Latest Developments in DMD Research

Duchenne Muscular Dystrophy (DMD) is a genetic
disorder that results in progressive muscle wasting and weakness in boys. A boy inherits DMD when he receives an X chromosome that fails to make the protein dystrophin, an essential building block of healthy muscle.

Current treatments for DMD consist primarily of steroids and physical support, such as braces, wheelchairs, and ventilators. While there have
been breakthroughs in understanding the disease,
there is no known cure.

Current Research

The Jett Foundation has submitted millions of dollars to support research and total care of the DMD child. We are pleased to say that other organizations like Charley’s Fund and Parent Project DMD have also been a strong force in sharing information and supporting groundbreaking research. We have gathered information here from those sites plus our own to share the latest research with you.

AT Still University of Health Sciences – Dr. George Carlson Anti Inflammatory Agents
Dr. Carlson is evaluating the utility of anti-inflammatory agents that prevent muscle cell death as potential treatments for DMD. Two of the drugs he is testing are currently in widespread use for other illnesses. Research indicates that they inhibit the NFkB pathway, an intervention that should have clinical benefit for boys with DMD. Dr. Carlson is administering the drugs to mice with muscular dystrophy and evaluating functional improvement.

AVI Biopharma – Portland, OR Exon Skipping
Together with Ercole Biotech, this Portland, OR-based company holds the predominant patent estate for exon skipping technology. We have funded a one-year project to conduct research and preclinical testing. AVI is collaborating with Dr. Qi Lu of Carolinas Medical Center and Dr. Steve Wilton of U of Western Australia in worldwide team effort to move this promising treatment forward.

BioFocus DPI – Netherlands Utrophin Upregulation
Dr. David Fischer’s team is developing a highly sensitive assay to measure expression of the protein utrophin in human muscle cells. Increasing production of utrophin can compensate for the absence of dystrophin in DMD patients. The high-through put assay will allow for the screening of potentially useful drugs

Brown University – Justin Fallon, PhD – Biglycan
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in DMD boys. Dr. Fallon has discovered that a protein called biglycan can upregulate utrophin expression in a muscular dystrophy mouse model. He has observed other beneficial effects of biglycan, including reduction of muscle fiber cell death. In Dr. Fallon’s previous studies, a single dose of biglycan was effective in the mouse model for three weeks. Dr. Fallon is currently testing biglycan in the mouse model to determine whether mice treated with biglycan show functional improvement.

Carolinas Medical Center – Qi Lu, PhD – Exon Skipping
Complementing Prosensa’s work, Principal Investigator Dr. Qi Lu and his team are fine-tuning systemic delivery of exon skipping. In a recently published paper, Dr. Lu showed for the first time that systemic delivery of exon skipping leads to functional improvement in a mouse model. Read Dr. Lu’s article in Nature Medicine Prosensa and Dr. Qi Lu, two of the world leaders in exon skipping, are now collaborating for the first time.

Children’s National Medical Center – Dr. Kanneboyina Nagaraju Testing supplements and pre-approved drugs in a mouse model
Dr. Nagaraju is investigating four experimental drugs (Celastrol, Resveratrol, Lipoxin A, Cyclosporine A analog) that may prevent muscle degeneration and increase muscle function. This project tests these drugs in the DMD mouse model, so we can determine whether human clinical trials are warranted.

Columbus Children’s Research Institute – Paul Martin, PhD – Galgt2
From previous studies, Dr. Martin concluded that Galgt2, a protein that adds sugars to other proteins, could be a therapeutic target for a treatment for DMD. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 overexpression may ameliorate the dystrophic condition. Dr. Martin is now developing a reporter cell line that can be used to screen compounds that would activate the human Galgt2 promoter, thereby causing overexpression of the protein.

CombinatoRx – Cambridge, MA
CombinatoRx, a unique pharmaceutical company focused on developing new medicines built from synergistic combinations of approved drugs. Our funding is being used for a 2-year research program with the specific aim of developing a treatment for DMD. CombinatoRx has assembled a highly qualified and motivated team for their DMD research. They are looking at millions of combinations of drugs that have been approved for other uses to see if any of the compounds can work in tandem to slow or stop the relentless progression of DMD. Click here to read a recent article about CombinatoRx in the New York Times.

DMDeTank – Worldwide Assay Development
InnoCentive, a web based company that matches top scientists from around the globe with relevant R&D challenges, has compiled a “virtual” think tank of DMD and drug development experts. The e-Tank is:

• identifying key problems facing DMD researchers
• seeking solutions via the world wide web for financial reward
• applying solutions to expedite therapeutics development

Project Catalyst - South Plainfield, NJ – Small Molecule Therapy
Project Catalyst is a targeted research program designed to develop oral medications that can delay muscle degeneration in DMD. The research is being conducted by PTC Therapeutics, a New Jersey biotech firm that currently has a DMD drug in Phase II human clinical trials. This drug, called PTC 124, will benefit 10-15% of boys with DMD who have a particular genetic mutation called a “stop codon” or “nonsense mutation.” PTC is now selecting additional drug candidates that will help the remaining 85% of children with DMD.

Prosensa - Leiden, The Netherlands – Exon Skipping
A Dutch biotechnology firm that is developing a novel therapy for DMD called exon skipping. One month later, Prosensa was the first company in the world to earn orphan drug status from the FDA for this therapy. Prosensa has begun the first-ever human clinical trial of exon skipping. Read press release. In this trial, researchers are injecting the biceps of boys with DMD to test safety and efficacy. The next step is to test intravenous systemic delivery so the therapy can be targeted to all the muscles of the body. For more information about this clinical trial, read an interview with Gerard Platenburg, Prosensa’s CEO 2008)

Prosensa announces the start of an international multi-center phase I/II clinical study with ‘smart drug’ PRO051 in patients with Duchenne Muscular Dystrophy(read more)

Summit plc (formerly VASTox plc) – United Kingdom Utrophin Upregulation
A UK-based biotechnology company, Summit plc is searching for new drugs that will increase expression of the protein utrophin. We teamed up with the Nash Avery Foundation to pay for Summit to purchase a library of 30,000 compounds so they can expand their search. Utrophin can compensate for dystrophin, the missing protein in DMD boys.

Mass General Hospital – Brian Tseng, MD, PhD – Molecular Sealant
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with DMD and strengthen the membranes. The sealant, called Poloxamer 407, is approved for use in commonly used mouthwashes and drugs. It is currently undergoing human clinical trials for other diseases.

University of Leuven, Belgium – Maurilio Sampaolesi, PhD Stem Cells
The most promising long term therapeutic strategy for DMD is correcting the genetic defect at the DNA level. Dr. Sampaolesi is developing a program for the stem cell treatment of DMD patients. He is investigating methods to culture specific stem cells called "multipotent adult progenitor cells" for potential use as therapeutic gene therapy agents. Having a supply of stem cells will permit Dr. Sampaolesi to investigate the mode of delivery that will affect as many muscle cells as possible and assess the type, number and quality of clinical grade stem cells required to obtain FDA approval to proceed with a clinical trial on DMD patients.

University of Minnesota - James Ervasti, PhD – TAT-Utrophin
Dr. Ervasti has come up with a way to transport utrophin - a protein that can act as a substitute for dystrophin -- to the muscle cells. This approach requires that utrophin is attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the chimera’s optimal dosage, frequency of administration, and mode of delivery.

University of Nevada, Reno – Dr. Dean Burkin Alpha-7 Integrin upregulation
Dr. Burkin, assistant professor of pharmacology, has developed an assay (scientific test) to identify compounds that can increase the production of alpha-7 integrin, a protein that stabilizes muscle membranes. With our support, Dr. Burkin is using his assay to search two libraries of FDA-approved drugs. We will use his assay to screen other drug libraries to expand the search for drugs that can counteract the muscle degeneration brought on by DMD.

UNC Animal Models Core Facility – Randy Thresher, PhD – New Mouse Model
UNC animal models core facility to develop a genetically modified mouse that mimics DMD in a human. Unlike the most widely used mouse in DMD research (mdx mouse), this new animal model contains human genetic material. This new model will be used to test the efficacy of systemic exon skipping, a required step before moving into human clinical trials.

University of Washington – Stanley Froehner, PhD – Phosphodiesterase Inhibitors
Dr. Froehner is testing phosphodiesterase inhibitors as potential drugs to treat DMD. PDE inhibitors may reduce inflammation, improve blood flow in the muscle, upregulate utrophin and inhibit myostatin, a negative regulator of muscle mass.

University of Western Australia – Dr. Steve Wilton Exon Skipping
Research pioneer Steve Wilton, PhD is developing an exon-skipping “cocktail” which will measure skipping efficiency in DMD patient cells. This research complements the work being done by AVI Biopharma, the biotechnology firm in Portland, OR that we are funding. Dr. Wilton’s work will help make exon skipping applicable to more children with DMD.

PTC Therapeutics PTC124 Clinical Trial Update
PTC124 targets a genetic change known as a nonsense mutation. A nonsense mutation causes a genetic disorder by prematurely stopping the production of a critical protein. PTC124 may have the potential to treat genetic disorders in patients for whom a nonsense mutation is the basis for the disease, as it is in some cases of Duchenne/Becker muscular dystrophy (DMD/BMD) and cystic fibrosis (CF). Over the past two years PTC Therapeutics has completed short-term clinical trials of PTC124 in DMD and CF; a summary of the results of these trials is available on our website (http://www.ptcbio.com/ptc124_summary).

PTC has now initiated a longer-term clinical study of PTC124 in patients with DMD/BMD in which the production of the dystrophin (muscle protein) is prematurely stopped. The main goals of this study are to determine whether PTC124 can improve walking, activity, muscle function, and strength and whether the drug can safely be given over a period of many months. This study is also intended to generate the information required to support PTC124 approval by the regulatory authorities so it can be made more broadly available. The study will be conducted in 11 countries on 4 continents.

To be considered for this study, patients must have had a DNA blood test to evaluate the dystrophin gene and know that a nonsense mutation is the basis for their DMD/BMD. This test is known as genotyping or full-length gene-sequencing. Facilities that perform gene-sequencing can be located through the Gene Tests website (www.genetests.org); click “Laboratory Directory” to search for the locations of gene-sequencing facilities using the search term “dystrophinopathies.”

In addition to having a nonsense mutation, study participants must be at least 5 years of age and be able to walk at least 75 meters (80 yards) unassisted in a 6-minute time period. They must also have exhibited evidence of DMD/BMD based on the medically documented onset of characteristic clinical symptoms or signs (ie, muscle weakness, waddling gait, Gowers' maneuver) by 9 years of age, an elevated creatine kinase level in the blood, and ongoing difficulty with walking. Other inclusion criteria will be explained prior to trial enrollment.

Study participants will be randomly assigned to receive either a higher dose of PTC124, a lower dose of PTC124, or a placebo (an inactive drug powder that looks and tastes the same as PTC124). The trial will be double blind, meaning that neither the researcher nor the patient will know which treatment the patient has been assigned.

Several of the approximately 38 study sites for the trial have already opened and all but a few of the rest are expected to open in May or June, with the remaining ones to follow shortly thereafter. All of the planned sites are listed on www.clinicaltrials.gov (search on PTC124) and on our website (www.ptcbio.com/PTC124_clinical_trial_locations). As soon as sites are open, contact details will be posted and participants or their families can contact a site directly to inquire about study participation. Personnel at the site will explain the study procedures and the potential benefits and risks associated with participation. Potential participants will be given an informed consent form further explaining the trial; once they have signed the form, they will be screened and considered for enrollment.

Please visit www.clinicaltrials.gov for a list of sites and more information about inclusion/exclusion criteria for the trial and or our website (www.ptcbio.com/ptc124_clinical_trials) for a map of trial sites and answers to frequently asked questions about the trial.

A study of PTC124 in people with cystic fibrosis due to a nonsense mutation and a DMD Phase 2a extension study are being planned to start over the coming months. Depending upon the progress of the program, we hope to conduct clinical studies in additional nonsense-mutation-mediated genetic disorders in the future.

Our patient advocacy team is happy to answer any questions you may have. Please contact us at patientinfo@ptcbio.com.

Additional studies and research

Santhera
a Swiss biotechnology company developing a drug (calpain blocker) that aims to slow the progression of DMD.

Asklepios
a biopharmaceutical company that recently launched the first human gene therapy trial targeting DMD Read article.

Johns Hopkins University – Hal Dietz, MD
Dr. Dietz recently found that a commonly prescribed blood pressure medication, Losartan, improved muscle regeneration and repair in the mdx mouse model. Researchers are in the process of organizing a clinical trial for DMD cohorts.

HCT – 1026
A group in Italy recently described the use of a nitric oxide (NO)-releasing compound that also functions as an anti-inflammatory. The drug, called HCT-1026, behaves as an NO donor (stimulating the up regulation of NOS). HCT1026 was tested in mice with muscular dystrophy for one year and was shown to slow the progression of the dystrophic condition. Human clinical trials are being considered.

Stem Cell Therapy – Dr. Giulio Cossu
Giulio Cossu and co-workers in Milan reported in the November 30, 2006 issue of Nature that dogs with muscular dystrophy who received a type of stem cell called mesangioblasts from a single donor had significant improvement over untreated control animals. Human clinical trials are being considered in the next two to three years.

Myo-029 – Wyeth Pharmaceutical
An antibody that inhibits myostatin activity (Myo-029) has been tested in Phase I/II clinical trials. Results from the trial will be released in the spring of 2007

Trichostatin A – Dr. Lorenzo Puri – Burnham Institute
Trichostatin A (TSA), used to treat breast cancer patients, was found to regenerate wasted muscles in a mouse with muscular dystrophy. Plans for human trials are currently being defined. (From PPMD)

NEW
(5/5/2008) FAQ for Phase 2b DMD-BMD PTC Trial (read more)

NEW
(5/2/2008) Update on Research Approaches for a Therapy of Duchenne Muscular Dystrophy

The Jett Foundation is not responsible for the accuracy of the content contained in the research articles posted on our website.

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