Shortened versions of the muscle protein dystrophin— produced by skipping a section of genetic instructions called exon 51— appear to be functional, says a new report from the United Kingdom.
The encouraging findings are based on analysis of muscle biopsies of four of the participants in a phase 1 trial in which the experimental drug eteplirsen was injected into a foot muscle. All trial participants were boys with Duchenne muscular dystrophy (DMD) who had dystrophin mutations potentially responsive to skipping exon 51.
The findings have led researchers to say that eteplirsen could become a "disease-modifying" agent for people with DMD who have specific dystrophin gene mutations.
In people with DMD, any of a large number of mutations in the dystrophin gene can lead to a complete, or nearly complete, absence of dystrophin protein at the muscle-fiber membrane.
In Becker muscular dystrophy (BMD), a different set of mutations in the dystrophin gene leads to the production of partially functional, shorter dystrophin protein and to a somewhat milder disease than DMD.
The goal of the experimental treatment strategy known as exon skipping is to make DMD-causing mutations behave like mutations that cause a BMD-like disorder.
The experimental exon-skipping compound eteplirsen (also known as AVI-4658) is being developed by AVI BioPharma. It's designed to cause skipping of the exon 51 region of the genetic instructions for dystrophin and induce production of shorter-than-normal but potentially functional dystrophin protein.
In January 2009, it was announced that boys with DMD whose foot muscles received a single injection of eteplirsen produced dystrophin.
In October 2010, eteplirsen was found to cause substantial dystrophin production in some trial participants with specific dystrophin mutations, when given intravenously once a week for 12 weeks.
However, until now it hasn't been clear that the shortened dystrophin produced by skipping exon 51 would carry out some of its major functions — namely, allowing essential proteins to assemble in their proper places in or near the muscle-fiber membrane (see graphic at bottom). These proteins are missing from the membrane when dystrophin is missing.
Now, researchers in the United Kingdom, writing in the February 2012 issue of Molecular Therapy, report restoration of at least two, and in some cases three, essential proteins to the muscle-fiber membrane in four children with DMD who received a single intramuscular injection of eteplirsen into a foot muscle. Francesco Muntoni at University College London Institute of Child Health coordinated the study team.
The restored proteins are alpha-sarcoglycan, beta-dystroglycan, and in some cases, neuronal nitric oxide synthase. This restoration shows that the newly synthesized dystrophin, despite being shorter than normal, is functional.
"These data confirm that restored dystrophin maintains essential domains for its function and further suggest the potential of PMO AVI-4658 [eteplirsen] to become a disease-modifying drug for DMD," the authors say.
A phase 2 study of intravenous eteplirsen in DMD at Nationwide Children's Hospital in Columbus, Ohio, is ongoing but closed to new participants. MDA is providing supplemental support for this trial.
AVI BioPharma and GlaxoSmithKline (GSK) are continuing to develop exon-skipping compounds for DMD. AVI will target exons 45 and 50, in addition to exon 51, while GSK is expanding testing of its drug GSK2402968, which targets exon 51.
Clusters of proteins are spaced at intervals along the membrane of each muscle fiber. The presence of dystrophin, or the related protein utrophin, appears to be necessary for the other proteins in the cluster to assemble at the membrane.