boys affected by Duchenne Muscular Dystrophy (DMD).
DMD is a fatal muscle wasting disorder with an incidence of 1:3500 boys. With onset in early childhood, progressive disability is typically followed by death in the early twenties. There are no effective treatments to halt the muscle breakdown. DMD is caused by genetic errors in the dystrophin gene.
We have already demonstrated that special molecular patches can target and bypass the faulty gene in a mouse model of DMD and cultured cells from DMD boys. We are currently evaluating the safety and efficacy of these molecular patches when administered to DMD boys following a direct intramuscular injection.
For these molecular patches to provide a clinical benefit to DMD boys, they will have to be administered systemically.
With this study we propose to assess the safety and efficacy of the repeated systemic administration of a molecular patch in a group of young DMD boys.
If effective, this approach could be applicable to other conditions where it is important to either increase or decrease levels of a protein for therapeutic effect.
DMD is a fatal muscle wasting disorder with an incidence of 1:3500 boys. With onset in early childhood, progressive disability is typically followed by death in the early twenties. There are no effective treatments to halt the muscle breakdown. DMD is caused by genetic errors in the dystrophin gene.
We have already demonstrated that special molecular patches can target and bypass the faulty gene in a mouse model of DMD and cultured cells from DMD boys. We are currently evaluating the safety and efficacy of these molecular patches when administered to DMD boys following a direct intramuscular injection.
For these molecular patches to provide a clinical benefit to DMD boys, they will have to be administered systemically.
With this study we propose to assess the safety and efficacy of the repeated systemic administration of a molecular patch in a group of young DMD boys.
If effective, this approach could be applicable to other conditions where it is important to either increase or decrease levels of a protein for therapeutic effect.
Technical Summary
Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disorder, arises from mutations in the dystrophin gene. Antisense oligonucleotide (AO) therapy has the potential to restore effectively the production of dystrophin, the defective protein, in 60% of DMD. This could result in increased life expectancy through improved muscle survival and function. Members of this Consortium have demonstrated the potential of this technique to skip mutated dystrophin exons, restore the reading frame and generate functional dystrophin protein. After having demonstrated proof-of-principle in human cell culture and animal model studies, we are currently involved in a Department of Health funded phase I/II trial aimed at assessing safety and efficacy of acutely administered AOs in DMD boys with deletions that can be rescued by skipping dystrophin exon 51.
The aim of the current proposal is to perform a repeated administration, systemic (IV) delivery phase I/II trial in 2 groups of individuals with DMD and different deletions, in whom dystrophin restoration could be achieved by using 2 different AOs. Indeed recent animal work indicates that repeated administration of IV AO is associated with the significant restoration of dystrophin expression in most muscles. In parallel, further laboratory studies will be focused on developing AO which could potentially restore dystrophin expression in most DMD mutations; and perfection methods of systemic delivery so that lower dosage of AO could be used.
This Consortium, reporting to a Scientific Board, will ensure directed progress and enable scientists to adapt research where necessary to achieve the desired goal of effective genetic therapy for individuals affected by DMD.
The aim of the current proposal is to perform a repeated administration, systemic (IV) delivery phase I/II trial in 2 groups of individuals with DMD and different deletions, in whom dystrophin restoration could be achieved by using 2 different AOs. Indeed recent animal work indicates that repeated administration of IV AO is associated with the significant restoration of dystrophin expression in most muscles. In parallel, further laboratory studies will be focused on developing AO which could potentially restore dystrophin expression in most DMD mutations; and perfection methods of systemic delivery so that lower dosage of AO could be used.
This Consortium, reporting to a Scientific Board, will ensure directed progress and enable scientists to adapt research where necessary to achieve the desired goal of effective genetic therapy for individuals affected by DMD.
