CRISPR/Cas9
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There is real promise on the horizon with innovative technology in gene therapy. I attached a webinar, provided by PPMD, that explains CRISPR/Cas9 which is REAL hope for a therapy for RJ. Gene editing is currently being studied by Dr. Eric Olson ay UT Southwestern Medical Center. New technology enables scientists to correct mistakes in the human genome. Studies have occurred in the mdx mouse with huge success in correcting the mutation and restoring the affected dystrophin. Research has found that even only correcting 15% of the normal level of dystrophin would provide enough protein to restore muscle function. Theoretically, CRISPR/Cas9 could treat up to 80% of Duchenne mutations; but similar to exon skipping, research will start with the most common mutation, which is exon 51. RJ's mutation is exons 22-29. There are over 3,000 mutations identified in boys with Duchenne which is another reason that finding a cure for all boys is so difficult. We pray that human trials will be on the horizon soon!
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Below are some highlights so you can understand what has been achieved recently, what needs to continually occur, and what still needs to be accomplished. Closest to our hearts is where research dollars are being spent to find a therapy or a cure. Most of the following information was referenced from Treat-NMD and Parent Project Muscular Dystrophy.
Combination Therapies
Duchenne muscular dystrophy is characterized by muscle wasting and associated loss of function. There are considerable efforts underway to develop drugs and biologics (cell and gene therapy) to address the primary problem in Duchenne--the absence of dystrophin. Restoring dystrophin or replacing dystrophin with replacement protein are considered foundational therapies.
The Duchenne community is well aware of the need for combination therapies. Combinations would include compounds that target what is referred to as the ‘downstream pathology’ or the changes that occur because dystrophin is absent. This includes anti-inflammatories, anti-fibrotics, factors that control muscle regeneration and fiber size, compounds that improve circulation to muscle, and compounds that improve mitochondrial function (mitochondria are considered the powerhouses of cells). Scientists are hopeful that by combining several of these targeted therapies, we could end Duchenne and stop progression for every individual.
The Duchenne community is well aware of the need for combination therapies. Combinations would include compounds that target what is referred to as the ‘downstream pathology’ or the changes that occur because dystrophin is absent. This includes anti-inflammatories, anti-fibrotics, factors that control muscle regeneration and fiber size, compounds that improve circulation to muscle, and compounds that improve mitochondrial function (mitochondria are considered the powerhouses of cells). Scientists are hopeful that by combining several of these targeted therapies, we could end Duchenne and stop progression for every individual.
Research Strategies
While there is still no cure for DMD, there is substantial active research and several potential new therapies being tested in clinical trials. There are numerous therapeutic approaches and the majority follow the same road of preclinical to clinical studies. First the approach is tested in cultured patient cells, then in animal models of the disease and then when the results in cells and animals are sufficiently convincing, in patients (clinical trials). Unfortunately, this part of therapeutic development can take a very long time.
Remember, DMD is a degenerative muscle disease caused by a genetic mutation (or error) in the gene that carries instructions for the [production of the] essential muscle protein dystrophin. Without dystrophin, muscle fibers are abnormally fragile and break down under the stress of contractions.
Gene Therapy
Gene therapy for Duchenne is centered on the goal of successfully introducing the correct code for the dystrophin protein into a muscle cell, thereby providing the cell with the recipe needed to produce dystrophin, and, ultimately, curing the disorder.
Gene therapy will only work, however, if scientists can find a means of transporting the correct genetic code for the dystrophin protein into each muscle cell in the body. Many scientists working with gene therapy are pursuing a plan to use viruses to transport this genetic information, since viruses have evolved to deposit their own genetic code into cells.
Currently, scientists can manipulate certain viruses to substitute the dystrophin code for the undesirable genetic code that the virus would naturally contain. If their theories prove correct, the manipulated virus would be injected into the patient. The result of this viral “infection” would be the successful recoding of each muscle cell in the patient’s body.
Cell Therapy
Scientists have also developed strategies that aim to coax muscle cells into producing dystrophin protein without recoding dystrophin’s basic genetic code. These proposed cell therapies attempt to at least partially offset the muscle damage caused by the flawed genetic code.
Scientists have begun to develop cell therapy techniques that use stem cells derived from muscle. These are essentially immature muscle cells with the potential to develop into a variety of types of tissues, including skeletal muscle.
Stem cells derived from muscle are very different from embryonic stem cells, which are immature cells harvested from human embryos that can develop into any type of body tissue, and are the subject of ongoing ethical debate.
Pharmacological Therapies
Pharmacological approaches to formulating treatments for Duchenne do not seek to repair or replace the missing genetic information in a muscle cell, or to otherwise devise mechanisms to cause the muscle cell to produce normal dystrophin. Instead, pharmacological approaches seek to treat the symptoms of Duchenne without necessarily addressing the root causes.
While pharmacological therapy may seem less dramatic than some of the newer methods being developed, pharmacological strategies also sidestep some of the most daunting obstacles associated with gene and cell therapies, most notably difficulties in achieving systemic delivery and overcoming immune response.
Utrophin Upregulators
In 1989, scientists discovered that a protein called utrophin exists in muscle cells, principally at the junction where the nerve meets the muscle cell. Since that time, scientists have observed that utrophin could potentially operate as a substitute for dystrophin (and protect the muscle cell membrane), if muscle cells could be coaxed into producing utrophin at locations other than the neuro-muscular junction.
This strategy could perhaps lead to an effective treatment for Duchenne, using a biological process substantially simpler than those involved in gene and cell therapies.
Myostatin Inhibitors
Scientists have long theorized that the body normally contains compounds that limit muscle growth. For example, certain breeds of cattle develop substantially more muscle than ordinary cattle. Researchers have isolated the cause of this disparity to a mutation in the gene that codes for the production of a hormone called myostatin, which tends to limit muscle growth. Scientists searching for a treatment theorize that inhibiting myostatin in boys with Duchenne will cause them to develop more muscle mass initially. Ideally, this surplus will offset the muscle loss associated with Duchenne, allowing boys to retain their ability to function for a longer period of time.
Exon-skipping
Exon skipping is a possible way to help the body make working dystrophin protein again. Most mutations that cause Duchenne result in the portion of the protein following the mutation to be made incorrectly. This leads to production of a non-functional dystrophin protein. The idea behind exon skipping is to skip over a section of the gene, called an exon, to enable correct production of the portion of the protein following the mutation. This results in a shorter – but still functional – form of dystrophin.
Oligonucleotides are compounds used by scientists seeking to repair the deficient genetic code in the dystrophin gene. The intended result is that the boy’s muscle cell will then produce dystrophin on its own. Scientists working with oligonucleotides hope to use a drug to “unzip” the genetic code, and then shift one side of the code to the right by a tiny degree, thereby giving the cell enough code to produce a viable dystrophin protein.
Remember, DMD is a degenerative muscle disease caused by a genetic mutation (or error) in the gene that carries instructions for the [production of the] essential muscle protein dystrophin. Without dystrophin, muscle fibers are abnormally fragile and break down under the stress of contractions.
Gene Therapy
Gene therapy for Duchenne is centered on the goal of successfully introducing the correct code for the dystrophin protein into a muscle cell, thereby providing the cell with the recipe needed to produce dystrophin, and, ultimately, curing the disorder.
Gene therapy will only work, however, if scientists can find a means of transporting the correct genetic code for the dystrophin protein into each muscle cell in the body. Many scientists working with gene therapy are pursuing a plan to use viruses to transport this genetic information, since viruses have evolved to deposit their own genetic code into cells.
Currently, scientists can manipulate certain viruses to substitute the dystrophin code for the undesirable genetic code that the virus would naturally contain. If their theories prove correct, the manipulated virus would be injected into the patient. The result of this viral “infection” would be the successful recoding of each muscle cell in the patient’s body.
Cell Therapy
Scientists have also developed strategies that aim to coax muscle cells into producing dystrophin protein without recoding dystrophin’s basic genetic code. These proposed cell therapies attempt to at least partially offset the muscle damage caused by the flawed genetic code.
Scientists have begun to develop cell therapy techniques that use stem cells derived from muscle. These are essentially immature muscle cells with the potential to develop into a variety of types of tissues, including skeletal muscle.
Stem cells derived from muscle are very different from embryonic stem cells, which are immature cells harvested from human embryos that can develop into any type of body tissue, and are the subject of ongoing ethical debate.
Pharmacological Therapies
Pharmacological approaches to formulating treatments for Duchenne do not seek to repair or replace the missing genetic information in a muscle cell, or to otherwise devise mechanisms to cause the muscle cell to produce normal dystrophin. Instead, pharmacological approaches seek to treat the symptoms of Duchenne without necessarily addressing the root causes.
While pharmacological therapy may seem less dramatic than some of the newer methods being developed, pharmacological strategies also sidestep some of the most daunting obstacles associated with gene and cell therapies, most notably difficulties in achieving systemic delivery and overcoming immune response.
- Corticosteroids - The aim of corticosteroids (like the Deflazacort RJ takes daily) is to suppress the immune system in order to reduce the formation of scar tissue. By suppressing the immune system with corticosteroids, muscle damage will be less severe and less scar tissue will be formed. The general consensus is that corticosteroids do work to delay the disease progression. It will delay wheelchair dependency by approximately1-3 years, will temporarily improve muscle strength and function and will delay the loss of respiratory function. The biggest challenge is that corticosteroids have to be taken regularly which results in side effects. The most common are weight gain, depression, behavioral problems, stunted growth, delayed puberty and loss of bone mass.
Utrophin Upregulators
In 1989, scientists discovered that a protein called utrophin exists in muscle cells, principally at the junction where the nerve meets the muscle cell. Since that time, scientists have observed that utrophin could potentially operate as a substitute for dystrophin (and protect the muscle cell membrane), if muscle cells could be coaxed into producing utrophin at locations other than the neuro-muscular junction.
This strategy could perhaps lead to an effective treatment for Duchenne, using a biological process substantially simpler than those involved in gene and cell therapies.
Myostatin Inhibitors
Scientists have long theorized that the body normally contains compounds that limit muscle growth. For example, certain breeds of cattle develop substantially more muscle than ordinary cattle. Researchers have isolated the cause of this disparity to a mutation in the gene that codes for the production of a hormone called myostatin, which tends to limit muscle growth. Scientists searching for a treatment theorize that inhibiting myostatin in boys with Duchenne will cause them to develop more muscle mass initially. Ideally, this surplus will offset the muscle loss associated with Duchenne, allowing boys to retain their ability to function for a longer period of time.
Exon-skipping
Exon skipping is a possible way to help the body make working dystrophin protein again. Most mutations that cause Duchenne result in the portion of the protein following the mutation to be made incorrectly. This leads to production of a non-functional dystrophin protein. The idea behind exon skipping is to skip over a section of the gene, called an exon, to enable correct production of the portion of the protein following the mutation. This results in a shorter – but still functional – form of dystrophin.
Oligonucleotides are compounds used by scientists seeking to repair the deficient genetic code in the dystrophin gene. The intended result is that the boy’s muscle cell will then produce dystrophin on its own. Scientists working with oligonucleotides hope to use a drug to “unzip” the genetic code, and then shift one side of the code to the right by a tiny degree, thereby giving the cell enough code to produce a viable dystrophin protein.
- Phase 3 human trial of the exon skipping 51 drug, Eteplirsen, is currently taking place at 39 sites across the country, including Nationwide Children's Hospital in Columbus, for those boys who are missing exon 51. RJ is missing exons 22-29 so he is not eligible for the study. However, our hope with this promising treatment is that scientists will continue to explore how this drug can work for boys who are missing other exons.
2014 MD-CARE Act Amendments
The MD CARE Act is a shining legislative success, exemplifying what can be achieved through genuine public-private partnerships to transform the biomedical research and drug discovery landscape. So many critical programs were made possible because of the bill and follow on reauthorization. In 2014, with the help of our Congressional champions, we were able to pass critical updates to the the existing law, addressing problems such as:
Since passage of the MD-CARE Act, $500 million has been leveraged for muscular dystrophy research and education programs, and of that, $250 million being Duchenne specific.
One of the many challenges faced by the Duchenne community is the lack of awareness about this devastating and life-altering disorder. Many people have never heard of Duchenne, so by increasing awareness this can become a powerful way to help in the fight against Duchenne.
- Expanding and sustaining research efforts across the muscular dystrophies including an expanded focus into cardiac and pulmonary functioning and into the health care needs of adults with muscular dystrophies;
- Updating existing Duchenne-Becker care standards, developing for the first time care standards for adults living with Duchenne and developing and disseminating care standards for those with other forms of muscular dystrophy;
- Intensifying surveillance of tracking of all the muscular dystrophies and ensuring that this valuable data informs the biomedical research agenda; and
- Ensuring that when potential therapies are submitted for evaluation they are reviewed as quickly as possible.
Since passage of the MD-CARE Act, $500 million has been leveraged for muscular dystrophy research and education programs, and of that, $250 million being Duchenne specific.
One of the many challenges faced by the Duchenne community is the lack of awareness about this devastating and life-altering disorder. Many people have never heard of Duchenne, so by increasing awareness this can become a powerful way to help in the fight against Duchenne.
Standard of Care
January 2010
A major international consensus document setting out best practices for care for DMD is now available for families. It is recognized that receiving the best care can dramatically improve the quality of life and life expectancy of individuals with DMD, enabling them to lead fulfilling, independent lives into adulthood. The importance of care recommendations such as these therefore cannot be underestimated. The international guidelines, which cover the diagnostics, cardiovascular, neuromuscular, gastroenterology/nutrition, orthopedic/surgical, psychosocial, rehabilitation and respiratory fields, can be used by doctors, patients and families as a guide to the treatment that individuals with Duchenne should receive at each stage of the disease. They are also a valuable tool for lobbying at a national level to enable incorporation of these recommendations into our national health systems.
A major international consensus document setting out best practices for care for DMD is now available for families. It is recognized that receiving the best care can dramatically improve the quality of life and life expectancy of individuals with DMD, enabling them to lead fulfilling, independent lives into adulthood. The importance of care recommendations such as these therefore cannot be underestimated. The international guidelines, which cover the diagnostics, cardiovascular, neuromuscular, gastroenterology/nutrition, orthopedic/surgical, psychosocial, rehabilitation and respiratory fields, can be used by doctors, patients and families as a guide to the treatment that individuals with Duchenne should receive at each stage of the disease. They are also a valuable tool for lobbying at a national level to enable incorporation of these recommendations into our national health systems.
MD-CARE Act
December 2001
A pivotal moment in the history of Duchenne Muscular Dystrophy occurred when The Muscular Dystrophy Community Assistance, Research, and Education (MD-CARE) Act was signed into law by President George W. Bush in December of 2001. This was the first legislation in the history of the US Congress that focused on muscular dystrophy. The bipartisan MD-CARE Act provides important authority and direction for muscular dystrophy research, including Duchenne.
This legislation included 4 major points:
A pivotal moment in the history of Duchenne Muscular Dystrophy occurred when The Muscular Dystrophy Community Assistance, Research, and Education (MD-CARE) Act was signed into law by President George W. Bush in December of 2001. This was the first legislation in the history of the US Congress that focused on muscular dystrophy. The bipartisan MD-CARE Act provides important authority and direction for muscular dystrophy research, including Duchenne.
This legislation included 4 major points:
- NIH would support Centers of Excellence focused on muscular dystrophy. These Centers would have several components – basic research, extensive collaboration, shared resources, as well as, a clinical study.
- CDC would establish programs focused on Duchenne muscular dystrophy. This would include improving diagnosis, data collection, and care considerations.
- NIH and related government agencies would convene the research and clinical community to develop a research plan.
- NIH and related government agencies would establish a steering committee to oversee progress (MDCC).