The main goal of the FP7 funded SCOPE-DMD project is to further advance and accelerate the development of PRO045, an exon-skipping compound for DMD. PRO045 is currently in a Phase IIb dose-escalating clinical trial to assess its safety and efficacy. The chemically-modified AON induces exon 45 skipping in the dystrophin gene and could be suitable for approximately 8% of all DMD patients.
When deletions are present in the DMD gene, these result in an out-of-frame dystrophin transcript and therefore, a truncated and non-functional dystrophin.
AONs are short nucleotide chains that can bind to a selected complementary nucleotide sequence of the (pre-)mRNA and can induce exon skipping mechanism by blocking splicing enhancer sequences present in the exon, leading to a lack of exon recognition by the RNA splicing mechanism (see figure b, where the AON named PRO045 binds sequences in exon 45).
This results in the restoration of the open reading frame of the dystrophin mRNA such that an internally truncated but semi-functional dystrophin protein (Becker-like dystrophin or BMD-like protein) is expressed in the muscles. Based on BMD clinical experience with typically improved prognosis, it is expected that AON treated patients will have improved muscle function due to expression of this BMD-like dystrophin. This RNA-based approach is not gene therapy, but rather genetic therapy or RNA modulation, as it does not change the DNA code. The effects of AON therapy on the pre-mRNA can be halted by stopping the systemic administration of the compound.