Duchenne – What is it?
Duchenne
Duchenne is the most prevalent, genetically inherited neuromuscular disorder worldwide and affects 1 in 3500 young males. This disorder is caused by mutations or deletions that prohibited the production of dystrophin. The lack of dystrophin in muscles of DMD patients leads to the wasting of these boy’s muscles. In Duchenne patients, the regenerative potential of dystrophic muscle fibers diminishes over time, resulting in progressively severe muscle wasting. This loss of muscle mass causes patients to be confined to wheelchairs in their early teenage years and to die by the second or third decade of life as a result of cardiac or respiratory failure. Although the molecular defect responsible for DMD was identified 20 years ago, there is still no effective treatment available for this devastating disease. Doctors recommend daily stretching and the use of corticosteroids that provides minimal short term benefits.
Symptoms
The muscle weakness associated with muscle wasting with the voluntary muscles being first affected, especially the pelvis and calf muscles. Muscle weakness also occurs in the arms, neck, and other areas, but not as early as in the lower half of the body. Symptoms usually appear before age 6 and may appear as early as infancy. Generalized weakness and muscle wasting first affecting the muscles of the hips, pelvic area, thighs and shoulders. Calves are often enlarged. The other physical symptoms are:
· Awkward manner of walking, stepping, or running. (patients tend to walk on their forefeet, because of an increased calf tonus. Also, toe walking is a compensatory adaptation to knee extensor weakness.)
· Frequent falls
· Fatigue
· Motor skills (running, hopping, jumping)
· Increased Lumbar Lordosis, leading to shortening of the hip-flexor muscles. This has an effect on overall posture and a manner of walking, stepping, or running.
· fibrosis occurs in connective tissue
· Progressive difficulty walking
· Muscle fibre deformities
· Pseudohypertrophy(enlarging) of tongue and calf muscles. The enlarged muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy.
· Higher risk of behavior and learning difficulties, due to adjustment problems and muscular fatigue.
· Eventual loss of ability to walk (usually by the age of 12)
· scoliosis in some cases
Signs and tests
· Gowers' sign reflects the more severe impairment of the lower extremities muscles. The child helps himself to get up with upper extremities: first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright.
· Affected children usually tire more easily and have less overall strength than their peers.
· Creatine kinase (CPK-MM) levels in the bloodstream are extremely high.
· Genetic testing can reveal genetic errors in the Xp21 gene.
Diagnosis
1) DNA Test
DNA testing and analysis can usually identify the specific type of mutation of the exon or exons that are affected. DNA testing confirms the diagnosis in most cases.
2) Muscle Biopsy
If DNA testing fails to find the mutation, a muscle biopsy test may be performed. A small sample of muscle tissue is extracted (usually with a scalpel instead of a needle) and a dye is applied that reveals the presence of dystrophin. Complete absence of the protein indicates the condition. Over the past several years DNA tests have been developed that detect more of the many mutations that cause the condition, and muscle biopsy is not required as often to confirm Prenatal tests. If one or both parents are 'carriers' of a particular condition there is a risk that their unborn child will be affected by that condition. 'Prenatal tests' are carried out during pregnancy, to try to find out if the fetus (unborn child) is affected. The tests are only available for some neuromuscular disorders. Different types of prenatal tests can be carried out after about 11 weeks of pregnancy. Chorion villus sampling (CVS) can be done at 11–14 weeks, and amniocentesis after 15 weeks, while fetal blood sampling can be done at about 18 weeks. Women and/or couples need to consider carefully which test to have and to discuss this with their genetic counselor. Earlier testing would allow early termination, but it carries a slightly higher risk of miscarriage than later testing (about 2%, as opposed to 0.5%).
Treatment
There is no known cure for Duchenne, although recent stem-cell research is showing promising vectors that may replace damaged muscle tissue. Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life, and include the following.
· Prednisone and Deflazacort increase energy and strentgh
· Bed rest can worsen the muscle disease.
· Physical therapy is helpful to maintain muscle strength, flexibility, and function.
· Supplements and vitamins can help with the disease.
· Appropriate respiratory support as the disease progresses is important
Prognosis
Duchenne is currently an incurable terminal disease that eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. The life expectancy typically ranges from the late teens to the mid-20s.
Duchenne is the most prevalent, genetically inherited neuromuscular disorder worldwide and affects 1 in 3500 young males. This disorder is caused by mutations or deletions that prohibited the production of dystrophin. The lack of dystrophin in muscles of DMD patients leads to the wasting of these boy’s muscles. In Duchenne patients, the regenerative potential of dystrophic muscle fibers diminishes over time, resulting in progressively severe muscle wasting. This loss of muscle mass causes patients to be confined to wheelchairs in their early teenage years and to die by the second or third decade of life as a result of cardiac or respiratory failure. Although the molecular defect responsible for DMD was identified 20 years ago, there is still no effective treatment available for this devastating disease. Doctors recommend daily stretching and the use of corticosteroids that provides minimal short term benefits.
Symptoms
The muscle weakness associated with muscle wasting with the voluntary muscles being first affected, especially the pelvis and calf muscles. Muscle weakness also occurs in the arms, neck, and other areas, but not as early as in the lower half of the body. Symptoms usually appear before age 6 and may appear as early as infancy. Generalized weakness and muscle wasting first affecting the muscles of the hips, pelvic area, thighs and shoulders. Calves are often enlarged. The other physical symptoms are:
· Awkward manner of walking, stepping, or running. (patients tend to walk on their forefeet, because of an increased calf tonus. Also, toe walking is a compensatory adaptation to knee extensor weakness.)
· Frequent falls
· Fatigue
· Motor skills (running, hopping, jumping)
· Increased Lumbar Lordosis, leading to shortening of the hip-flexor muscles. This has an effect on overall posture and a manner of walking, stepping, or running.
· fibrosis occurs in connective tissue
· Progressive difficulty walking
· Muscle fibre deformities
· Pseudohypertrophy(enlarging) of tongue and calf muscles. The enlarged muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy.
· Higher risk of behavior and learning difficulties, due to adjustment problems and muscular fatigue.
· Eventual loss of ability to walk (usually by the age of 12)
· scoliosis in some cases
Signs and tests
· Gowers' sign reflects the more severe impairment of the lower extremities muscles. The child helps himself to get up with upper extremities: first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright.
· Affected children usually tire more easily and have less overall strength than their peers.
· Creatine kinase (CPK-MM) levels in the bloodstream are extremely high.
· Genetic testing can reveal genetic errors in the Xp21 gene.
Diagnosis
1) DNA Test
DNA testing and analysis can usually identify the specific type of mutation of the exon or exons that are affected. DNA testing confirms the diagnosis in most cases.
2) Muscle Biopsy
If DNA testing fails to find the mutation, a muscle biopsy test may be performed. A small sample of muscle tissue is extracted (usually with a scalpel instead of a needle) and a dye is applied that reveals the presence of dystrophin. Complete absence of the protein indicates the condition. Over the past several years DNA tests have been developed that detect more of the many mutations that cause the condition, and muscle biopsy is not required as often to confirm Prenatal tests. If one or both parents are 'carriers' of a particular condition there is a risk that their unborn child will be affected by that condition. 'Prenatal tests' are carried out during pregnancy, to try to find out if the fetus (unborn child) is affected. The tests are only available for some neuromuscular disorders. Different types of prenatal tests can be carried out after about 11 weeks of pregnancy. Chorion villus sampling (CVS) can be done at 11–14 weeks, and amniocentesis after 15 weeks, while fetal blood sampling can be done at about 18 weeks. Women and/or couples need to consider carefully which test to have and to discuss this with their genetic counselor. Earlier testing would allow early termination, but it carries a slightly higher risk of miscarriage than later testing (about 2%, as opposed to 0.5%).
Treatment
There is no known cure for Duchenne, although recent stem-cell research is showing promising vectors that may replace damaged muscle tissue. Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life, and include the following.
· Prednisone and Deflazacort increase energy and strentgh
· Bed rest can worsen the muscle disease.
· Physical therapy is helpful to maintain muscle strength, flexibility, and function.
· Supplements and vitamins can help with the disease.
· Appropriate respiratory support as the disease progresses is important
Prognosis
Duchenne is currently an incurable terminal disease that eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. The life expectancy typically ranges from the late teens to the mid-20s.
Duchenne - Research Updates and Trials
Gene Modification Therapy - (“Exon Skipping”)
AVI Biopharma – Bothell, WA
This Portland, OR-based company holds the predominant patent estate for exon skipping technology. The promising drug candidate will soon be in the final stages of preclinical evaluation, including efficacy and safety and toxicity studies. AVI has collaborated with Dr. Steve Wilton of U of Western Australia in worldwide team effort to move this promising treatment forward. Please click here to read the press release about the extended collaboration.
Carolinas Medical Center -- Qilong Lu, PhD – Charlotte, NC
Principal Investigator Dr. Qi Lu and his team have tested several modes of drugs useful for exon skipping. He demonstrated that these sequences worked in human Duchenne cells to produce a shortened dystrophin. He evaluated the systemic delivery of exon skipping drugs that can lead to functional improvement in the mouse model. He also collaborates with several research institutes and biotech companies who will use his information to design preclinical safety studies in animals prior to moving into humans. Please click here to read an abstract of the results.
Prosensa - Leiden, The Netherlands
Prosensa was the first company in the world to earn orphan drug status from the FDA for this therapy. Prosensa has begun the first-in-human clinical trial of exon skipping. In this trial, researchers are injecting the biceps of boys with Duchenne to test safety and efficacy. Prosensa has initiated a Phase I/II clinical trial to test intravenous systemic delivery so the therapy can be targeted to all the muscles of the body. The trial began at the end of 2008. For more information about exon skipping, please read the following report.
University of Western Australia –Steve Wilton, PhD - Nedlands, Australia
Research pioneer Steve Wilton, PhD is developing an exon-skipping “cocktail” which will measure skipping efficiency in Duchenne patient cells. This research complements the work being done by AVI Biopharma, the biotechnology firm in Portland, OR. Dr. Wilton’s work will help make exon skipping applicable to more children with Duchenne. ___________________________________________________________________________________________________________________
Drug Therapy - Small Molecules/Approved Drugs
AT Still University of Health Sciences -- George Carlson, PhD – Kirksville, Missouri
Anti-Inflammatory Agents
Dr. Carlson evaluated the utility of anti-inflammatory agents that prevent muscle cell death as potential treatments for Duchenne. He administered two separate drugs that are currently in widespread use for other illnesses in mice with muscular dystrophy and evaluated functional improvement. Research indicates that they inhibit the NFkB pathway, an intervention that should have clinical benefit for boys with Duchenne. One of the drugs showed no benefit while the second dramatically inhibited NFkB and showed a moderate functional improvement. The latter compound is being considered for use in a clinical trial. Please click here to read about the results of the study.
BioFocus DPI – Leiden, the Netherlands
Utrophin Upregulation Assay
Increasing the production of the protein utrophin can compensate for the absence of dystrophin in DMD patients. The BioFocus team developed a highly sensitive assay to measure expression of utrophin in human skeletal muscle cells. The assay allowed for the screening of potentially useful drugs. Nine compounds were identified as having the potential to increase the production of utrophin. Some of these drugs will now be tested in the dystrophin deficient mouse model. For more information, please click here.
Children’s National Medical Center – Kanneboyina Nagaraju, PhD – Washington D.C.
Testing Supplements and Pre-approved Drugs in a Mouse Model
Dr. Nagaraju investigated four experimental drugs (Celastrol, Resveratrol, Thalidomide, Cyclosporine A analog) that may prevent muscle degeneration and increase muscle function. This project tested these drugs in the DMD mouse model to determine whether human clinical trials were warranted. All of the drugs were well tolerated but did not show significant improvement in the mouse model. These drugs will now be tested in the Duchenne mouse model.
The Research Institute at Nationwide Children’s Hospital-- Paul Martin, PhD -- Columbus, Ohio
Increase in Protein Galgt2 Helps Muscle Cells
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 Duchenne. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 over expression may ameliorate the dystrophic condition. In the previous funding period, Dr. Martin developed a reporter cell line that can be used to screen compounds that would increase the expression of Galgt2.
CombinatoRx --Cambridge, MA
High-Throughput Screening of Combinations of Approved Drugs
CombinatoRx, is a unique pharmaceutical company focused on developing new medicines built from synergistic combinations of approved drugs. CombinatoRx has assembled a highly qualified and motivated team for their Duchenne 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 Duchenne. Promising combinations of drugs have been found for two targets and plans are being developed to test them in animal models. Please click here to read the October, 2008 press release.
University of Nevada, Reno -- Dean Burkin, PhD – Reno, NV
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. Dr. Burkin has used his assay to search two compound libraries containing FDA-approved drugs and natural products. He has found three compounds that show an increase in alpha-7-intergin. These compounds will be considered for testing in the dystrophin deficient mouse model.
University of Pennsylvania – Tejvir Khurana, PhD —Philadelphia, PA
Utrophin Upregulation Assay
Dr. Khurana, a world renowned expert on the utrophin promoter, is testing a compound collection of FDA approved drugs using a promoter assay he developed to see if any of these compounds will increase the expression of utrophin in vitro. Three compounds have been identified which will be tested in Duchenne mice. He is also developing a novel utrophin assay that blocks a protein which prevents utrophin expression. This assay is based on one of the awards from the DMD etank initiative
University of Washington – Stanley Froehner, PhD -- Seattle, WA
Phosphodiesterase Inhibitors
Dr. Froehner tested phosphodiesterase (PDE) inhibitors as potential drugs to treat Duchenne. PDE inhibitors reduce inflammation, improve blood flow in the muscle, upregulate utrophin and inhibit myostatin, a negative regulator of muscle mass. Dr. Froehner found that certain PDEs significantly improved cardiac muscle functions in the mouse model. Dr. Froehner also showed that PDEs may prevent heart damage in older mice. Based on promising results, this compound is being moved into human clinical trials at Johns Hopkins University. Please click here to read about the results.
___________________________________________________________________________________________________________________
Small Molecules/Novel Therapeutics
Project Catalyst – Sout h Plainfield, NJ
High-Throughput Screening for new drugs
Project Catalyst is a targeted research program designed to develop oral medications that may delay muscle degeneration in DMD. The research is being conducted by PTC Therapeutics, a New Jersey biotech firm that currently has a Duchenne drug in Phase II human clinical trials. This drug, called PTC 124, will benefit 10-15% of boys with Duchenne 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 Duchenne from hundreds of thousands of compounds. Several classes of compounds have been identified for four Duchenne protein targets and are being optimized for safety and efficacy. Lead candidates may eventually be tested in human clinical trials targeted for 2011. For more information, please click here.
Summit plc (formerly VASTox plc) – Oxfordshire, United Kingdom
Utrophin Upregulation
A UK-based biotechnology company, Summit plc is searching for new drugs that will increase expression of the protein utrophin. Several compounds were found to increase the level of utrophin in cell culture. These compounds are being optimized for safety and efficacy. One compound, SMTC 1100 also known as BMN 195 will be tested in a clinical trial some time next year. Please click here to read the press release.
___________________________________________________________________________________________________________________
Biologicals
Brown University -- Justin Fallon, PhD – Providence, RI
Biglycan
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in Duchenne boys. Dr. Fallon has discovered that a protein called biglycan can up regulate 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 tested biglycan in the mouse model to show significant functional improvement. Dr. Fallon is now scaling up the production of biglycan in preparation for preclinical safety studies.
University of Minnesota - James Ervasti, PhD -- Minneapolis, MN
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 be attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Dr. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the optimal dosage, frequency of administration, and mode of delivery of TAT-utrophin. In addition, Dr. Ervasti is investigating ways to scale production of TAT-utrophin in preparation for preclinical safety and toxicology studies in animals. Please click here to read an abstract of the paper.
___________________________________________________________________________________________________________________
STEM CELL THERAPY
University of Leuven, Belgium -- Maurilio Sampaolesi, PhD - Leuven, Belgium
Stem Cells
The most promising long term therapeutic strategy for Duchenne is correcting the genetic defect at the DNA level. Dr. Sampaolesi is developing a program for the stem cell treatment of Duchenne 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.
___________________________________________________________________________________________________________________
OTHER
University of Colorado -- Brian Tseng, MD, PhD
Molecular Sealant (Dr. Tseng is now at Massachusetts General Hospital)
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with Duchenne 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. Unfortunately this sealant did not show the desired benefits so no further work is currently planned.
UNC Animal Models Core Facility -- Randy Thresher, PhD
New Mouse Model
Unlike the most widely used mouse in Duchenne 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. Unfortunately this project was much more difficult than originally anticipated and although the mice incorporated the appropriate human genetic material, they were unable to reproduce to develop a colony.
AVI Biopharma – Bothell, WA
This Portland, OR-based company holds the predominant patent estate for exon skipping technology. The promising drug candidate will soon be in the final stages of preclinical evaluation, including efficacy and safety and toxicity studies. AVI has collaborated with Dr. Steve Wilton of U of Western Australia in worldwide team effort to move this promising treatment forward. Please click here to read the press release about the extended collaboration.
Carolinas Medical Center -- Qilong Lu, PhD – Charlotte, NC
Principal Investigator Dr. Qi Lu and his team have tested several modes of drugs useful for exon skipping. He demonstrated that these sequences worked in human Duchenne cells to produce a shortened dystrophin. He evaluated the systemic delivery of exon skipping drugs that can lead to functional improvement in the mouse model. He also collaborates with several research institutes and biotech companies who will use his information to design preclinical safety studies in animals prior to moving into humans. Please click here to read an abstract of the results.
Prosensa - Leiden, The Netherlands
Prosensa was the first company in the world to earn orphan drug status from the FDA for this therapy. Prosensa has begun the first-in-human clinical trial of exon skipping. In this trial, researchers are injecting the biceps of boys with Duchenne to test safety and efficacy. Prosensa has initiated a Phase I/II clinical trial to test intravenous systemic delivery so the therapy can be targeted to all the muscles of the body. The trial began at the end of 2008. For more information about exon skipping, please read the following report.
University of Western Australia –Steve Wilton, PhD - Nedlands, Australia
Research pioneer Steve Wilton, PhD is developing an exon-skipping “cocktail” which will measure skipping efficiency in Duchenne patient cells. This research complements the work being done by AVI Biopharma, the biotechnology firm in Portland, OR. Dr. Wilton’s work will help make exon skipping applicable to more children with Duchenne. ___________________________________________________________________________________________________________________
Drug Therapy - Small Molecules/Approved Drugs
AT Still University of Health Sciences -- George Carlson, PhD – Kirksville, Missouri
Anti-Inflammatory Agents
Dr. Carlson evaluated the utility of anti-inflammatory agents that prevent muscle cell death as potential treatments for Duchenne. He administered two separate drugs that are currently in widespread use for other illnesses in mice with muscular dystrophy and evaluated functional improvement. Research indicates that they inhibit the NFkB pathway, an intervention that should have clinical benefit for boys with Duchenne. One of the drugs showed no benefit while the second dramatically inhibited NFkB and showed a moderate functional improvement. The latter compound is being considered for use in a clinical trial. Please click here to read about the results of the study.
BioFocus DPI – Leiden, the Netherlands
Utrophin Upregulation Assay
Increasing the production of the protein utrophin can compensate for the absence of dystrophin in DMD patients. The BioFocus team developed a highly sensitive assay to measure expression of utrophin in human skeletal muscle cells. The assay allowed for the screening of potentially useful drugs. Nine compounds were identified as having the potential to increase the production of utrophin. Some of these drugs will now be tested in the dystrophin deficient mouse model. For more information, please click here.
Children’s National Medical Center – Kanneboyina Nagaraju, PhD – Washington D.C.
Testing Supplements and Pre-approved Drugs in a Mouse Model
Dr. Nagaraju investigated four experimental drugs (Celastrol, Resveratrol, Thalidomide, Cyclosporine A analog) that may prevent muscle degeneration and increase muscle function. This project tested these drugs in the DMD mouse model to determine whether human clinical trials were warranted. All of the drugs were well tolerated but did not show significant improvement in the mouse model. These drugs will now be tested in the Duchenne mouse model.
The Research Institute at Nationwide Children’s Hospital-- Paul Martin, PhD -- Columbus, Ohio
Increase in Protein Galgt2 Helps Muscle Cells
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 Duchenne. Mice with muscular dystrophy have a 3-fold increase in natural expression of Galgt2. This observation led Dr. Martin to conclude that Galgt2 over expression may ameliorate the dystrophic condition. In the previous funding period, Dr. Martin developed a reporter cell line that can be used to screen compounds that would increase the expression of Galgt2.
CombinatoRx --Cambridge, MA
High-Throughput Screening of Combinations of Approved Drugs
CombinatoRx, is a unique pharmaceutical company focused on developing new medicines built from synergistic combinations of approved drugs. CombinatoRx has assembled a highly qualified and motivated team for their Duchenne 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 Duchenne. Promising combinations of drugs have been found for two targets and plans are being developed to test them in animal models. Please click here to read the October, 2008 press release.
University of Nevada, Reno -- Dean Burkin, PhD – Reno, NV
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. Dr. Burkin has used his assay to search two compound libraries containing FDA-approved drugs and natural products. He has found three compounds that show an increase in alpha-7-intergin. These compounds will be considered for testing in the dystrophin deficient mouse model.
University of Pennsylvania – Tejvir Khurana, PhD —Philadelphia, PA
Utrophin Upregulation Assay
Dr. Khurana, a world renowned expert on the utrophin promoter, is testing a compound collection of FDA approved drugs using a promoter assay he developed to see if any of these compounds will increase the expression of utrophin in vitro. Three compounds have been identified which will be tested in Duchenne mice. He is also developing a novel utrophin assay that blocks a protein which prevents utrophin expression. This assay is based on one of the awards from the DMD etank initiative
University of Washington – Stanley Froehner, PhD -- Seattle, WA
Phosphodiesterase Inhibitors
Dr. Froehner tested phosphodiesterase (PDE) inhibitors as potential drugs to treat Duchenne. PDE inhibitors reduce inflammation, improve blood flow in the muscle, upregulate utrophin and inhibit myostatin, a negative regulator of muscle mass. Dr. Froehner found that certain PDEs significantly improved cardiac muscle functions in the mouse model. Dr. Froehner also showed that PDEs may prevent heart damage in older mice. Based on promising results, this compound is being moved into human clinical trials at Johns Hopkins University. Please click here to read about the results.
___________________________________________________________________________________________________________________
Small Molecules/Novel Therapeutics
Project Catalyst – Sout h Plainfield, NJ
High-Throughput Screening for new drugs
Project Catalyst is a targeted research program designed to develop oral medications that may delay muscle degeneration in DMD. The research is being conducted by PTC Therapeutics, a New Jersey biotech firm that currently has a Duchenne drug in Phase II human clinical trials. This drug, called PTC 124, will benefit 10-15% of boys with Duchenne 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 Duchenne from hundreds of thousands of compounds. Several classes of compounds have been identified for four Duchenne protein targets and are being optimized for safety and efficacy. Lead candidates may eventually be tested in human clinical trials targeted for 2011. For more information, please click here.
Summit plc (formerly VASTox plc) – Oxfordshire, United Kingdom
Utrophin Upregulation
A UK-based biotechnology company, Summit plc is searching for new drugs that will increase expression of the protein utrophin. Several compounds were found to increase the level of utrophin in cell culture. These compounds are being optimized for safety and efficacy. One compound, SMTC 1100 also known as BMN 195 will be tested in a clinical trial some time next year. Please click here to read the press release.
___________________________________________________________________________________________________________________
Biologicals
Brown University -- Justin Fallon, PhD – Providence, RI
Biglycan
Utrophin is a compensatory protein that can act as a substitute for dystrophin, the missing protein in Duchenne boys. Dr. Fallon has discovered that a protein called biglycan can up regulate 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 tested biglycan in the mouse model to show significant functional improvement. Dr. Fallon is now scaling up the production of biglycan in preparation for preclinical safety studies.
University of Minnesota - James Ervasti, PhD -- Minneapolis, MN
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 be attached to another protein called TAT. This new fused protein (or chimera) is then transported into the cell. Dr. Ervasti has promising preliminary results that demonstrate improvement in a mouse model treated with this therapy. Currently, Dr. Ervasti is investigating the optimal dosage, frequency of administration, and mode of delivery of TAT-utrophin. In addition, Dr. Ervasti is investigating ways to scale production of TAT-utrophin in preparation for preclinical safety and toxicology studies in animals. Please click here to read an abstract of the paper.
___________________________________________________________________________________________________________________
STEM CELL THERAPY
University of Leuven, Belgium -- Maurilio Sampaolesi, PhD - Leuven, Belgium
Stem Cells
The most promising long term therapeutic strategy for Duchenne is correcting the genetic defect at the DNA level. Dr. Sampaolesi is developing a program for the stem cell treatment of Duchenne 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.
___________________________________________________________________________________________________________________
OTHER
University of Colorado -- Brian Tseng, MD, PhD
Molecular Sealant (Dr. Tseng is now at Massachusetts General Hospital)
Dr. Tseng is developing a “molecular sealant” to patch the holes in the muscles cells of boys with Duchenne 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. Unfortunately this sealant did not show the desired benefits so no further work is currently planned.
UNC Animal Models Core Facility -- Randy Thresher, PhD
New Mouse Model
Unlike the most widely used mouse in Duchenne 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. Unfortunately this project was much more difficult than originally anticipated and although the mice incorporated the appropriate human genetic material, they were unable to reproduce to develop a colony.
