Duchenne muscular dystrophy

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Duchenne muscular dystrophy
Duchenne-muscular-dystrophy.jpg
Microscopic image of cross-sectional calf muscle from a person with Duchenne muscular dystrophy, showing extensive replacement of muscle fibers by fat cells.
Pronunciation
Specialty Pediatric neurology, neuromuscular medicine, medical genetics
Symptoms Muscle weakness, trouble standing up, scoliosis [2] [3]
Usual onsetAround age 4 [2]
Causes Genetic (X-linked recessive) [3]
Diagnostic method Genetic testing [3]
TreatmentPharmacological treatment, physical therapy, braces, speech therapy, occupational therapy, surgery, assisted ventilation [2] [3]
Medication Corticosteroids
Prognosis life expectancy: 26 years [4]
FrequencyIn males, 1 in 3,500-6,000 [3]
In females, 1 in 50,000,000 [5]

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. [3] Muscle weakness usually begins around the age of four, and worsens quickly. [2] Muscle loss typically occurs first in the thighs and pelvis followed by the arms. [3] This can result in trouble standing up. [3] Most are unable to walk by the age of 12. [2] Affected muscles may look larger due to increased fat content. [3] Scoliosis is also common. [3] Some may have intellectual disability. [3] Females with a single copy of the defective gene may show mild symptoms. [3]

Contents

The disorder is X-linked recessive. [3] About two thirds of cases are inherited from a person's mother, while one third of cases are due to a new mutation. [3] It is caused by a mutation in the gene for the protein dystrophin. [3] Dystrophin is important to maintain the muscle fiber's cell membrane. [3] Genetic testing can often make the diagnosis at birth. [3] Those affected also have a high level of creatine kinase in their blood. [3]

Although there is no known cure, physical therapy, braces, and corrective surgery may help with some symptoms. [2] Assisted ventilation may be required in those with weakness of breathing muscles. [3] Medications used include steroids to slow muscle degeneration, anticonvulsants to control seizures and some muscle activity, and immunosuppressants to delay damage to dying muscle cells. [2] Gene therapy, as a treatment, is in the early stages of study in humans. [3] A small initial study using gene therapy has given some children improved muscle strength, but long term effects are unknown as of 2020. [6]

DMD affects about one in 3,500 to 6,000 males at birth. [3] It is the most common type of muscular dystrophy. [3] The life expectancy is 26; [4] however, with excellent care, some may live into their 30s or 40s. [3] The disease is much more rare in girls, occurring approximately once in 50,000,000 live female births. [5]

Signs and symptoms

Drawing of seven-year-old boy with Duchenne muscular dystrophy. There is excessive development of the lower limbs (pseudohypertrophy), and thinness of the arms. In the figure on the right, lumbar hyperlordosis is visible. Drawing of boy with Duchenne muscular dystrophy.png
Drawing of seven-year-old boy with Duchenne muscular dystrophy. There is excessive development of the lower limbs (pseudohypertrophy), and thinness of the arms. In the figure on the right, lumbar hyperlordosis is visible.

DMD causes progressive muscle weakness due to muscle fiber disarray, death, and replacement with connective tissue or fat. [3] The voluntary muscles are affected first, especially those of the hips, pelvic area, thighs, calves. [7] [8] It eventually progresses to the shoulders and neck, followed by arms, respiratory muscles, and other areas. [8] Fatigue is common. [9]

Signs usually appear before age five, and may even be observed from the moment a boy takes his first steps. [10] There is general difficulty with motor skills, which can result in an awkward manner of walking, stepping, or running. [11] They tend to walk on their toes, [11] in part due to shortening of the Achilles tendon, [12] and because it compensates for knee extensor weakness. [8] Falls can be frequent. [13] It becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates before age 13. [11] Most men affected with DMD become essentially "paralyzed from the neck down" by the age of 21. [10] Cardiomyopathy, particularly dilated cardiomyopathy, is common, seen in half of 18-year-olds. [11] The development of congestive heart failure or arrhythmia (irregular heartbeat) is only occasional. [8] In late stages of the disease, respiratory impairment and swallowing impairment can occur, which can result in pneumonia. [14]

Gowers's sign Gowers's sign.png
Gowers's sign

A classic sign of DMD is trouble getting up from lying or sitting position, [13] as manifested by a positive Gowers's sign. When a child tries to arise from lying on his stomach, he compensates for pelvic muscle weakness through use of the upper extremities: [11] first by rising to stand on his arms and knees, and then "walking" his hands up his legs to stand upright. Another characteristic sign of DMD is pseudohypertrophy (enlarging) of the muscles of the tongue, calves, buttocks, and shoulders (around age 4 or 5). The muscle tissue is eventually replaced by fat and connective tissue, hence the term pseudohypertrophy. Muscle fiber deformities and muscle contractures of Achilles tendon and hamstrings can occur, which impair functionality because the muscle fibers shorten and fibrose in connective tissue. [8] Skeletal deformities can occur, such as lumbar hyperlordosis, scoliosis, anterior pelvic tilt, and chest deformities. Lumbar hyperlordosis is thought to be compensatory mechanism in response to gluteal and quadriceps muscle weakness, all of which cause altered posture and gait (e.g.: restricted hip extension). [15] [16]

Non musculoskeletal manifestations of DMD occur. There is a higher risk of neurobehavioral disorders (e.g., ADHD), learning disorders (dyslexia), and non-progressive weaknesses in specific cognitive skills (in particular short-term verbal memory), [11] which are believed to be the result of absent or dysfunctional dystrophin in the brain. [17]

Cause

DMD is inherited in a X-linked recessive manner. X-linked recessive.svg
DMD is inherited in a X-linked recessive manner.

DMD is caused by a mutation of the dystrophin gene, located on the short arm of the X chromosome (locus Xp21) [18] that codes for dystrophin protein. Mutations can either be inherited or occur spontaneously during germline transmission,[ citation needed ] causing to a large reduction or absence of dystrophin, a protein that provides structural integrity in muscle cells. [19] Dystrophin is responsible for connecting the actin cytoskeleton of each muscle fiber to the underlying basal lamina (extracellular matrix), through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the sarcolemma (the cell membrane). [20] Alterations in calcium and signalling pathways cause water to enter into the mitochondria, which then burst.[ citation needed ]

In skeletal muscle dystrophy, mitochondrial dysfunction gives rise to an amplification of stress-induced cytosolic calcium signals and an amplification of stress-induced reactive-oxygen species production. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.[ citation needed ]

Depiction of dystrophin connecting intracellular actin to extracellular matrix Dystrophin diagram.jpg
Depiction of dystrophin connecting intracellular actin to extracellular matrix

DMD is inherited in an X-linked recessive pattern. Females typically are carriers of the genetic trait while males are affected. A female carrier will be unaware she carries a mutation until she has an affected son. The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier and a 50% chance of having two normal copies of the gene. In all cases, an unaffected father either passes a normal Y to his son or a normal X to his daughter. Female carriers of an X-linked recessive condition, such as DMD, can show symptoms depending on their pattern of X-inactivation.[ citation needed ]

DMD is extremely rare in females (about 1 in 50,000,000 female births). [5] It can occur in females with an affected father and a carrier mother, in those who are missing an X chromosome, or those who have an inactivated X chromosome (the most common of the rare reasons). [21] The daughter of a carrier mother and an affected father will be affected or a carrier with equal probability, as she will always inherit the affected X-chromosome from her father and has a 50% chance of also inheriting the affected X-chromosome from her mother. [22]

Disruption of the blood-brain barrier has been seen to be a noted feature in the development of DMD. [23]

Diagnosis

Genetic counseling is advised for people with a family history of the disorder. DMD can be detected with about 95% accuracy by genetic studies performed during pregnancy. [14] Creatine kinase (CPK-MM) levels in the bloodstream are extremely high. An electromyography (EMG) shows that weakness is caused by destruction of muscle tissue rather than by damage to nerves.[ citation needed ]

DNA test

The muscle-specific isoform of the dystrophin gene is composed of 79 exons, and DNA testing (blood test) 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. [24]

Muscle biopsy

If DNA testing fails to find the mutation, a muscle biopsy test may be performed. [25] A small sample of muscle tissue is extracted using a biopsy needle. The key tests performed on the biopsy sample for DMD are immunohistochemistry, immunocytochemistry, and immunoblotting for dystrophin, and should be interpreted by an experienced neuromuscular pathologist. [26] These tests provide information on the presence or absence of the protein. Absence of the protein is a positive test for DMD. Where dystrophin is present, the tests indicate the amount and molecular size of dystrophin, helping to distinguish DMD from milder dystrophinopathy phenotypes. [27] 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 the presence of DMD. [28]

Prenatal tests

A prenatal test can be considered when the mother is a known or suspected carrier. [29]

Prenatal tests can tell whether the unborn child has one of the most common mutations. Many mutations are responsible for DMD, and some have not been identified, so genetic testing may be falsely negative if the suspected mutation in the mother has not been identified.[ citation needed ]

Prior to invasive testing, determination of the fetal sex is important; while males are sometimes affected by this X-linked disease, female DMD is extremely rare. This can be achieved by ultrasound scan at 16 weeks or more recently by free fetal DNA (cffDNA) testing. Chorion villus sampling (CVS) can be done at 11–14 weeks, and has a 1% risk of miscarriage. Amniocentesis can be done after 15 weeks, and has a 0.5% risk of miscarriage. Non invasive prenatal testing can be done around 10–12 weeks. [30] Another option in the case of unclear genetic test results is fetal muscle biopsy.

Treatment

Salbutamol (albuterol) -- a b2 agonist Salbutamol.svg
Salbutamol (albuterol) — a β2 agonist

No cure for DMD is known, and an ongoing medical need has been recognized by regulatory authorities. [31] Gene therapy has shown some success. [32]

Treatment is generally aimed at controlling symptoms to maximize the quality of life which can be measured using specific questionnaires, [33] and include:

The medication eteplirsen, a Morpholino antisense oligo, has been approved in the United States for the treatment of mutations amenable to dystrophin exon 51 skipping. The US approval has been controversial [37] as eteplirsen failed to establish a clinical benefit; [38] it has been refused approval by the European Medicines Agency. [39]

The medication ataluren (Translarna) is approved use in the European Union. [40] [41]

The antisense oligonucleotide golodirsen (Vyondys 53) was approved for medical use in the United States in 2019, for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. [42] [43]

The Morpholino antisense oligonucleotide viltolarsen (Viltepso) was approved for medical use in the United States in August 2020, for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. [44] It is the second approved targeted treatment for people with this type of mutation in the United States. [44] Approximately 8% of people with DMD have a mutation that is amenable to exon 53 skipping. [44]

Casimersen was approved for medical use in the United States in February 2021, [45] and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. [45]

Comprehensive multidisciplinary care guidelines for DMD have been developed by the Centers for Disease Control and Prevention, and were published in two parts in The Lancet Neurology in 2010. [25] An update was published in 2018. [46] [47]

Physical therapy

Physical therapists are concerned with enabling patients to reach their maximum physical potential. Their aim is to:[ citation needed ]

Respiration assistance

Tracheotomy
1 - Vocal folds
2 - Thyroid cartilage
3 - Cricoid cartilage
4 - Tracheal rings
5 - Balloon cuff Traqueostomia.png
Tracheotomy
1 – Vocal folds
2 – Thyroid cartilage
3 – Cricoid cartilage
4 – Tracheal rings
5 – Balloon cuff

Modern "volume ventilators/respirators", which deliver an adjustable volume (amount) of air to the person with each breath, are valuable in the treatment of people with muscular dystrophy-related respiratory problems. The ventilator may require an invasive endotracheal or tracheotomy tube through which air is directly delivered, but for some people, noninvasive delivery through a face mask or mouthpiece is sufficient. Positive airway pressure machines, particularly bilevel ones, are sometimes used in this latter way. The respiratory equipment may easily fit on a ventilator tray on the bottom or back of a power wheelchair with an external battery for portability.[ citation needed ]

Ventilator treatment may start in the mid- to late teens when the respiratory muscles can begin to collapse. If the vital capacity has dropped below 40% of normal, a volume ventilator/respirator may be used during sleeping hours, a time when the person is most likely to be underventilating (hypoventilating). Hypoventilation during sleep is determined by a thorough history of sleep disorder with an oximetry study and a capillary blood gas (see pulmonary function testing).[ citation needed ] A cough assist device can help with excess mucus in lungs by hyperinflation of the lungs with positive air pressure, then negative pressure to get the mucus up. If the vital capacity continues to decline to less than 30 percent of normal, a volume ventilator/respirator may also be needed during the day for more assistance. The person gradually will increase the amount of time using the ventilator/respirator during the day as needed. However, there are also people with the disease in their 20s who have no need for a ventilator.[ citation needed ]

Future developments

There is no cure for any of the muscular dystrophies. [48] Several drugs designed to address the root cause are under development, including gene therapy (Microdystrophin), and antisense drugs (Ataluren, Eteplirsen etc.). [49] Other medications used include corticosteroids (Deflazacort), calcium channel blockers (Diltiazem) to slow skeletal and cardiac muscle degeneration, anticonvulsants to control seizures and some muscle activity, and immunosuppressants (Vamorolone) to delay damage to dying muscle cells. [2] Physical therapy, braces, and corrective surgery may help with some symptoms [2] while assisted ventilation may be required in those with weakness of breathing muscles. [3] Outcomes depend on the specific type of disorder. [50] [49]

A paper published by Stanford University on 10 March 2022 demonstrated that patients with muscular dystrophies could benefit from new therapies targeting the specific pathways contributing directly to muscle disorders. Three recent advances are likely to enhance the landscape of treatments for muscular dystrophies such as DMD. First, induced pluripotent stem cells (iPSCs) allow researchers to design effective treatment strategies. Second, artificial intelligence (AI) can help identify therapeutic targets. Third, a high volume of multi-omics data gathered from diverse sources through disease models can provide valuable information about converging and diverging pathways. [19]

Prognosis

Duchenne muscular dystrophy is a rare progressive disease which eventually affects all voluntary muscles and involves the heart and breathing muscles in later stages. Life expectancy is estimated to be around 25–26, [14] [4] but this varies. With excellent medical care, affected men often live into their 30s. [51] David Hatch of Paris, Maine, may be the oldest person in the world with the disease; as of 2021, he was 58. [52]

The most common direct cause of death in people with DMD is respiratory failure. Complications from treatment, such as mechanical ventilation and tracheotomy procedures, are also a concern. The next leading cause of death is cardiac-related conditions such as heart failure brought on by dilated cardiomyopathy. With respiratory assistance, the median survival age can reach up to 40. In rare cases, people with DMD have been seen to survive into their forties or early fifties, with proper positioning in wheelchairs and beds, and the use of ventilator support (via tracheostomy or mouthpiece), airway clearance, and heart medications. [53] Early planning of the required supports for later-life care has shown greater longevity for people with DMD. [54]

Curiously, in the mdx mouse model of Duchenne muscular dystrophy, the lack of dystrophin is associated with increased calcium levels and skeletal muscle myonecrosis. The intrinsic laryngeal muscles (ILMs) are protected and do not undergo myonecrosis. [55] ILMs have a calcium regulation system profile suggestive of a better ability to handle calcium changes in comparison to other muscles, and this may provide a mechanistic insight for their unique pathophysiological properties. [56] The ILM may facilitate the development of novel strategies for the prevention and treatment of muscle wasting in a variety of clinical scenarios. [57] In addition, patients with Duchenne muscular dystrophy also have elevated plasma lipoprotein levels, implying a primary state of dyslipidemia in patients. [58]

Epidemiology

DMD is the most common type of muscular dystrophy; it affects about one in 5,000 males at birth. [3] DMD has an incidence of one in 3,600 male infants. [14]

In the US, a 2010 study showed a higher amount of those with DMD age ranging from 5 to 54 who are Hispanic compared to non-Hispanic Whites, and non-Hispanic Blacks. [59]

History

Dr Guillaume Duchenne de Boulogne G. Duchenne-2.jpg
Dr Guillaume Duchenne de Boulogne

The disease was first described by the Neapolitan physician Giovanni Semmola in 1834 and Gaetano Conte in 1836. [60] [61] [62] However, DMD is named after the French neurologist Guillaume-Benjamin-Amand Duchenne (1806–1875), who in the 1861 edition of his book Paraplegie hypertrophique de l'enfance de cause cerebrale, described and detailed the case of a boy who had this condition. A year later, he presented photos of his patient in his Album de photographies pathologiques. In 1868, he gave an account of 13 other affected children. Duchenne was the first to do a biopsy to obtain tissue from a living patient for microscopic examination. [63] [64]

Notable cases

Alfredo ("Dino", "Alfredino") Ferrari (born January 1932 in Modena), the son of Enzo Ferrari, designed the 1.5 L DOHC V6 engine for the model F2 at the end of 1955. But Dino never saw the engine produced: he died on 30 June 1956 in Modena at the age of 24, before his namesakes Dino and Fiat Dino were made.[ citation needed ]

Rapper Darius Weems had the disease and used his notoriety to raise awareness and funds for treatment. [65] He died at the age of 27 (his brother also had the disease, until his death at the age of 19). The film Darius Goes West documents Weems's journey of growth and acceptance of having the disease.[ citation needed ]

Jonathan Evison's novel, The Revised Fundamentals of Caregiving , published in 2012, depicted a young man affected by the disease. In 2016, Netflix released The Fundamentals of Caring , a film based on the novel. [66]

Research

Current research includes exon-skipping, stem cell replacement therapy, analog up-regulation, gene replacement, and supportive care to slow disease progression.[ citation needed ]

Efforts are ongoing to find medications that either return the ability to make dystrophin or utrophin. [67] Other efforts include trying to block the entry of calcium ions into muscle cells. [68]

Exon-skipping

Antisense oligonucleotides (oligos), structural analogs of DNA, are the basis of a potential treatment for 10% of people with DMD. [69] The compounds allow faulty parts of the dystrophin gene to be skipped when it is transcribed to RNA for protein production, permitting a still-truncated but more functional version of the protein to be produced. [70] It is also known as nonsense suppression therapy. [71]

Two kinds of antisense oligos, 2'-O-methyl phosphorothioate oligos (like drisapersen) and Morpholino oligos (like eteplirsen), have tentative evidence of benefit and are being studied. [72] Eteplirsen is targeted to skip exon 51. "As an example, skipping exon 51 restores the reading frame of ~ 15% of all the boys with deletions. It has been suggested that by having 10 AONs to skip 10 different exons it would be possible to deal with more than 70% of all DMD boys with deletions." [69] This represents about 1.5% of cases. [69]

Reading Frame Reading Frame.png
Reading Frame

People with Becker's muscular dystrophy, which is milder than DMD, have a form of dystrophin which is functional even though it is shorter than normal dystrophin. [73] In 1990 England et al. noticed that a patient with mild Becker muscular dystrophy was lacking 46% of his coding region for dystrophin. [73] This functional, yet truncated, form of dystrophin gave rise to the notion that shorter dystrophin can still be therapeutically beneficial. Concurrently, Kole et al. had modified splicing by targeting pre-mRNA with antisense oligonucleotides (AONs). [74] Kole demonstrated success using splice-targeted AONs to correct missplicing in cells removed from beta-thalassemia patients [75] [76] Wilton's group tested exon skipping for muscular dystrophy. [77] [78]

Gene therapy

Researchers are working on a gene editing method to correct a mutation that leads to Duchenne muscular dystrophy (DMD). [79] Researchers used a technique called CRISPR/Cas9-mediated genome editing, which can precisely remove a mutation in the dystrophin gene in DNA, allowing the body's DNA repair mechanisms to replace it with a normal copy of the gene. [80] [81] The benefit of this over other gene therapy techniques is that it can permanently correct the "defect" in a gene rather than just transiently adding a "functional" one.[ citation needed ]

Genome editing through the CRISPR/Cas9 system is not currently feasible in humans. However, it may be possible, through advancements in technology, to use this technique to develop therapies for DMD in the future. [82] [83] In 2007, researchers did the world's first clinical (viral-mediated) gene therapy trial for Duchenne MD. [84]

Biostrophin is a delivery vector for gene therapy in the treatment of Duchenne muscular dystrophy and Becker muscular dystrophy. [85]

Related Research Articles

Muscular dystrophy Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

Limb–girdle muscular dystrophy Medical condition

Limb–girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD usually has an autosomal pattern of inheritance. It currently has no known cure or treatment.

Dystrophin Rod-shaped cytoplasmic protein

Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

Becker muscular dystrophy Genetic muscle disorder

Becker muscular dystrophy is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, but has a milder course.

Morpholino Chemical compound

A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule used in molecular biology to modify gene expression. Its molecular structure contains DNA bases attached to a backbone of methylenemorpholine rings linked through phosphorodiamidate groups. Morpholinos block access of other molecules to small specific sequences of the base-pairing surfaces of ribonucleic acid (RNA). Morpholinos are used as research tools for reverse genetics by knocking down gene function.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

Sarepta Therapeutics, Inc. is a medical research and drug development company with corporate offices and research facilities in Cambridge, Massachusetts, United States. Incorporated in 1980 as AntiVirals, shortly before going public the company changed its name from AntiVirals to AVI BioPharma soon with stock symbol AVII and in July 2012 changed name from AVI BioPharma to Sarepta Therapeutics and SRPT respectively. As of the end of 2019, the company has two approved drugs.

The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.

Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. In humans, there are at least two isoforms of dystrobrevin, dystrobrevin alpha and dystrobrevin beta.

Ataluren

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

mir-31

miR-31 has been characterised as a tumour suppressor miRNA, with its levels varying in breast cancer cells according to the metastatic state of the tumour. From its typical abundance in healthy tissue is a moderate decrease in non-metastatic breast cancer cell lines, and levels are almost completely absent in mouse and human metastatic breast cancer cell lines. Mir-31-5p has also been observed upregulated in Zinc Deficient rats compared to normal in ESCC and in other types of cancers when using this animal model. There has also been observed a strong encapsulation of tumour cells expressing miR-31, as well as a reduced cell survival rate. miR-31's antimetastatic effects therefore make it a potential therapeutic target for breast cancer. However, these two papers were formally retracted by the authors in 2015.

Drisapersen is an experimental drug that was under development by BioMarin, after acquisition of Prosensa, for the treatment of Duchenne muscular dystrophy. The drug is a 2'-O-methyl phosphorothioate oligonucleotide that alters the splicing of the dystrophin RNA transcript, eliminating exon 51 from the mature dystrophin mRNA.

Eteplirsen

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

Ezutromid

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

Golodirsen, sold under the brand name Vyondys 53, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). It is an antisense oligonucleotide drug of phosphorodiamidate morpholino oligomer (PMO) chemistry.

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Cure Rare Disease

Cure Rare Disease is a non-profit biotechnology company based in Boston, Massachusetts that is working to create novel therapeutics using gene therapy, gene editing and antisense oligonucleotides to treat people impacted by rare and ultra-rare genetic neuromuscular conditions.

Toshifumi (Toshi) Yokota is a medical scientist and professor of medical genetics at the University of Alberta, where he also holds the titles of the Friends of Garrett Cumming Research & Muscular Dystrophy Canada Endowed Research Chair and the Henri M. Toupin Chair in Neurological Science. He is best known for his studies of antisense oligonucleotide-based therapeutics for muscular dystrophy that led to the development of an FDA-approved drug viltolarsen. His research interests include precision medicine for muscular dystrophy and genetic diseases. He has co-edited two books both published in the Methods in Molecular Biology series from Humana Press, Springer-Nature, and has published more than 100 refereed papers and patents. He is a member of the editorial boards for the International Journal of Molecular Sciences, Genes, Frontiers in Genome Editing, Frontiers in Physiology, and Nucleic Acid Therapeutics, a member of the Medical and Scientific Advisory Committee of Muscular Dystrophy Canada, and a co-founder of the Canadian Neuromuscular Network (CAN-NMD).

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO).

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