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Explanation: DMD transcript imbalance determines dystrophin levels

Explanation: DMD transcript imbalance determines dystrophin levels | Duchenne Research | Scoop.it

Since exon skipping modulates the amounts of dystrophin RNA transcripts (i.e. the DNA copies that are translated into protein), we wanted to study this in more detail. What we see is that much more dystrophin RNA and protein is produced in heart than skeletal muscle, and slightly more dystrophin in diaphragm than skeletal muscle. This may in part explain why exon skipping works less in heart than other muscles: if there is more transcripts, skipping levels will be lower even when similar amounts of antisense oligonucleotide (the exon skipping compound) end up in heart and a limb muscle (example: 10 AONs vs 100 dystrophin RNAs in e.g. calf muscle = 10% skip, but 10 AONs vs 1000 dystrophin RNAs in heart = 1% skip) (note that another part of the explanation is that antisense oligonucleotides reach the heart with lower efficiency, so this is part of the explanation, not the full explanation).

 

The next thing we show is that the dystrophin transcripts are not all complete, so the amount of transcripts containing exon 1/the beginning is higher than the amount of transcripts containing later exons/the end (and in order for the transcripts to be translated into a functional dystrophin, they have to be complete from start to end). The cause of this phenomenon (them not being complete) is not known. In healthy mouse muscle, there is a slight imbalance, in mdx muscle (without dystrophin) there is a much bigger imbalance (so the percentage of transcripts being incomplete is higher). When the reading frame is restored in mdx muscle by exon skipping, the imbalance is not restored. Also, in Becker patient muscles we see this imbalance - the level of imbalance is between that found in healthy muscle and muscle without dystrophin and varies a lot between Becker patients. To put it very simple, we find in Becker patients that the amount of dystrophin they produce relates not to the amount of dystrophin transcripts but to the amount of COMPLETE transcripts (this is very logical, but the imbalance of dystrophin has not been well studied, so we did not know this before).

 

ParentProjectMD's insight:

Annemieke Aartsma-Rus has provided the following explanation to the recently published article in The FASEB Journal:

"DMD transcript imbalance determines dystrophin levels"

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Sarepta Therapeutics Announces Fourth Quarter and Full-Year 2014 Financial Results and Recent Corporate Developments

Sarepta Therapeutics Announces Fourth Quarter and Full-Year 2014 Financial Results and Recent Corporate Developments | Duchenne Research | Scoop.it

- NDA submission for eteplirsen planned for mid-year 2015 -

- Plan to discuss new data and NDA submission with FDA in 2nd Quarter –

- Cash and Other Investments of $211 Million at Year End 2014 -

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Upcoming Webinar - Dystrophin 101: Everything You Always Wanted to Know About the Duchenne Protein (And Were Not Afraid to Ask)

Upcoming Webinar - Dystrophin 101: Everything You Always Wanted to Know About the Duchenne Protein (And Were Not Afraid to Ask) | Duchenne Research | Scoop.it

March 3, 2015 from 1pm to 2pm ET
This webinar will review the basic biology of dystrophin (the gene, structure-function of the protein, its role in the dystrop…

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March 3, 2015 from 1pm to 2pm ET

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Summit shares climb as unveils US listing plans

Summit shares climb as unveils US listing plans | Duchenne Research | Scoop.it
Shares in drug developer Summit jumped more than 10% on Monday as it told investors it continues to make progress on a number of fronts and unveiled plans to list on the NASDAQ exchange in the US.
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Rare feat: BioMarin rewrites playbook for small-market drug approvals

Rare feat: BioMarin rewrites playbook for small-market drug approvals | Duchenne Research | Scoop.it
BioMarin Pharmaceutical looks to Europe to save time and money in developing rare-disease drugs.
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Eli Lilly Tadalafil Phase 3 Trial has Completed Enrollment

Eli Lilly Tadalafil Phase 3 Trial has Completed Enrollment | Duchenne Research | Scoop.it
DuchenneConnect serves as a central hub linking the resources and needs of the Duchenne and Becker muscular dystrophy community: young men with Duchenne; their families and caregivers; and the provider community: clinical care providers, policymakers, industry professionals and the medical research fields.âWe offer registered members resources to: assist with early, appropriate and least invasive diagnosis; explore the benefits and limitations of genetic testing; offer access to resources and services, including care and treatment; and assist in understanding and development of new treatment trials.
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Prosensa Announces Shareholder Approval of Certain Matters Relating to the BioMarin Tender Offer (NASDAQ:RNA)

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Capricor Therapeutics Announces $10 Million Private Placement of Common Stock

Capricor Therapeutics Announces $10 Million Private Placement of Common Stock | Duchenne Research | Scoop.it
ParentProjectMD's insight:

"This capital raise will also fuel a clinical development program in our recently announced program to treat Duchenne Muscular Dystrophy (DMD) associated cardiomyopathy with CDCs, which we hope to be in the clinic in 2015. "

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Heart Failure Drugs Slow Deadly Damage in Duchenne, Offering New Hope

Heart Failure Drugs Slow Deadly Damage in Duchenne, Offering New Hope | Duchenne Research | Scoop.it
In a new study led by Dr. Subha Raman of The Ohio State University Wexner Medical Center, researchers were able to dramatically slow the rate of heart damage…
ParentProjectMD's insight:

Early use of available heart failure drugs slows the progressive decline in heart function before cardiac symptoms are apparent in boys and young men with Duchenne, according to a new study published online by The Lancet Neurology. Thank you for helping PPMD fund this promising research!

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Pfizer Initiates Phase 2 Study of PF-06252616 in Duchenne Muscular Dystrophy

Pfizer Initiates Phase 2 Study of PF-06252616 in Duchenne Muscular Dystrophy | Duchenne Research | Scoop.it
Pfizer Inc. announced today enrollment of the first patient in a multicenter Phase II clinical trial of the investigational compound PF-06252616 in boys with D…
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Summit Receives Regulatory Approval to Initiate a Modified Diet Clinical Trial of SMT C1100 in DMD Patients

Summit Receives Regulatory Approval to Initiate a Modified Diet Clinical Trial of SMT C1100 in DMD Patients | Duchenne Research | Scoop.it

Summit announces that it has received approval from the UK Medicines and Healthcare products Regulatory Agency and the Ethics Review Committee to initiate a Phase 1b modified diet trial of SMT C1100. SMT C1100 is an oral small molecule utrophin modulator in development for the potential treatment of all patients with DMD, regardless of the underlying dystrophin fault causing the disease. This new trial aims to increase the plasma levels of SMT C1100 by providing patients with specific dietary guidance intended to improve drug absorption.  The trial will also evaluate the potential impact that SMT C1100 is having on enzyme markers of muscle health.  Top-line data from the Phase 1b modified diet trial are expected to be reported in mid-2015.   

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Prosensa Wins Scrip 'Biotech Company of the Year' 2014 Award (NASDAQ:RNA)

Prosensa Wins Scrip 'Biotech Company of the Year' 2014 Award (NASDAQ:RNA) | Duchenne Research | Scoop.it

Prosensa Holding N.V. (NASDAQ: RNA), the biopharmaceutical company focusing on RNA-modulating therapeutics for rare diseases with a high unmet medical need, is delighted to have won the Scrip 'Biotech Company of the Year' Award for 2014, announced last week in London, UK.

The prestigious Scrip Awards provide an opportunity to acknowledge and applaud the highest achievers across the biotechnology and pharmaceutical industry, recognizing both corporate and individual accomplishments. The award for 'Biotech Company of the Year' is given to the company which has demonstrated the greatest achievements for the year.

Hans Schikan, CEO of Prosensa, said, "Winning Scrip's 'Biotech Company of the Year' Award is a great honor and a testament to the dedication and hard work of the Prosensa team.  Our drive to succeed is fueled by patients and their families, who continue to inspire us to make innovative therapies available as quickly and efficiently as possible."

The other five finalists were: Ablynx; Horizon Discovery; Isis Pharmaceuticals; Mesoblast; and Silence Therapeutics.

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PTC Therapeutics Announces Launch of Translarna™ (ataluren) in Germany

SOUTH PLAINFIELD, N.J., Dec. 3, 2014 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced that Translarna™ (ataluren) is now commercially available to patients in Germany, the first country to launch in the European Union (EU), with first shipments expected to begin this week.  

"The launch of Translarna in Germany marks another exciting milestone for the DMD community," said Stuart W. Peltz, Ph.D., Chief Executive Officer of PTC Therapeutics.  "Through our reimbursed early access programs and commercial efforts, we are working hard to bring Translarna to those who may benefit from this drug. We remain committed to bringing Translarna to patients in Europe, and around the world, as quickly as possible.  We know every day counts for the patients and their families."  

The launch follows the European Commission marketing authorization, which was received in August 2014 for the use of Translarna to treat ambulatory patients with nonsense mutation Duchenne muscular dystrophy who are 5 years and older. A confirmatory Phase 3 clinical trial of Translarna, ACT DMD, in nonsense mutation Duchenne muscular dystrophy patients completed enrollment in September 2014. Top-line data is expected in the fourth quarter of 2015. Currently, Translarna is not approved for use in the United States.

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Sarepta Therapeutics to Host Webcast and Conference Call for the Duchenne Muscular Dystrophy Community on December 2, 2014

Sarepta Therapeutics to Host Webcast and Conference Call for the Duchenne Muscular Dystrophy Community on December 2, 2014 | Duchenne Research | Scoop.it
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Parent Project Muscular Dystrophy & Foundation to Eradicate Duchenne Award $1 Million Grant to ReveraGen BioPharma

Parent Project Muscular Dystrophy & Foundation to Eradicate Duchenne Award $1 Million Grant to ReveraGen BioPharma | Duchenne Research | Scoop.it
Parent Project Muscular Dystrophy (PPMD) is excited to join forces with Foundation to Eradicate Duchenne (FED) to award ReveraGen BioPharma (ReveraGen) a $1…
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PPMD Awards University of Missouri $50,000 Exploratory Grant to Explore SERCA2A in Duchenne Dog Study

PPMD Awards University of Missouri $50,000 Exploratory Grant to Explore SERCA2A in Duchenne Dog Study | Duchenne Research | Scoop.it
PPMD has awarded a $50,000 Exploratory Grant to University of Missouri to test SERCA2A gene therapy as a potential treatment for dogs with Duchenne. Dr. Dongs…
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Parent Project Muscular Dystrophy Awards UCLA $50,000 Exploratory Grant for Evaluation of Exon Skipping Enhancers in Duchenne

Parent Project Muscular Dystrophy Awards UCLA $50,000 Exploratory Grant for Evaluation of Exon Skipping Enhancers in Duchenne | Duchenne Research | Scoop.it
PPMD announced today that they will award Dr. M. Carrie Miceli and her team at UCLA’s David Geffen School of Medicine and College of Letters and Science, a $5…
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Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016

Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016 | Duchenne Research | Scoop.it
A Northbrook company said it has won fast-track status for approval of a drug that could become the first in the United States to treat Duchenne muscular dystrophy , a fatal muscle disease found most often in boys.
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Sarepta Therapeutics Announces First Patient Dosed in European Phase I/II Study of SRP-4053 in Duchenne Muscular Dystrophy Patients

Sarepta Therapeutics Announces First Patient Dosed in European Phase I/II Study of SRP-4053 in Duchenne Muscular Dystrophy Patients | Duchenne Research | Scoop.it

Sarepta Therapeutics Inc. today announced that it has initiated dosing of SRP-4053 in its first human trial, a Phase I/II study in Duchenne muscular dystrophy (DMD). This multiple-dose study will assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in DMD patients with genotypes amenable to exon-53 skipping.

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Sarepta Therapeutics Inc - Investors - News Release

Sarepta Therapeutics Inc - Investors - News Release | Duchenne Research | Scoop.it

Sarepta Therapeutics Reports Long-Term Outcomes through 168 Weeks from Phase IIb Study of Eteplirsen in Duchenne Muscular Dystrophy

ParentProjectMD's insight:

“PPMD’s benefit-risk pilot data demonstrated that parents’ highest priority is to slow DMD progression. With this priority in mind, these Phase II data have exceeded our expectations” said Pat Furlong, Founding President and CEO of Parent Project Muscular Dystrophy (PPMD), a nonprofit organization focused on finding a cure for Duchenne muscular dystrophy. “In practical terms, continued ambulation and preservation of respiratory function have immense benefit for individuals with Duchenne. It is important to keep in mind, that individuals participating in this study lived with Duchenne for over 9 years on average prior to receiving eteplirsen, an age when the pathological process that occurs based on the absence of dystrophin is typically well underway. Understanding this, in the eyes of the community these Phase II data are significant and represent an important step toward changing the landscape.”

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Tivorsan Pharmaceuticals Achieves Key Development Milestones under its Parent Project Muscular Dystrophy and Muscular Dystrophy Association Awards

Tivorsan Pharmaceuticals Achieves Key Development Milestones under its Parent Project Muscular Dystrophy and Muscular Dystrophy Association Awards | Duchenne Research | Scoop.it
Tivorsan Pharmaceuticals, Inc. (Tivorsan) today announced that it met its fourth (4th) set of critical milestones under its existing grants from Paren
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PTC Therapeutics Begins Rolling NDA Submission to the FDA for Translarna to Treat Duchenne Muscular Dystrophy (NASDAQ:PTCT)

PTC Therapeutics, Inc. today announced that it has commenced a rolling submission of a New Drug Application (NDA) to the United States Food and Drug Administration (FDA) for Translarna™ for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). A rolling submission allows completed portions of the application to be submitted and reviewed by the FDA on an ongoing basis. PTC expects to finalize the application in the fourth quarter of 2015 following the completion of the ACT DMD confirmatory Phase 3 clinical trial.

ParentProjectMD's insight:

We are excited that PTC will begin their rolling NDA submission to the FDA for Translarna! There is so much hope for 2015 in this community. Thank you to ALL of the companies that remain dedicated to our mission – end Duchenne.

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PPMD To Collaborate With Catabasis Pharmaceuticals, Inc. On CAT-1004 Development

PPMD To Collaborate With Catabasis Pharmaceuticals, Inc. On CAT-1004 Development | Duchenne Research | Scoop.it
Parent Project Muscular Dystrophy (PPMD) announced today a collaboration with Catabasis Pharmaceuticals, Inc. (Catabasis) to assist in a Phase 2 clinical tri…
ParentProjectMD's insight:

We are excited to announce a collaboration with Catabasis Pharmaceuticals, Inc. to assist in a Phase 2 clinical trial of its CAT-1004 product candidate for the treatment of patients with Duchenne. As part of this collaboration, PPMD will provide funding to support participant travel. The trial is expected to begin in the first half of 2015. Click below to learn more about CAT-1004.

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Parent Project Muscular Dystrophy Awards Akashi Therapeutics, Inc. $500,000 Grant

Parent Project Muscular Dystrophy Awards Akashi Therapeutics, Inc. $500,000 Grant | Duchenne Research | Scoop.it
Parent Project Muscular Dystrophy (PPMD) has awarded Akashi Therapeutics, Inc. (Akashi) a $500,000 grant to fund clinical trials to test the safety and effica…
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TREAT-NMD : Message on Carmeseal-MD™ on behalf of UPPMD and TREAT-NMD

TREAT-NMD : Message on Carmeseal-MD™ on behalf of UPPMD and TREAT-NMD | Duchenne Research | Scoop.it
Advancing diagnosis, care and treatment for people with neuromuscular diseases around the world.
ParentProjectMD's insight:

You may have seen the recent announcement from Phrixus about the availability of Carmaseal(TM) in the European Union (http://bit.ly/15SF1GN). UPPMD and TREAT-NMD have released a comment that provides more information about this topic.

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PPMD and Santhera Pharmaceuticals Team Up on New Benefit/Risk Study Focused on Pulmonary Therapies

PPMD and Santhera Pharmaceuticals Team Up on New Benefit/Risk Study Focused on Pulmonary Therapies | Duchenne Research | Scoop.it
PPMD is proud to announce a collaboration with Santhera Pharmaceuticals on a benefit/risk study that will focus specifically on patient and caregiver preferen…
ParentProjectMD's insight:

We are proud to announce a collaboration with Santhera Pharmaceuticals on a new benefit/risk study that will focus specifically on patient and caregiver preferences regarding pulmonary therapies in the disease, and will be based on data from Santhera’s successful phase III clinical trial of idebenone. 

PPMD will be reaching out to the community in the coming months to participate in this new study. Both patients and caregivers will be able to participate, even if you participated in PPMD’s previous benefit/risk study. We hope you’ll add your experiences so that we can continue to provide the FDA with as much information as possible in order to accelerate the decision-making process!

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