Our Translational Gene Therapy Center has used small molecules for exon skipping and mutation suppression and gene transfer to replace or provide surrogate genes as tools for molecular-based approaches for the treatment of
muscular dystrophies. Exon skipping is targeted at the
pre-mRNA level allowing one or more exons to be omitted to restore the reading frame. In
Duchenne Muscular Dystrophy (DMD), clinical trials have been performed with two different oligomers, a 2'O-methyl-ribo-oligonucleoside-phosphorothioate (2'OMe) and a phosphorodiamidate
morpholino (PMO). Both have demonstrated early evidence of efficacy. A second molecular approach involves suppression of
stop codons to promote readthrough of the DMD gene. We have been able to establish proof of principle for mutation suppression using the
aminoglycoside,
gentamicin. A safer, orally administered, alternative agent referred to as
Ataluren (
PTC124) has been used in clinical trials and is currently under consideration for approval by the FDA. Using a gene
therapy approach, we have completed two trials and have initiated a third. For DMD, we used a mini-
dystrophin transferred in adeno-associated virus (AAV). In this trial an immune response was seen directed against transgene product, a quite unexpected outcome that will help guide further studies. For
limb girdle muscular dystrophy 2D (
alpha-sarcoglycan deficiency), the transgene was again transferred using AAV but in this study, a muscle specific
creatine kinase promoter controlled gene expression that persisted for six months. A third gene therapy trial has been initiated with transfer of the
follistatin gene in AAV directly to the quadriceps muscle. Two diseases with selective quadriceps muscle weakness are undergoing gene transfer including
sporadic inclusion body myositis (sIBM) and
Becker muscular dystrophy (BMD). Increasing the size and strength of the muscle is the goal of this study. Most importantly, no adverse events have been encountered in any of these clinical trials.