Exon Skipping
I was hoping someone might be able to answer some questions. On the old web site there was a discussion regarding the skipping of exon 51 and the trials and drug that are currently being tested. Our son has a deletion of exon 48-50. Would this trial for exon 51 help us? I also read that someone else has a deletion of 45 & 46 but stated that the deletion was predicted in frame and therefor exon skipping would not help them; What does this mean? Does anyone know when this exon skipping trial will be available in Canada? My last question.... Is this something I should be excited about, do you think exon skipping will be the answer we are praying for?
Replies to This Discussion
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Permalink Reply by Tulika on
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Hi,
Some new updates on the toxiciity developments on PPMO at http://lib.bioinfo.pl/pmid:18796528
Paper is slightly technical and a bit difficult to read, however suggests that factors that influence the toxicity have been identified and what needs to be done next to make PPMO non toxic.
Usualluy papers take some time when they are created to when they are actually published, I assume that findings in this paper are at least 4 to 5 months old.
Is there someone who is planning to attend the UBS Global Life Sciences Conference in NY city. We can ask AVI CEO Dr. Hudson on any specific updates on the toxic studies of PPMO.
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Permalink Reply by Tina on
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Lately, there has been so much discussion on exon skipping ( this is a good thing!). And, there remain questions about the outcome of skipping certain exons. Will skipping certain exons cause a BMD phenotype or remain a DMD one? I came across this article and found it very encouraging for those who need this type of skip ( 45- 51).
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Grandpa and I have Dystrophinopathy?: Approach to Asymptomatic HyperCKemia
Montri Saengpattrachai MD, Peter N. Ray PhD†, Cynthia E. Hawkins MD, PhD†, Alan Berzen ChB, MB‡ and Brenda L. Banwell MD, ,
†Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada ‡Division of Molecular and Clinical Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada. Division Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada
Received 3 October 2005; accepted 3 January 2006. Available online 25 July 2006.
This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness.
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StaffPermalink Reply by Pat Furlong on -
Hello Rick,
First, your son's mutation may well fit into the exon 51 skipping strategy, though mutations are a bit more complicated than 48-50. Information about specific exact breaking points must be understood but as a general statement, your son fits into this strategy. Several companies (prosensa and avi biopharm) are involved in trials targeting exon 51. At the moment the trials are concerned with safety and dose escalation, in order to figure out how much is needed in order to achieve sufficient dystrophin expression. Your last question about excitement - yes, this is a very promising strategy. Trials will be expanded into the US in 2009. I am not certain about Canada but clearly in order to recruit sufficient numbers of boys into these trials, there will need to be a number of clinical sites involved. Your question about 'is this the answer we are paying for" - this strategy attempts to change the duchenne phenotype to a becker, a slower progression. We are all hopeful exon skipping is a major step forward. The goal is to get proof of concept from these early trials. Keep praying.
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Permalink Reply by Ofelia Marin on
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Pat,
Would you be able to give more details about this statement: "though mutations are a bit more complicated than 48-50. Information about specific exact breaking points must be understood"? All I know is that the deletion should start/end in the introns not too close to the splicing sites. Do you have more details?
Thanks,
Ofelia
Pat Furlong said:Hello Rick,
First, your son's mutation may well fit into the exon 51 skipping strategy, though mutations are a bit more complicated than 48-50. Information about specific exact breaking points must be understood but as a general statement, your son fits into this strategy. Several companies (prosensa and avi biopharm) are involved in trials targeting exon 51. At the moment the trials are concerned with safety and dose escalation, in order to figure out how much is needed in order to achieve sufficient dystrophin expression. Your last question about excitement - yes, this is a very promising strategy. Trials will be expanded into the US in 2009. I am not certain about Canada but clearly in order to recruit sufficient numbers of boys into these trials, there will need to be a number of clinical sites involved. Your question about 'is this the answer we are paying for" - this strategy attempts to change the duchenne phenotype to a becker, a slower progression. We are all hopeful exon skipping is a major step forward. The goal is to get proof of concept from these early trials. Keep praying.
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AVI BioPharma Strengthens Patent Position in Exon Skipping
http://www.avibio.com/pr/pr399.php
For Immediate Release
PORTLAND, OR — November 24, 2008 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA–based drugs, today announced the signing of an exclusive worldwide license agreement with the University of Western Australia (UWA) to a patent application related to the treatment of Duchenne Muscular Dystrophy (DMD). The patent application, “Antisense Oligonucleotides for Inducing Exon Skipping and Methods of Use Thereof” (U.S. Patent publication number US2008/0200409 A1 and foreign counterparts) claims compositions and methods for treating DMD in humans by skipping exons in the dystrophin gene using antisense oligomers. Among the inventors on the licensed patent application is Stephen D. Wilton, Ph.D., Head of the Molecular Genetic Therapies Group at UWA, a renowned pioneer in the use of exon skipping to treat DMD.
“Dr. Wilton is a longtime collaborator of AVI, and our securing of this license to UWA’s patent application further strengthens AVI’s leading position in the field of exon skipping for DMD,” said Leslie Hudson, Ph.D., President and Chief Executive Officer of AVI BioPharma.
In addition to the UWA patent application, AVI’s patent position in exon skipping includes exclusive rights to Dr. Ryszard Kole’s general RNA splice altering patents gained though AVI’s acquisition of Ercole Biotech earlier this year, as well as other AVI–filed patents and in–licensed intellectual property specific to exon skipping of the dystrophin gene as a therapeutic target.
AVI is currently evaluating the exon skipping therapeutic AVI–4658 for the treatment of DMD. Preclinical studies have demonstrated sustained production of functional dystrophin in numerous tissues, including the heart, diaphragm and skeletal muscles. A clinical trial is currently underway at the Imperial College of London where patients with DMD are receiving a single–dose, intramuscular administration of AVI–4658. The Company was granted orphan drug designation for AVI–4658 by the U.S. Food and Drug Administration in November of 2007 and has been recommended for orphan product designation by the European Medicines Agency (EMEA) Committee for Orphan Medicinal Products.
Dr. Wilton and AVI researchers have collaborated on research in exon skipping and have published articles detailing their research. The most recently published research includes an article appearing in the December issue of the Journal of Gene Medicine titled “By–passing the Nonsense Mutation in the 4(CV) Mouse Model of Muscular Dystrophy by Induced Exon Skipping.” A link to the preview of this publication, posted online in advance of print publication, can be found under the “Publications” section of the AVI BioPharma website at www.avibio.com
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 before age 6. 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. 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 in decades, there are a range of promising therapies in or moving into development.
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.
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EXON SKIPPING NEWS
Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, DC 20010, USA.
A renaissance for antisense oligonucleotide drugs in neurology: exon skipping breaks new ground.Yokota T, Takeda S, Lu QL, Partridge TA, Nakamura A, Hoffman EP
As long-standing barriers are successfully circumvented, attention turns toward scale-up of production, long-term toxicity studies, and the challenges to traditional drug regulatory attitudes presented by tightly targeted sequence-specific drugs.
Antisense oligonucleotides are short nucleic acid sequences designed for use as small-molecule drugs. They recognize and bind to specific messenger RNA (mRNA) or pre-mRNA sequences to create small double-stranded regions of the target mRNA that alter mRNA splicing patterns or inhibit protein translation. Antisense approaches have been actively pursued as a form of molecular medicine for more than 20 years, but only one has been translated to a marketed drug (intraocular human immunodeficiency virus treatment). Two recent advances foreshadow a change in clinical applications of antisense strategies. First is the development of synthetic DNA analogues that show outstanding stability and sequence specificity yet little or no binding to modulator proteins. Second is the publication of impressive preclinical and clinical data using antisense in an exon-skipping strategy to increase dystrophin production in Duchenne muscular dystrophy.
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Permalink Reply by BOZ4J on
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Someone asked here about deletion 50,51 and Linden detabase . (2 patients diagnosed withDMD). My son can be example of debate if he is DMD or BMD. From genetic mutation he is DMD . By the symptoms ,I was already told by few doctors and other people in the field that he looks like he is Becker. Personally for me is not important how they will name it. They can call it BMD or Mild DMD, What is more important for us , what they can do about it . Clock is ticking.I already do not expeckt any big miracles with my son being 9,5 years old and exon 51 just starting trials , when 53 is what we need. The only miracles I can expect is the miracle in known pharmacology or stem cells.In mean time I do many things in my life to make sure that I do not hear the clock. I fixed my car today for example.. BUT no matter how busy I stay , how loud I am , I hear the clock .Good luck.As younger your kids are ,the biggest chance they have .
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Permalink Reply by Bob McDonald on
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Exon skipping will not be a cure. It MAY, for some patients, offer a transition to a Becker form of muscular dystrophy though a muscular dystrophy nonetheless. This a VERY important distinction. There is a very varied phenotype in Becker which means a patient can be virtually the same as a Duchenne patient or in very rare cases have an exceptionally mild form of the disease. At present we cannot predict which it would be. There are also quite a few unknowns with exon skipping such as the practical matters of adequate delivery of the AON into the cell, the possibility the new proteins (which are not identical to native dystrophin) might be recognized by the immune system as foreign and attacked with antibodies over time and the possibility of "off target effects" where there could be unintended effects etc. We also do not know if the FDA will require every of AON to be individually approved which could further delay use in patients.
Even if we assume a rapid deployment of this therapy to all applicable patients, we must be simultaneously looking at alternative therapies to replace the functions of the dystrophin molecule and the DGC since this does not fully replace dystrophin and there are obvious deficiencies; otherwise Becker patients would be normal.
It may be entirely possible to use other pharmacologic means (drugs, supplements etc.) to prevent the initial cellular injury and reduce the cascade of effects that follow downstream and lead to fibrosis and the eventual exhaustion of the satellite cells ability to replace the damaged myocytes. This will require a combination of drugs in a manner used for AIDS, many rheumatologic and malignant (cancer) diseases. Additionally, there needs to be continued research into ways to help reverse some of the fibrotic changes and allow for regeneration of functional muscle for boys and young men with advanced disease.
We have a little boy with this terrible disease and of course want a "magic bullet" to cure him, but my experience tells me it will take more than one thing to get to our common goal of as normal and long a life for all of our sons as possible. Exon skipping might be a big part the overall treatment for some or even many boys, but not a "cure".
I hope this helps answer some of your questions.
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AVI BioPharma and Collaborators Demonstrate In Vivo Effectiveness of PPMO-based Splice Switching Oligomers (SSOs) in Genetic Disease Target
For Immediate Release
PORTLAND, OR — January 12, 2009 — AVI BioPharma, Inc. (NASDAQ: AVII), a developer of RNA–based drugs, announced today new pre–clinical results published in Proceedings of the National Academy of Sciences (Saovaros Svasti et al (January 12, 2009) Proc. Natl Acad. Sci. USA, 10.1073/pnas 0805434105) demonstrating the effectiveness of a systemically delivered PPMO–based splice switching oligomer or SSO (a morpholino oligomer conjugated to an arginine–rich peptide) in vivo in a mouse model of an inherited blood disorder. The results show that PPMO–based SSOs may be effective in vivo not only in muscle cells for DMD treatment, but also for another genetic disease and in target cells more challenging than muscle fibers.
The paper’s co–authors include Drs. Ryszard Kole and Hong Moulton from AVI as well as Nobel laureate Dr. Oliver Smithies of the University of North Carolina. The research was conducted by scientists at the Departments of Pharmacology, Pathology and Lineberger Comprehensive Cancer Center, University of North Carolina and the Thalassemia Research Center, Mahidol University, Bangkok, Thailand in collaboration with AVI scientists.
“The significance of these findings includes confirmation that our PPMO–based SSOs are effective in additional tissues and cells, establishing the potential that this technology may be selectively applied to commercially viable genetic disease targets in the future,” said Ryszard Kole, Ph.D., SVP of Discovery Research at AVI BioPharma. “The results from this research were particularly impressive since immature red blood cells are challenging targets and other oligonucleotides that were tested were ineffective.”
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.
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Permalink Reply by Kelvinsmom - Michelle on
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Exon 53 skipping is said to be "next", whenever that does happen, at least some reports say that, including Kelvin's doctors, they say it is "ready" too. The compound for 53 has already been developed, at least that I understand (53 and a few others are "ready" already, but can't be tested and nothing can be done with it until 51 is "approved", but I just thought I'd add it, since my son needs 53 also. Michelle
BOZ4J said:Someone asked here about deletion 50,51 and Linden detabase . (2 patients diagnosed withDMD). My son can be example of debate if he is DMD or BMD. From genetic mutation he is DMD . By the symptoms ,I was already told by few doctors and other people in the field that he looks like he is Becker. Personally for me is not important how they will name it. They can call it BMD or Mild DMD, What is more important for us , what they can do about it . Clock is ticking.I already do not expeckt any big miracles with my son being 9,5 years old and exon 51 just starting trials , when 53 is what we need. The only miracles I can expect is the miracle in known pharmacology or stem cells.In mean time I do many things in my life to make sure that I do not hear the clock. I fixed my car today for example.. BUT no matter how busy I stay , how loud I am , I hear the clock .Good luck.As younger your kids are ,the biggest chance they have .
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Permalink Reply by MicahsDaddy on
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I was told by a researcher that every possible exon that is skippable has been developed. Just gotta wait through the process...
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