Duchenne Muscular Dystrophy: Emerging Tribulations
Duchenne Muscular Dystrophy: Emerging Tribulations
Adeno Associated Viruses (AAVs) have emerged as the preferred vector for gene replacement therapy. Testing has shown that AAV can only carry transcripts less than 5 kb; however, the full length open reading frame of the dystrophin gene is 11.2 kb, which is too large to be packaged into an AAV. Previous reports have proposed the use of various inframe, internally deleted forms of the dystrophin transcript (known as 'microdystrophin') as potential candidates for gene replacement therapy. Although sufficient expression of microdystrophin would likely slow the course of the disease in DMD patients, it would not fully restore the function of the dystrophin gene. Different forms of microdystrophin have been tested in mice, dogs, and humans (reviewed in). Although good success was achieved in animal models, the human studies did not succeed because of likely autoimmunity to dystrophin. This suggests that successful dystrophin gene replacement therapy in humans may require concomitant immunosuppressive treatment.
More recently, Lostal et al. have proposed that co-infection of three AAV vectors with each containing different portions of the dystrophin gene. The three vector genomes are engineered to undergo recombination to form the full length of the dystrophin gene if they are co-infected into the same cell. Although the efficiency of co-infection in this report was low, this method provides a potential strategy to restore a full length of the dystrophin gene in DMD patients.
Gene Replacement Therapy
Adeno Associated Viruses (AAVs) have emerged as the preferred vector for gene replacement therapy. Testing has shown that AAV can only carry transcripts less than 5 kb; however, the full length open reading frame of the dystrophin gene is 11.2 kb, which is too large to be packaged into an AAV. Previous reports have proposed the use of various inframe, internally deleted forms of the dystrophin transcript (known as 'microdystrophin') as potential candidates for gene replacement therapy. Although sufficient expression of microdystrophin would likely slow the course of the disease in DMD patients, it would not fully restore the function of the dystrophin gene. Different forms of microdystrophin have been tested in mice, dogs, and humans (reviewed in). Although good success was achieved in animal models, the human studies did not succeed because of likely autoimmunity to dystrophin. This suggests that successful dystrophin gene replacement therapy in humans may require concomitant immunosuppressive treatment.
More recently, Lostal et al. have proposed that co-infection of three AAV vectors with each containing different portions of the dystrophin gene. The three vector genomes are engineered to undergo recombination to form the full length of the dystrophin gene if they are co-infected into the same cell. Although the efficiency of co-infection in this report was low, this method provides a potential strategy to restore a full length of the dystrophin gene in DMD patients.
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