just no other dmd drug offers what Sarepta's does..simple
it is only future earnings / just a short sale excuse.
when and if''bmrn drug goes to market it will be very toxic to treat with that drug long term.''GSK knew this'' the very low benefit of that drug along with toxic outcomes is crazy.
O'Donovan L, Okamoto I, Arzumanov AA, et al.
Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy. [Journal Article] Nucleic Acid Ther 2015 Feb; 25(1):1-10.
Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy. Abstract
We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the SELection of PEPtide CONjugates (SELPEPCON) approach previously developed for parallel peptide-peptide nucleic acid (PNA) synthesis. However, these new methods allow for the utilization of commercial PMO as cargo with both C- and N-termini unfunctionalized. The synthetic methods involve conjugation in solution phase, followed by rapid purification via biotin-streptavidin immobilization and subsequent reductive release into solution, avoiding the need for painstaking high-performance liquid chromatography purifications. The synthesis methods were applied for screening of PMO conjugates of a 16-member library of variants of a 10-residue ApoE peptide, which was suggested for blood-brain barrier crossing. In this work the conjugate library was tested in an exon skipping assay using skeletal mouse mdx cells, a model of Duchene's muscular dystrophy where higher activity peptide-PMO conjugates were identified compared with the starting peptide-PMO. The results demonstrate the power of the parallel synthesis methods for increasing the speed of optimization of peptide sequences in conjugates of PMO for therapeutic screening.
you may want to look up the full whole thing.
GAINESVILLE, Fla. — Patients with the most common form of muscular dystrophy, Duchenne, often lose the ability to walk by the time they reach age 12 and typically only live to reach their 20s. Now, University of Florida Health researchers are participating in a key late-stage clinical trial that could lead to a new therapy for some children with this condition.
Sarepta Therapeutics will provide up to $1.6 million to UF Health to serve as a major site for the third phase of a clinical trial that, if successful, could help some patients with Duchenne maintain mobility and pulmonary function longer.
Early results from the first two phases of the clinical trial for a drug called eteplirsen have been promising in some patients with the disease, extending the length of time they were able to walk compared with a control group of study participants who did not receive the drug, said Barry Byrne, M.D., Ph.D., principal investigator for the hub site at UF Health and a professor of pediatrics in the College of Medicine.
Results announced in January from the second phase of the study showed that participants were still able to walk and had stable respiratory function 168 weeks into the study.
Duchenne muscular dystrophy is an inherited condition that occurs when a faulty gene located on a person’s X chromosome prevents the body from producing the protein dystrophin. Dystrophin plays a key role in helping muscles remain intact and protecting them from injury. Because the gene is found on the X chromosome, the condition only affects boys because they have only one X chromosome. Girls have two, giving them an extra dystrophin gene that works properly.
The hope is that in some Duchenne patients, eteplirsen can be used to produce a shorter-than-typical version of the dystrophin gene. The idea is similar to what occurs naturally in patients with another form of muscular dystrophy, Becker muscular dystrophy, Byrne said.
HARD WORKING MAN,,
notes from last year...
Jun 5, 2014 ... Shire's Best Takeover Defense Is Deal Offense: Real M&A .... Shire also could
consider buying Prosensa or Sarepta Therapeutics to expand in ...
State of Rare: Taking Stock of Rare Disease Research Today & Tomorrow
Monday, February 23 2015
9:00 am – 10:30 am
Location: Great Hall, Massachusetts State House, Boston
There are approximately 30 million people living with a rare disease in the USA,between 27 and 36 million in the EU, and collectivelyaround the globe, the rare disease community is estimated to include 350 million people. There are more than 7,000 rare diseases, many of them with no treatment or cure.
Many rare disease therapies are under development in Massachusetts and these leading researchers are pushing for accelerated approval pathways.
This second annual Rare Disease Day panel discussion will feature key leaders in orphan drug development, emphasize the importance of research and development in rare disease, and highlight the role that patients play in bringing much-needed therapies to market.
Norman Barton, M.D., Ph.D., Vice President, Clinical Development, Shire
Ed Kaye, M.D., Senior Vice President, Chief Medical Officer, Sarepta Therapeutics
Karen Peluso, Executive Director, Neurofibromatosis Northeast
Steve Uden M.D., Senior Vice President, Research, Alexion Pharmaceuticals
"While efforts to develop antiviral therapies are important, provision of high-quality supportive care that includes diligent fluid and electrolyte repletion is fundamental to treating patients infected with Ebola virus," Dr. West said. "Based on the available evidence to date, these supportive interventions are likely to be key factors in improving survival from Ebola virus disease."
Dr. Patrick L. Iversen from Sarepta Therapeutics, Inc. in Cambridge, Massachusetts, has studied several compounds for their activity against Ebola virus.
"Both brincidofovir from Chimerix and TKM-Ebola have been used in humans in the current Ebola outbreak but efficacy data are limited or adverse events have been severe so I would not recommend them," Dr. Iversen, also at Oregon State University in Corvallis, told Reuters Health by email.
"The selective estrogen receptor agonists such as toremifene and the antimalarial agent chloroquine have demonstrated efficacy in mouse models of Ebola at more modest doses than favipiravir and both are readily available suggesting equivalent rationale to favipiravir for current human studies," he said.
A compound under development by Sarepta (AVI-7537) and a Biocryst compound (BCX4430) have also shown promise in animal models, and both are in phase 1 trials in humans.
Dr. Iversen concluded, "The most ethical approach to Ebola patients would be to use the most advanced Ebola antiviral drugs, those agents that have demonstrated efficacy in multiple animal models including nonhuman primates and those agents with human safety data. Pharmacokinetic data comparisons between nonhuman primates and humans would also be preferred over comparisons between mouse and human."
OLIGOMER 2015 OXFORDWelcome to OLIGO 2015 Oxford We are delighted to announce our first Oxford Symposium on antisense and therapeutic oligonucleotides.
The symposium is aimed at bringing together chemists and biologists from academia and industry to discuss the latest advances and breakthroughs in the development of synthetic oligonucleotides as therapeutics. We hope this symposium will form the foundations of an annual gathering of oligonucleotide researchers at Oxford.
The symposium agenda is currently in progress. We invite proposal for oral presentations, in particular on THERAPEUTIC APPLICATIONS AND DELIVERY STRATEGIES of synthetic oligonucleotides, including:
Toxicity and pharmacokinetics
Effective therapies for the prevention and treatment of the deadly Ebola virus are urgently needed. A promising approach involves the use of synthetic antisense molecules called phosphorodiamidate morpholino oligomers (PMOs), which are able to target viral mRNA and suppress translation.
US researchers have previously shown that a combination PMO targeting genes that code for two proteins, VP24 and VP35, protected monkeys from lethal Ebola virus infection. Now, the team has found that a PMO targeting VP24 alone conferred protection, whereas a PMO targeting VP35 alone was ineffective.
The finding suggests that VP24 is an important virulence factor encoded by the Ebola virus, the researchers conclude in mBio (online, 10 February 2015). Furthermore, using a single PMO will simplify drug development and regulatory approval.
Use of the compounds PMO and 2OMePS as currently in clinical trials is limited by their low efficiency and high variability in exon skipping and dystrophin induction in all muscles, as revealed from studies in both animal models and the clinical trials. One special concern is the very low efficiency of exon skipping in cardiac muscle, which in boys with DMD is severely affected by the lack of dystrophin expression. Results from animal model studies suggest that a detectable dystrophin induction in cardiac muscle will require biweekly injections of PMO at 60 mg/kg.23 This has led to the use of cationic peptides and other polymers to improve the efficiency of PMO delivery.15,16,24–28 PMOs conjugated with an arginine-rich peptide (PPMO) were able to restore dystrophin expression to near-normal levels in bodywide skeletal muscle and to approximately 50% in cardiac muscle at a dose of 30 mg/kg by single injection. Such high levels of dystrophin expression significantly improved function of both skeletal and cardiac dystrophic muscle.15 However, it is well documented that the use of positively charged peptides and polymers increases toxicity considerably.15,16,26–28 This together with the requirement of lifelong AO drug administration for treating DMD necessitates investigation of these modified PMOs for their long-term applicability and efficacy in relevant animal models in vivo.
In the present study, we investigated the acute toxicity and dose-related 1-year efficacy of PPMO treatment targeting mouse dystrophin exon 23 systemically in dystrophic mdx mice. Our results show that PPMO has a high level of acute toxicity (the LD50 is approximately 85 mg/kg). However, the effective dose for inducing 20% dystrophin in skeletal muscle and 5% dystrophin in cardiac muscle requires only 6 mg/kg biweekly injections with no obvious acute or chronic adverse effects were detected. PPMO could therefore be an effective candidate compound as AO drugs for long-term treatment of DMD.