Exon Skipping Drug Prevents Muscle Wasting and Maintains Muscle Function in Severely Affected, Dystrophin Deficient Mice

This is a PPMO treatment (similar to AVI-5038 skipping exon 50), delivery on the heart works as opposed to the PMO treatment. A video of the mouse is enclosed:

http://www.avibio.com/news_detail.php?newsId=0061

Exon Skipping Drug Prevents Muscle Wasting and Maintains Muscle Function in Severely Affected, Dystrophin Deficient Mice
New Publication in Molecular Therapy Outlines Dramatic Effects in Animals Treated with Splice Switching PPMO, Demonstrates Promise for Treatment of Duchenne Muscular Dystrophy

Publication Videos Show Remarkable Physical Improvement
For Immediate Release
Oxford, United Kingdom & Bothell, WA, USA — October 20, 2009 — 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 week 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, PhD, 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.

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Exceptional news for mice and men. Thanks Ofelia!
Good for the mice. Now AVI needs to figure out how to more quickly and efficiently navigate the FDA process. Otherwise Alex is going to need a heart transplant before this is available to him.
I hope they figure out how to get it quickly to everyone that can benefit with this approach.
Paul, I am very hopeful for our boys, but I would not be surprised if many of them need transplants. That has actually been in the back of my mind almost since the moment Ewan was diagnosed 2 1/2 years ago. Not only heart transplants, but also liver for all of the damage the steroids are doing. I can deal with a transplant or two, though, considering the alternative if there is no treatment for the underlying disease.
Are there any articles showing that the start of ACE inhibitors, beta blockers or other heart meds early help delay the onset of cardiomyopathy? I did not have time to research this so far…

What about any info about how many heart transplants are done in Becker patients? I do know that the insurance companies do no cover transplants in DMD patients at this point, is it the same for Becker patients?
Ofelia,

Here's what I think to be the latest on managing the heart problems

http://www.parentprojectmd.org/site/DocServer/Aug_09_Ogata_bblocker...

Alex' cardiologist and neurologist both told me that they believe that the best practice is to begin the ACE inhibitors as soon as diagnostic tests like and FMRI or echocardiogram first show some signs of dysfunction. I do remember hearing on the old message board that a boy somewhere in the US with DMD was given a heart transplant, though I don't know anything about the insurance issues.
Paul,

Two boys that I know of were given heart transplants. The one from the old message board is Tammy's son, Josh. He graduated from high school, last year I believe.

Julie

Paul Cliff said:
Ofelia,

Here's what I think to be the latest on managing the heart problems

http://www.parentprojectmd.org/site/DocServer/Aug_09_Ogata_bblocker...

Alex' cardiologist and neurologist both told me that they believe that the best practice is to begin the ACE inhibitors as soon as diagnostic tests like and FMRI or echocardiogram first show some signs of dysfunction. I do remember hearing on the old message board that a boy somewhere in the US with DMD was given a heart transplant, though I don't know anything about the insurance issues.
Thanks Paul. I wonder if starting ACE inhibitors before any signs could delay the start. I think there are some boys starting taking them very early (5+).

Paul Cliff said:
Ofelia,

Here's what I think to be the latest on managing the heart problems

http://www.parentprojectmd.org/site/DocServer/Aug_09_Ogata_bblocker...

Alex' cardiologist and neurologist both told me that they believe that the best practice is to begin the ACE inhibitors as soon as diagnostic tests like and FMRI or echocardiogram first show some signs of dysfunction. I do remember hearing on the old message board that a boy somewhere in the US with DMD was given a heart transplant, though I don't know anything about the insurance issues.
Ofelia,

I have wondered the same thing. The two doctors I asked both said that the drugs have a number of relatively common side effects including a constant dry cough, and I guess that could be counterproductive in a DMD boy who would then be burning out his diaphragm early in order to avoid heart damage that hasn't even started. I do intend to look at this further.
Hi,

I read of a study that showed some benefit to starting ACE inhibitors in DMD before heart problems began. I asked the cardiologist about it and he said he hadn't heard of it, however recently I asked the neurologist and he said that he had heard of a study that had been done that showed some benefit, and that it would be published in November(sorry I am not sure where). The study that I read about was on the MDA website almost a year ago.

Jennifer

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