An exon skipping PPMO has demonstrated dramatic effects in the
prevention and treatment of severely affected, dystrophin and
utrophin-deficient mice, preventing severe deterioration of the
treated animals and extending their lifespan. These findings were
published online today in the journal Molecular Therapy and support
the promise of this therapeutic approach for the treatment of
Duchenne muscular dystrophy (DMD). These results were published by
researchers at University of Oxford, AVI BioPharma, Inc. (NASDAQ:
AVII) and the University of Western Australia, Perth.
DMD is an incurable muscle-wasting disease associated with
errors in the gene that makes dystrophin. Studies and research have
shown that the ability to skip certain exons in dystrophin pre-mRNA
could circumvent these dystrophin gene errors and provide a
potential treatment for DMD patients. The paper "Prevention of
Dystrophic Pathology in Severely Affected
Dystrophin/Utrophin-deficient Mice by Morpholino-oligomer-mediated
Exon-skipping" details the successful exon skipping and treatment
of utrophin/dystrophin double knockout (dKO) mice with a
cell-penetrating peptide-conjugated phosphorodiamidate morpholino
oligomers (PPMO) targeting exon 23 in dystrophin pre-mRNA.
Videos accompanying the online publication show visual evidence
of pronounced curving of the spine and dramatically reduced
mobility as a result of deficiency of both dystrophin and utrophin
proteins (dKO Mouse No Treatment/Supplementary Video S1). Treatment
of affected mice from 10 days of age for six weeks with the
mouse-specific PPMO at a dosage of 25 mg/kg/week resulted in a
nearly complete skipping of exon 23 in all of the muscles examined
except the heart. Skipping of exon 23 restored the reading frame of
dystrophin mRNA and led to widespread continued translation of
dystrophin protein. Treated dKO mice showed near normal measures
for most of the examined parameters, including striking prevention
of kyphosis and maintaining of near normal mobility. The
publication also featured a video illustrating the impact of the
treatment on the dKO mice (dKO Mouse Post-Treatment with
PPMO/Supplementary Video S2).
"This research demonstrates remarkable prevention of dystrophic
pathology and retained near normal muscle function in severely
affected dKO mice following treatment with a PPMO," said Dame Kay
Davies, Ph.D, Director of the MRC Functional Genomics Unit and Head
of the Department of Physiology, Anatomy and Genetics at University
of Oxford and senior author on the paper. "Notably, this study
demonstrates for the first time the efficiency of such an
exon-skipping approach in the dKO mouse, which is a much more
severe and progressive mouse model of DMD. These findings, should
they prove to be replicated in human studies, suggest great
potential for the treatment of DMD patients with a PPMO."
"Antisense-mediated exon-skipping represents one of the most
promising approaches for the treatment of DMD because of its
capacity to correct the reading frame and restore dystrophin
expression," said Steve Wilton, Ph.D. Professor at the Center for
Neuromuscular and Neurological Disorders, University of Western
Australia, Perth, Western Australia, Australia and co-author of the
study.
The dystrophin-deficient mdx mouse has historically been used as
the primary model of DMD, although this mouse does not experience
the severe, body-wide dystrophy that considerably shortens lifespan
in humans. Therefore, double-knockout (dKO) mice, which present a
much more severe and progressive dystrophic phenotype than mdx
mice, could represent a more appropriate model to test the
therapeutic potential of the antisense approach.
"In a very challenging model of severe DMD, this study confirms
our belief that PPMO, a next generation of AVI drug candidates
under development, holds great promise as a treatment for incurable
muscle wasting in DMD patients," said Ryszard Kole, Ph.D, Senior
Vice President of Discovery Research at AVI BioPharma and co-author
of the study.
AVI BioPharma is developing AVI-4658 for the treatment of DMD.
This first generation PMO drug candidate is designed to skip exon
51 of the dystrophin gene, allowing for restoration of the reading
frame in the dystrophin mRNA sequence. Results from a Phase 1
proof-of-concept trial showed that injection of the drug into the
muscles of a series of boys with DMD successfully induced
dystrophin production in a dose-responsive manner. Further, the
drug was well tolerated, with no significant drug-related adverse
events detected. AVI is currently conducting an ongoing Phase 1b/2
dose-finding clinical trial evaluating the systemic delivery of
AVI-4658 for treatment of DMD. This is an open label, 12-week
safety trial, which includes measures of drug efficacy and
pharmacokinetics and is being conducted in London, UK at the UCL
Institute of Child Health / Great Ormond Street Hospital NHS Trust
facilities and at the Royal Victoria Infirmary,
Newcastle-Upon-Tyne, UK which is the coordinating center for the
European Treat Neuromuscular Diseases (Treat-NMD) initiative.
AVI BioPharma is also developing a second generation chemistry
exon skipping drugs, with a PPMO, AVI-5038, nearing IND submission
for the treatment of DMD by skipping exon 50.
About Duchenne Muscular Dystrophy (DMD)
DMD is one of the most common fatal genetic disorders to affect
children around the world. Approximately one in every 3,500 boys
worldwide is afflicted with Duchenne Muscular Dystrophy with 20,000
new cases reported each year. It is a devastating and incurable
muscle-wasting disease associated with specific inborn errors in
the gene that codes for dystrophin, a protein that plays a key
structural role in muscle fiber function. Symptoms usually appear
in male children by age three. Progressive muscle weakness of the
legs and pelvis eventually spreads to the arms, neck, and other
areas. By age 10, braces may be required for walking, and most
patients are confined to a wheelchair by age 12. Eventually, this
progresses to complete paralysis and increasing difficulty in
breathing, requiring ventilatory support. The condition is terminal
and death usually occurs before the age of 30. The outpatient cost
of care for a non-ambulatory DMD boy is among the highest of any
disease. There is currently no cure for DMD, but for the first time
ever, there are promising therapies in or moving into clinical
development.
About University of Oxford
Oxford University's Medical Sciences Division is one of the
largest biomedical research centres in Europe. It represents almost
one-third of Oxford University's income and expenditure, and
two-thirds of its external research income. Oxford's world-renowned
global health programme is a leader in the fight against infectious
diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu)
and other prevalent diseases (such as cancer, stroke, heart disease
and diabetes). Key to its success is a long-standing network of
dedicated Wellcome Trust-funded research units in Asia (Thailand,
Laos and Vietnam) and Kenya, and work at the MRC Unit in The
Gambia. Long-term studies of patients around the world are
supported by basic science at Oxford and have led to many exciting
developments, including potential vaccines for tuberculosis,
malaria and HIV, which are in clinical trials.
About AVI BioPharma
AVI BioPharma is focused on the discovery and development of
RNA-based drugs utilizing proprietary derivatives of its antisense
chemistry (morpholino-modified phosphorodiamidate oligomers or
PMOs) that can be applied to a wide range of diseases and genetic
disorders through several distinct mechanisms of action. Unlike
other RNA therapeutic approaches, AVI's antisense technology has
been used to directly target both messenger RNA (mRNA) and its
precursor (pre-mRNA), allowing for both up- and down-regulation of
targeted genes and proteins. AVI's RNA-based drug programs are
being evaluated for the treatment of Duchenne muscular dystrophy as
well as for the treatment of cardiovascular restenosis through our
partner Global Therapeutics, a Cook Group Company. AVI's antiviral
programs have demonstrated promising outcomes in Ebola Zaire and
Marburg Musoke virus infections and may prove applicable to other
viral targets such as HCV or Dengue viruses. For more information,
visit www.avibio.com.
"Safe Harbor" Statement under the Private Securities Litigation
Reform Act of 1995: The statements that are not historical facts
contained in this release are forward-looking statements that
involve risks and uncertainties, including, but not limited to, the
results of research and development efforts, the results of
preclinical and clinical testing, the effect of regulation by the
FDA and other agencies, the impact of competitive products, product
development, commercialization and technological difficulties, and
other risks detailed in the company's Securities and Exchange
Commission filings.
AVI Press and Investor Contact: Julie Rathbun Investor Relations
(541) 224-2575 Investorrelations@avibio.com
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