7 Dic 2006
AVI BioPharma, Inc. (Nasdaq: AVII) today announced the initiation of a clinical program for the treatment of Duchenne Muscular Dystrophy (DMD) using its ESPRIT (Exon Skipping Pre-RNA Interference Technology) exon-skipping technology. The clinical program is based on positive preclinical data amassed over the past two years, including collaborator studies published in the October 2006 issue of Neuromuscular Disorders and the February 2006 issue of Nature Medicine. This new technology application is designed to delete disease-causing gene sequences in patients with certain genetic diseases, including DMD.
"AVI introduced this new approach to treating genetic disorders in fall 2005," said Denis R. Burger, Ph.D., chief executive officer of AVI. "ESPRIT therapeutics enable the body to bypass defective genetic information at the RNA processing level, providing a new and very potent tool for altering many disease mechanisms."
AVI's clinical program will start in collaboration with the United Kingdom-based MDEX Consortium, which was established and funded to conduct clinical trials in DMD. In this proof-of-principle, controlled, dose-escalating trial, up to nine young boys with DMD will receive a single, intramuscular administration of AVI-4658, which targets exon 51. After four to six weeks, the muscle will be biopsied and examined for molecular evidence of dystrophin production, representing a positive end point. Positive results will support the expansion of AVI-4658 clinical development to systemic administration. In collaborative preclinical studies in the mdx mouse model, dystrophin was produced for at least 16 weeks following initial systemic dosing.
The principal investigator for this study is professor Francesco Muntoni, Department of Paediatrics, Hammersmith Hospital Campus, Imperial College, London. The coordinating investigator of the project is professor Dominic Wells, MA, VetMB, Ph.D., MRCVS, Department of Cellular and Molecular Neuroscience, Imperial College Faculty of Medicine, London. Imperial College will serve as the sponsor for the trial, with AVI BioPharma serving as its clinical development collaborator. The study received a favorable review by the U.K.'s Gene Therapy Advisory Committee (GTAC) in September 2006.
In addition, AVI plans to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) in 2007 for a company-sponsored, multicenter DMD clinical study in the United States. This trial will eventually expand beyond exon 51 to other exons implicated in DMD.
As part of this initiative, AVI is planning to host a clinical investigator meeting in the first quarter of 2007. DMD-experienced clinical investigators who are interested in participating should contact Peter O'Hanley, Ph.D., M.D., senior vice president, Clinical Development and Regulatory Affairs, AVI, for more information.
Finally, AVI is exploring sponsorship and support for future DMD clinical trials in Australia and elsewhere with its collaborators.
Published Preclinical Results
The first published use of AVI's ESPRIT therapeutics was conducted in collaboration with professor Steve Wilton, head of the experimental molecular medicine group at the Australian Neuromuscular Research Institute in Western Australia. Targeting the defective DMD dystrophin gene transcript with an ESPRIT compound, Wilton was able to force the cell to snip out the disease-causing mutation in that region. Using this approach, a functional dystrophin protein was made from a DMD gene that would previously have only made a nonfunctional protein.
These results were reported in the February issue of the journal Nature Medicine in an article titled "Systemic delivery of morpholino oligonucleotide restores dystrophin expression body wide and improves dystrophin pathology." Wilton used the mdx mouse model of muscular dystrophy to show that the early stop signal in exon 23 can be efficiently skipped in the modified mRNA so significant amounts of dystrophin are produced and correctly localized. The efficient delivery of these compounds generated promising results with near-normal dystrophin being produced and persisting for months from a single treatment.
AVI recently published additional data with its Australian collaborators in Neuromuscular Disorders, 2006 October;16(9-10):583-90. The article, "Induced dystrophin exon skipping in human muscle explants," described a study in which researchers induced exon skipping in muscle explants derived from both normal and DMD human tissue. Previously, the exon-skipping approach had been limited to studies using animal models or cultured human muscle cells. These studies are closer to clinical trial conditions than previous studies and provide the final preclinical data before beginning clinical trials in patients.
"Antisense oligomers can alter gene expression by snipping out the disease-causing mutation of a gene transcript during the splicing step of gene expression to convert DMD to the much less disabling Becker muscular dystrophy," said Wilton. "AVI's morpholino antisense oligomers appear to be the most efficient chemistry approach for exon skipping."
About ESPRIT Technology
In normal genetic function, gene transcription produces a full-length pre-RNA that is then processed to a much shorter and functional messenger RNA. The mRNA is the template for creating a protein. During pre-RNA processing, packets of useful genetic information, called exons, are snipped out of the full-length RNA and spliced together to make the functional mRNA template. AVI's proprietary third-generation NEUGENE(R) chemistry can be used to target splice-joining sites in the pre-RNA, thus forcing the cell machinery to skip over targeted exons, providing altered mRNA, which in turn produces altered proteins. When the skipped exon contains a disease-causing mutation, the altered protein may restore function and potentially overcome the devastating clinical consequences of the mutation.