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”)
Sarepta
Currently developing a suite of exon skipping drugs, Sarepta Therpaeutics’ lead compound, Eteplirsen, is currently in Phase 2 trials in the US and Europe. 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. Please click here to view website.
___________________________________________________________________________________________________________________
Drug Therapy - Small Molecules/Approved Drugs
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.
Please click here to view website
___________________________________________________________________________________________________________________
Small Molecules/Novel Therapeutics
Project Catalyst – South 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. Please click here to view website
Summit plc
Utrophin Upregulation
Summit is a UK-based company focused on the discovery and development of novel drug candidates to treat areas of high unmet medical need. One of two focus areas is Duchenne Muscular Dystrophy. Summit is developing a drug candidate that is designed to upregulate utrophin, a protein that can compensate for lack of dystrophin. Summit recently completed a phase 1 trial in healthy adult volunteers and is now planning a phase 2 clinical trial for Duchenne patients.
Please click here to view website
_________________________________________________________________________________________________________________
Biologicals
Tivorsan - Brown University -- Justin Fallon, PhD – Providence, RI
Tivorsan was co-founded by Dr. Justin Fallon, Professor of Neuroscience at Brown University, to develop biglycan as a therapy for Duchenne. The company is moving ahead with an aggressive timeline to get biglycan into the clinic. Please click here to view website
Retrophin
Retrophin is an emerging biotechnology company focused on rare and life-threatening diseases. Retrophin’s lead compound, RE-001, is based on a therapeutic approach that was conceived of and developed by Dr. James Ervasti at the University of Minnesota. Dr. Ervasti has conducted crucial animal studies that demonstrated the potential efficacy of Tat-utrophin as a treatment for Duchenne. Please click here to view website
___________________________________________________________________________________________________________________
OTHER
Pilot Trials Now
Pilot Trials Now is a collaboration between several nonprofit foundations including Charley’s Fund, the Nash Avery Foundation, Action Duchenne, Cure Duchenne, Hope for Javier and Zubin’s Wish. These organizations have helped fund clinical trials for repurposed FDA-approved drugs. These clinical trials are the outcome of years of screening, discovery and animal studies financed by Charley’s Fund to identify FDA-approved drugs (alone and in combination) that can help boys with
Duchenne. Two clinical trials are currently underway. Sildenafil, a drug that could delay and possibly even prevent heart failure, is being tested at Johns Hopkins/Kennedy Krieger. Increlex, a drug that could stabilize muscle membranes and offset the egregious side effects of steroids, is being studied at Cincinnati Children’s Hospital. A third multi-center trial will begin in 4Q2011. Please click here to view website
Sarepta
Currently developing a suite of exon skipping drugs, Sarepta Therpaeutics’ lead compound, Eteplirsen, is currently in Phase 2 trials in the US and Europe. 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. Please click here to view website.
___________________________________________________________________________________________________________________
Drug Therapy - Small Molecules/Approved Drugs
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.
Please click here to view website
___________________________________________________________________________________________________________________
Small Molecules/Novel Therapeutics
Project Catalyst – South 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. Please click here to view website
Summit plc
Utrophin Upregulation
Summit is a UK-based company focused on the discovery and development of novel drug candidates to treat areas of high unmet medical need. One of two focus areas is Duchenne Muscular Dystrophy. Summit is developing a drug candidate that is designed to upregulate utrophin, a protein that can compensate for lack of dystrophin. Summit recently completed a phase 1 trial in healthy adult volunteers and is now planning a phase 2 clinical trial for Duchenne patients.
Please click here to view website
_________________________________________________________________________________________________________________
Biologicals
Tivorsan - Brown University -- Justin Fallon, PhD – Providence, RI
Tivorsan was co-founded by Dr. Justin Fallon, Professor of Neuroscience at Brown University, to develop biglycan as a therapy for Duchenne. The company is moving ahead with an aggressive timeline to get biglycan into the clinic. Please click here to view website
Retrophin
Retrophin is an emerging biotechnology company focused on rare and life-threatening diseases. Retrophin’s lead compound, RE-001, is based on a therapeutic approach that was conceived of and developed by Dr. James Ervasti at the University of Minnesota. Dr. Ervasti has conducted crucial animal studies that demonstrated the potential efficacy of Tat-utrophin as a treatment for Duchenne. Please click here to view website
___________________________________________________________________________________________________________________
OTHER
Pilot Trials Now
Pilot Trials Now is a collaboration between several nonprofit foundations including Charley’s Fund, the Nash Avery Foundation, Action Duchenne, Cure Duchenne, Hope for Javier and Zubin’s Wish. These organizations have helped fund clinical trials for repurposed FDA-approved drugs. These clinical trials are the outcome of years of screening, discovery and animal studies financed by Charley’s Fund to identify FDA-approved drugs (alone and in combination) that can help boys with
Duchenne. Two clinical trials are currently underway. Sildenafil, a drug that could delay and possibly even prevent heart failure, is being tested at Johns Hopkins/Kennedy Krieger. Increlex, a drug that could stabilize muscle membranes and offset the egregious side effects of steroids, is being studied at Cincinnati Children’s Hospital. A third multi-center trial will begin in 4Q2011. Please click here to view website
