There are over 7,000 rare diseases, the customized therapeutic platform CRD is developing has positive implications for the following rare diseases:
Duchenne’s Muscular Dystrophy
What is Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It is one of nine types of muscular dystrophy. DMD causes progressive weakness and loss (atrophy) of skeletal and heart muscles. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact.
What is the prevalence/incidence of Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. The muscular dystrophies as a whole are estimated to affect 250,000 individuals in the United States.
What are the symptoms of Duchenne Muscular Dystrophy?
Muscle weakness can begin as early as age three, first affecting the muscles of the hips, pelvic area, thighs and shoulders, and later the skeletal (voluntary) muscles in the arms, legs and trunk. The calves often are enlarged. By the early teens, the heart and respiratory muscles also are affected. Other symptoms may include difficulty sitting, walking, standing, climbing, running. Scoliosis may develop within several years of full-time wheelchair use. By the early teens, the respiratory and heart muscles are also affected In some cases, learning and memory issues (cognitive impairment) may occur, but do not worsen as DMD progresses. Communication may be more difficult for some. Social behavior may be affected, as well as the ability to read facial cues.
What are the causes of Duchenne Muscular Dystrophy?
DMD is caused by mutations in the dystrophin gene, which is responsible for providing information for producing dystrophin, a protein that helps stabilize and protect muscle fibers. When dystrophin is missing, the muscle cells become damaged more easily. In response to the damage, inflammation occurs, which only worsens the process. Over time, the muscle cells without dystrophin weaken and die, leading to the muscle weakness and heart problems seen in DMD. The non-progressive memory and learning problems, as well as social behavioral problems, in some boys with DMD are most likely linked to loss of dystrophin in the neurons of the hippocampus and other parts of the brain where dystrophin is normally produced in small amounts, but at this point it is not known why this occurs and why only some people with DMD have these problems.
What are the Duchenne Muscular Dystrophy carriers?
Genetic changes causing Duchenne muscular dystrophy (DMD) can be passed down in families. The DMD gene is located on the X chromosome, one of the two types of sex chromosomes. Males have an X and a Y chromosome; whereas females have two X chromosomes. Since males only have one X chromosome, they also only have one copy of the DMD gene. If this copy has a genetic change that causes DMD, the male will have DMD. Males get their X chromosome from their mother and the Y chromosome from their father. Since females have two X chromosomes, they have two copies of the DMD gene. Having two changed copies of the DMD gene that can cause DMD is unlikely, but would cause DMD in females. A female with only one changed copy of the DMD gene is called a “carrier”. She can pass on the changed gene, but usually does not have symptoms of DMD. Carriers of changes in the DMD gene that can cause DMD are at an increased risk of developing heart problems, including cardiomyopathy. In addition, due to a process called X-inactivation, in rare cases, female carriers may have mild, moderate, or severe DMD. If a man with DMD has children, all of his daughters will be carriers. Since boys inherit the Y chromosome from their father, sons will not inherit DMD from their fathers, even if the father has DMD. Women who are carriers of a change in the DMD gene that can cause DMD have a 50% chance of passing it on to each child, whether the child is a boy or a girl. In other words, each daughter will have a 50% risk of being a carrier. Each son will have a 50% risk of having DMD.
What is the life expectancy of Duchenne Muscular Dystrophy?
Until recently, boys with DMD usually didn’t survive much beyond their teen years. Life expectancy is increasing due to medical advancements and most survive into their early 30s, with some into their 40s and 50s.
What is the status of research in DMD?
Currently, there is no curative treatment, Most treatments are aimed towards symptoms for specific individuals. Treatment options should include physical therapy and active and passive exercise to build muscle strength and prevent contractures. Surgery may be recommended in some patients to treat contractures or scoliosis. Braces may be used to prevent the development of contractures. The use of mechanical aids (e.g., canes, braces, and wheelchairs) may become necessary to aid walking (ambulation). Corticosteroids are used as standard of care to treat individuals with DMD. These drugs slow the progression of muscle weakness in affected individuals and delay the loss of ambulation by 2-3 years. In 2017, Emflaza (deflazacort) was FDA approved to treat patients age 5 years and older with DMD. Emflaza is marketed by PTC Therapeutics. There are clinical trials going on for gene modification and some even include heart related surgeries.
A milder variant of the DMD, Becker muscular dystrophy (BMD) is one of nine types of muscular dystrophy, a group of genetic, degenerative diseases primarily affecting voluntary muscles.
What is the prevalence/incidence of Becker’s Muscular Dystrophy?
The incidence rate, which refers to the rate of occurrence of new cases of BMD is between 1 in 18,000 and 1 in 30,000 male births. The prevalence rate that estimates all the people affected with BMD at a given time are broad and ranges differ based on source. According to Medscape Reference, the prevalence of BMD is estimated to be between 17 to 27 cases per million people.
What are the symptoms of Becker’s Muscular Dystrophy?
BMD’s onset is usually in late childhood or adolescence, and the course is slower and less predictable than that of DMD. Generalized weakness first affects muscles of the hips, pelvic area, thighs and shoulders. Calves are often enlarged. There can be significant heart involvement. Other symptoms may include abnormal urinary color, difficulty climbing, walking and exercising, cognitive problems, fatigue, loss of balance and coordination, and problems breathing. The condition also affects the heart muscles, causing dilated cardiomyopathy. This form of heart disease enlarges and weakens the heart muscle, preventing it from pumping blood efficiently. Dilated cardiomyopathy progresses rapidly and is life-threatening in many cases.
What are the causes of Becker’s Muscular Dystrophy?
Similar to DMD, Becker is also caused by specific mutations in the DMD gene, which provides essential information to the body to make dystrophin protein that helps stabilize and protect muscle fibers. Muscle cells without fully functional dystrophin become damaged as muscles contract and relax with use. They then weaken and die over time, leading to the muscle weakness and heart problems in people with BMD.
What are the BMD carriers?
Becker muscular dystrophy is inherited in an X-linked recessive manner. A condition is considered X-linked if the mutated gene that causes the condition is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one mutated copy of the gene in each cell is enough to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the condition. Males are affected by X-linked recessive disorders much more frequently than females. A specific characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
In about two thirds of cases, an affected male inherits the mutation from his mother who carries a mutated copy of the dystrophin gene. The other third of cases probably result from new mutations in the gene.
What is the life expectancy of BMD?
Most people affected survive into the 40s and beyond. If the cardiac aspects of the disease are minimal, or if they are adequately controlled through medical intervention, a normal or nearly normal life span can be expected.
What is the status of research in BMD?
Although there is no cure for BMD, there are therapies and other methods that help patients improve overall quality of life. Researchers are actively pursuing several strategies in BMD. Among the major strategies are gene replacement; gene modification; stem cells; inhibiting a protein called myostatin; expanding the distribution and increasing the level of a protein called utrophin; and increasing blood flow to muscles.
Limb-girdle muscular dystrophy is an inherited disease that causes progressive weakness and wasting of the proximal muscles (muscles closest to the torso) in the shoulder and hip (limb-girdle) areas. Affected part of the body include the shoulders, upper arms, thighs and pelvis.
What is the prevalence/incidence of LGMD?
Although it is difficult to measure the prevalence due to the fact that the symptoms overlap with other muscular dystrophies, an approximate estimate ranges from 1 in 14,500 to 1 in 123,000 individuals.
What are the symptoms of disease?
The severity and age of onset vary among the various types of LGMD. They can be different even among members of the same family. In the early stages, affected individuals may present with an unusual way of walking; they may waddle or walk on the balls of their feet, and consequently have trouble running or climbing the stairs. People sometimes have difficulty standing up from a squatting position because their thigh muscles are weak. Overgrowth of the calf muscles to compensate can sometimes occur.
As the disease spreads to the upper body, individuals have difficulty lifting their arms above their heads or carrying heavy objects. With progression of the disease, patients may eventually need a wheelchair to get around. Due to the muscle wasting, changes in posture and the appearance of the affected areas becomes evident. Specifically, because of weak shoulder muscles, the shoulder blades tend to protrude in the back called “winging of the scapula.” People can also develop scoliosis (spine curvature to the side) or lumbar lordosis (lower spine curvature to the front). Stiffening joints that restrict mobility is common.
Complications of the cardiovascular system can ensue, where the heart muscle weakens and results in cardiomyopathy. Those with severe disease have affected respiratory muscles and issues with breathing. In severe cases of this, individuals may need mechanical ventilation to assist with breathing. Developmental delays and intellectual disability can occur in rare cases.
What are the causes of LGMD?
There are various forms of limb-girdle muscular dystrophy and each one is caused by mutations in many different genes that code for proteins located on the membrane of muscle cells or inside the muscle cells. The proteins complex together with larger proteins have several different functions such as maintenance of the structure of muscle tissue, contraction, cell signaling, cell membrane repair, or the removal of toxic wastes. If one of these proteins is deficient or defective, muscle cells will not be able to perform these functions.
The types of Limb-girdle muscular dystrophy are classified based on inheritance pattern and disease-causing gene involved:
Type 1 – Autosomal dominant
1B – Caused by mutations in the LMNA gene
1C — Caused by mutations in the CAV3 gene.
Type 2 – Autosomal recessive
2A – Caused by mutations in the CAPN3 gene. This is the most common type
2B — Caused by mutations in the DYSF gene.
2C, D, E, F – Caused by mutations in SGCA, SGCB, SGCD genes, respectively.
2G – Caused by mutations in the TCAP
2H – caused by mutations in the TRIM-32
2I – caused by mutations in the FKRP gene
2J – Caused by mutations in the TTN gene.
2L – Caused by mutations in the ANO5 gene
There are many other forms of limb-girdle muscular dystrophy that have also been identified though are not listed here.
What are the carriers of LGMD?
Most forms are inherited in an autosomal recessive which means both copies of the gene mutation is necessary to cause the disease. Each parent of a child with Limb-Girdle carries one copy of the mutated gene, but they do not show signs and symptoms. They are known as disease carriers.
Although it is rare, there are some forms that can be inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is needed to cause the disease.
What is the life expectancy of LGMD?
LGDM does not shorten an individual’s lifespan. People can become dependent on the wheelchair within 20 to 30 years. Most people live on until their adulthood, but may not reach a normal full life expectancy depending on the severity and type of disease. If the heart and lung muscles become involved, sudden death could occur.
What is the status of research in LGMD?
Researchers in the field of LGMD have discovered many genes that cause the disease if defective, a focus of research that continues to this day. Researchers are trying to figure out the function of these disease-causing genes to learn more about whether those missing functions can be compensated in another way. Gene therapy, the process of inserting a new gene to replace the non-functioning gene, has shown promise in autosomal recessive forms. In dominant forms of LGMD, inhibiting ill effects of the gene through antisensing methods have been shown to be useful. Antisense technology prevents cells from interpreting specific genetic information.
Since LGMD overlaps with other more commonly researched muscular dystrophies, researchers are honing in on those studies to see if they can be applied to this disease. In Duchenne muscular dystrophy, drugs that cause cells to read through premature stop codons that cause cells to stop reading genetic information before proteins are made have been tested and may be applied to LGMD in the future. The use of exon skipping technology to cut out the part of the DNA sequence that has errors is also being studied for its relevance in LGMD.
Scientists are also looking into the use of stem cells to replace atrophied muscle tissue with mature muscle fibers.
The latest breakthrough in treatment is through the development of a gene therapy approach. In a joint development between Sarepta Therapeutics and Myonexus Therapeutics, a new wave of gene therapy approaches are in varying stages of preclinical and clinical development. Currently, the following approaches are in preclinical development for LGMD:
MYO-103 (LGMD2C γ-sarcoglycan)
MYO-301 (LGMD2L Anoctamin 5)
And the following approaches are in clinical development for LGMD:
Spinal muscular atrophy (SMA) is a genetic disease affecting the part of the nervous system (specifically, the nerve cells called motor neurons) that controls voluntary muscle movement. Most of the nerve cells that control muscles are located in the spinal cord, which accounts for the word spinal in the name of the disease. SMA is muscular because its primary effect is on muscles, which don’t receive signals from these nerve cells. Atrophy is the medical term for getting smaller, which is what generally happens to muscles when they’re not active. There are five types of SMA.
What is the prevalence/incidence of SMA?
Spinal muscular atrophy affects 1 per 8,000 to 10,000 people worldwide. Spinal muscular atrophy type I is the most common type, accounting for about half of all cases. Types II and III are the next most common and types 0 and IV are rare. In the US, one in 6,000 to one in 10,000 infants are born with this disorder.
What are the symptoms of SMA?
The symptoms can be from mild to very severe. The primary symptom of chromosome 5-related (SMN-related) SMA is weakness of the voluntary muscles. The muscles most affected are those closest to the center of the body, such as those of the shoulders, hips, thighs and upper back. Special complications occur if the muscles used for breathing and swallowing are affected, resulting in abnormalities in these functions. If the muscles of the back weaken, spinal curvatures can develop.
What are the causes of SMA?
All types of SMA are caused by mutations in the SMN1 gene, usually there is a shortage of the gene. The changes in SMN2 gene determines which type develops. The SMN1 and SMN2 genes both provide instructions for making a protein called the survival motor neuron (SMN) protein. Normally, most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Most people with spinal muscular atrophy are missing a piece of the SMN1 gene, which impairs SMN protein production. Shortage of SMN protein leads to motor neuron death, resulting in signals not transmitting between the brain and muscles. Muscles cannot function without receiving signals from the brain, so many skeletal muscles become weak and waste away, leading to the signs and symptoms of spinal muscular atrophy. There are many other unknown factors that affect the severity of SMA.
What are the SMA carriers?
Both SMN1 and SMN2 genes carry instructions to make a survival motor neuron protein. The SMN protein is one of a group of proteins called the SMN complex, which is important for the maintenance of motor neurons. Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense, which allows the body to move. SMA is inherited in such a way that both copies of the SMN1 gene in each cell have mutations. This pattern is known as autosomal recessive pattern.
What is the life expectancy of SMA?
The life expectancy depends on the type of SMA. With type 1, most individuals do not survive beyond the age of two. Type 2 and type 3 typically have a normal life expectancy.
What is the status of research in SMA?
In this case, there has been significant research primarily focusing on increasing the body’s SMN protein production. Other approaches include procedures to assist motor neurons to survive in all circumstances. The U.S. Food and Drug Administration on Dec. 23, 2016, approved nusinersen (brand name Spinraza) for the treatment of SMA. This drug helps in treating the defect of SMA. The other breakthrough treatment is through AveXis (recently purchased by Novartis). The approach is to deliver a humanized SMN gene through a viral vector (gene therapy). Clinical trials are underway for this approach and will target Type 1 and Type 2 patients.
Cystic fibrosis (CF) is a genetic disease of the cells in mucus glands and sweat glands, which then affects the breathing passages of the sinuses and lungs, the digestive tract, and reproductive organs. CF is one of the most common chronic lung diseases amongst children and adults. It causes your mucus to be thick, sticky and clog the lungs causing breathing problems. This dysfunction makes it easy for bacteria to grow leading to repeated life-threatening lung infections, inflammation and subsequent lung damage.
What is the prevalence/incidence of CF?
According to the Cystic Fibrosis Foundation Patient Registry, more than 30,000 people in the U.S. and more than 70,000 worldwide live with cystic fibrosis. The incidence rate is 1 in 3,400 people per year in the US and Europe. It is most prevalent in those of northern or central European origin.
What are the symptoms of CF?
The screening of newborns for CF is now performed all over the country and can therefore be diagnosed very early on before symptoms develop. More than 75% of those with CF are diagnosed by age 2.
Individuals present with salty-tasting skin, persistent coughing sometimes with thick phlegm, frequent lung infections including pneumonia or bronchitis, wheezing, shortness of breath, intolerance to exercise, and a stuffy nose from inflammation. Since the inside of the nose is constantly inflamed, sometimes polyps can grow inside and block the passage even further. CF is one of the main causes of bronchiectasis, lung damage resulting from chronic infections and inflammation.
The buildup of mucus in the pancreas causes greasy, bulky and foul-smelling stools. However, severe constipation can also occur. People may experience malnutrition and poor growth. The thick mucus can also block the bile duct and cause liver disease. Newborn babies may have intestinal blockage known as meconium ileus. As the pancreas is affected, many patients with CF develop diabetes by the age of 30.
Most affected men with CF develop issues with infertility due to the fact that mucus blocks the vas deferens, a tube that connects the testes and prostate gland.
Signs and symptoms vary depending on the severity of the disease. They may manifest at different times in different patients, some people may not experience it until their teen or adult years.
What are the causes of CF?
CF is due to mutation in a gene that normally codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. As the protein becomes dysfunctional, it is unable to perform its normal function of helping to move chloride (a component of salt) and water to the surface of the cell. Due to this dysfunction, the mucus in various organs becomes thick and sticky. Instead of its normal function as a lubricant the mucus plugs up and blocks the passageways of these organs, especially the pancreas and lungs.
What are the carriers of CF?
CF is inherited in an autosomal recessive manner which means that a person should have the mutation of both copies of the CFTR gene. Both parents need to have one mutated copy of the gene for a child to have CF. If an individual inherits one mutated copy of the gene, they are referred to as a carrier and are typically asymptomatic.
Furthermore, when two carriers of CF have children, each child has different probabilities of acquiring CF. They have a 25% chance of having CF, 50% chance of being a carrier of CF, and a 25% chance of being normal.
When a carrier of CF has a child with a person with CF, each child has a 50% chance of having CF and a 50% chance of being a carrier of CF.
As there are numerous known mutations of the disease and most genetic tests only detect common mutations, this screening may not reliably identify an individual as a carrier.
What is the life expectancy of CF?
Despite CF being a debilitating disease, with advancements in specialized care, individuals can live a normal life up until adulthood. The average life expectancy is currently 37 years of age, but it is not uncommon to see people live into their 40s or 50s.
What is the status of research in CF?
CF has received a wide range of research interest amongst dedicated scientists and clinicians, which has greatly contributed to the quadrupling of the median life expectancy to the age of 37 in the United States by the discovery of medicines that combat devastating complications. New antibiotics such as inhaled Tobramycin and Pulmozyme® have been shown to be effective in treating lung infections caused by Pseudomonas aeruginosa and other bacteria. Mechanical chest therapy devices have been developed to help clear mucus from patients’ lungs. New gene therapies that aim to provide a working CFTR protein to patients are underway. Treatments are being tested to improve the salt-water balance, helping them clear mucus from the lungs. Scientists are identifying modifier genes that may be used to predict which patients will acquire more severe lung diseases.
Approved medications used to treat patients with cystic fibrosis may include pancreatic enzyme supplements, multivitamins (particularly fat-soluble vitamins), mucolytics, antibiotics (including inhaled, oral, or parenteral), bronchodilators and anti-inflammatory agents.
Clinical trials are underway for anti-inflammatory drugs that aim to increase the production of anti-inflammatory molecules, inhibit neutrophil elastase which breaks down healthy lung tissue, or combat the imbalance of omega-3 and omega-6 fatty acids. These new treatment modalities have helped to improve the quality of life, but there is still no cure and the therapies are still strenuous and demanding to take.
There are several groundbreaking progress and discoveries in the past 10 years:
FDA approval of aztreonam as an inhaled solution, an antibiotic for patients with resistance due to recurring lung infections
FDA approval of Ivacaftor, a drug addressing the underlying cause of CF
Ivacaftor thereafter was approved as a combination drug in order to increase the number of patients eligible to receive it
Tezacaftor + ivacaftor (Symdeko™) is a combinatorial therapy which combines tezacaftor, a compound designed to move the defective CFTR protein to the proper place in the airway cell surface, with ivacaftor, which helps facilitate the opening of the chloride channels on the cell surface to allow chloride and sodium (salt) to move in and out of the cell. This treatment is used for the most common CF mutation.
Canavan disease is a genetic neurological disorder in which the brain degenerates into spongy tissue riddled with microscopic fluid-filled spaces. Canavan disease is one of a group of genetic disorders referred to as the leukodystrophies. Recent research has shown that the cells in the brain which make myelin sheaths, known as oligodendrocytes, fail to properly complete this essential developmental task. Canavan disease is an inherited disorder that negatively affects the ability of neurons in the brain to send and receive messages. This is very common among infants, who show no signs until the age of 3 to 5 months. They have trouble developing motor skills like controlling head movement, sitting without support. They may also have a large head, weak muscles, difficulty in eating, seizures and irregular sleeping patterns. It can be identified through a parental blood test.
What is the prevalence/incidence of Canavan Disease?
This is most common among the eastern and central European Jewish population, studies suggest that it affects 1 in 6,400 to 13,500 people. The incidence in other populations is not known.
What are the symptoms of Canavan Disease?
Signs may vary throughout cases. Symptoms of Canavan disease usually appear in the first 3 to 6 months of life and progress rapidly. Symptoms include lack of motor development, feeding difficulties, abnormal muscle tone (weakness or stiffness), and an abnormally large, poorly controlled head. Paralysis, blindness, or hearing loss may also occur. Children are characteristically quiet and apathetic.Another symptom is an excess of N-acetylaspartic acid (NAA) in the brain.
What are the causes of Canavan Disease?
This disorder is caused by the mutations in the ASPA gene, which provides instructions for making an enzyme called aspartoacylase. The function of this enzyme is to break down a compound called N-acetylaspartic acid (NAA) found in the neurons in the brain. Mutations reduces the function of the enzyme, reducing normal breakdown of NAA. Studies suggest that if NAA is not broken down properly, the resulting chemical imbalance interferes with the formation of the myelin sheath as the nervous system develops. A buildup of NAA also leads to the progressive destruction of existing myelin sheaths. Nerves without this protective covering malfunction, which disrupts normal brain development.
What are the Canavan Disease carriers?
Both parents must be carriers of the defective ASPA gene in order to have an affected child. When both parents are found to carry the Canavan gene mutation, there is a one in four (25 percent) chance with each pregnancy that the child will be affected with Canavan disease.
What is the life expectancy of Canavan Disease?
The life expectancy varies for each patient. Most people with Canavan that manifests during infancy only live until childhood. Rarely do affected children survive beyond childhood. People who develop the disorder during their juvenile stages live a regular spanned life.
What is the status of research in Canavan Disease?
Canavan disease causes progressive brain atrophy. As of now, there is no cure, nor is there a standard course of treatment. Treatment is symptomatic and supportive. A recently completed study in diseased mice, showed slowing the course of disease through the delivery of the ASPA gene. Given the lack of effective treatment development, Cure Rare Disease believes that a customized therapeutic approach holds significant potential for these patients.
Charcot-Marie-Tooth disease (CMT) is a genetic neurological disorder. It was named after three physicians who first described it – Jean Martin Charcot, Pierre Marie from France and Howard Henry Tooth from UK. It is also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy. It affects the peripheral nerves which are nerves that lie outside of the brain and spinal cord. Their function is to carry signals between the central nervous system (brain and spinal cord) and the muscles; they are responsible for transmitting sensations like pain or touch in the limbs. There is currently no treatment or cure.
What is the prevalence/incidence of CMT?
It affects approximately 1 in 3,300 people in the United States.
What are the symptoms of CMT?
The symptoms of CMT progress gradually and are due to the involvement of motor and sensory nerves. This results in weakness and some loss of sensation in the foot and lower leg muscles. Affected individuals develop what is known as foot drop and a high-stepping gait leading to frequent tripping and falls. Due to weakness of the small muscles in the feet, several characteristic foot deformities can be seen such as high arched feet and hammertoes where the middle joint of a toe bends upwards. The calves can also develop an inverted champagne bottle appearance. As the disease progresses, weakness and muscle atrophy (thinning) spreads to the hands and the individual develops difficulty with fine motor skills which involve coordination of small movements in the fingers, wrists, hands and feet. Often CMT causes stiffening of the joints and abnormal curving of the spine known as scoliosis. The onset is dependent on the type and can begin anywhere from childhood to adulthood, although it most often is seen in adolescence or early adulthood. The severity of symptoms varies between individuals, and some may need to rely on the use of foot or leg braces or other orthopedic devices to maintain mobility.
What are the causes of CMT?
CMT causes damage to the peripheral nervous system. Peripheral neurons (nerve cells) normally communicate information by sending electrical signals down a long, thin string-like end called the axon. Axons relay sensations from the body’s tissues towards the spinal cord and muscle controls in the spinal cord out towards the muscles. Myelin is a substance that insulates and nourishes the axon by enclosing it like a jelly-filled doughnut. Myelin prevents the loss of electrical signals, as well as increases the speed of transporting them. Without an intact axon or myelin sheath, peripheral nerve cells are unable to reach their muscle targets or relay sensory information to and from the limbs and the brain.
CMT is caused by mutations in genes that produce proteins in the axon or myelin sheath. There are more than 80 genes affected creating variations of CMT types in which different proteins are abnormal in each type. The nerves slowly degenerate and lose the ability to communicate.
What are the CMT carriers?
CMT is a hereditary disorder that is passed down through generations. The gene mutations are usually inherited through an autosomal dominant, autosomal recessive, or x-linked fashion.
Autosomal dominant – Only one copy of the abnormal gene is needed to cause the disease. This type is easier to recognize in a family tree.
Autosomal recessive – Both copies of the abnormal gene must be present to cause the disease. This type is less distinct in a family tree. The mother or both parents may be carriers of CMT, meaning they have one copy of the genetic mutation that they can pass to their children. Carriers have no symptoms and usually no knowledge they carry this mutation.
X-linked – Abnormal gene is located on the X chromosome. This type usually affects males more severely than females. It can’t be passed from a father to a son.
New spontaneous mutation – Mutation occurs spontaneously in the genetic material and has not been passed down through the family. It can be passed onto the next generation.
What is the life expectancy of CMT?
CMT is generally not fatal, and most forms of the disease allow a normal life expectancy. In rare cases, individuals may develop respiratory muscle weakness in which case could potentially be life-threatening.
What is the status of research in CMT?
There is ongoing research that has produced numerous insights into various CMT genes, how mutations occur, and treatments that could potentially reverse or ultimately defeat the disorder.
A few studies in the works:
Exploring concepts of calcium handling in peripheral nerve fibers
Identification of signaling pathways that influence nerve-fiber health and injury in CMT
How a loss of function in a different proteins (mitofusin 2, fig 4, aminoacyl-tRNA synthetases) leads to CMT
Groundbreaking antisense technology for CMT Type 1A by Ionis Pharmaceuticals & Charcot-Marie-Tooth Association (CMTA); they used antisense oligonucleotides that targeted products of the disease-causing genes to then develop antisense drugs that would reduce the production of PMP22, the protein causing CMT type 1A.
Testing of a new molecule, Sephin, shown to improve CMT1B in mouse models
Research on how inhibiting axon degeneration pathways can stabilize neurons for all types is being supported by the CMTA
Four mouse models developed for the testing of therapeutic approaches such as inhibition of macrophages by CMTA
Sickle cell disease (SCD), also referred to as sickle cell anemia, is an inherited red blood cell disorder in which your blood makes an abnormal form of hemoglobin called Hemoglobin S. This changes the normally round shape of red blood cells to a C-shape, resembling a sickle. Currently the only cure is a blood and bone marrow transplant, and only a small number of people are able to undergo it.
What is the prevalence/incidence of SCD?
In the U.S., SCD affects approximately 100,000 people. It occurs among 1 in every 365 African-American births and 1 in every 16,300 Hispanic-American births. Sickle cell trait, the carrier form, occurs in about 1 in 13 African-American births.
What are the symptoms of SCD?
Symptoms of sickle cell disease are related to jaundice and anemia. Individuals feel fatigue, dizziness, shortness of breath, pale skin or yellowing of the skin and eyes in the case or jaundice. Severe anemia in a child with sickle cell disease can be due to aplastic crises (a viral infection) or trapping of blood in the spleen that causes it to enlarge painfully. Pain crises are a common manifestation which result in sudden attacks of severe pain that occur without warning due to a lack of oxygen in the tissues. Pain crises can be brought on by several factors including: high altitude, dehydration, illness, stress and temperature changes. Usually children are pain-free between these episodes, but chronic ongoing pain can manifest in adulthood. Painful swelling of the hands and feet, known as dactylitis, is another common symptom. Children often experience frequent infections and delayed growth. Over the course of the disease, other organs may be affected such as the spleen, brain, eyes, lungs, liver, heart, kidneys, penis, joints, bones, or skin. These can manifest as acute chest syndrome, a stroke, damage of the retina, enlargement of the heart, pulmonary hypertension, dysfunctional kidneys that lead to blood in the urine, prolonged painful erections (priapism), gallstones, leg ulcers, liver dysfunction.
What are the causes of SCD?
Sickle cell disease is caused by an inheritance of a mutated beta globin gene which produces an abnormal hemoglobin, called hemoglobin S. It is present at birth and occurs when a child receives two sickle cell genes from each parent. African Americans and Hispanics people have a strong predisposition for sickle cell disease. Mutations in the beta globin gene which functions to make hemoglobin occur. Hemoglobin is a protein in red blood cells that delivers oxygen from the lungs to tissues in the body. Red blood cells with normal hemoglobin are round in shape and flexible allowing them to move easily through blood vessels. In sickle cell disease, the shape of the red blood changes to a crescent (sickle) shape because of the abnormal hemoglobin. These sickle-shaped cells are not flexible, stick to vessel walls, and cause a slowing of blood flow and delivery of oxygen to tissues. The sickle cells also die earlier than the normal lifespan of a red blood cell which causes a deficiency.
What are the SCD carriers?
There are different types of SCD classified by the gene mutation. In all types, at least one gene will have mutated to form the abnormal hemoglobin S. These are the most common forms:
HbSS – This is the classic form, known as Sickle Cell Anemia, and is the most severe form of the disease. The individual will have inherited two sickle cell genes (S) from each parent.
HbSC – This is a milder form in which individuals inherit a sickle cell gene (S) from one parent and another abnormal hemoglobin gene (C) from the other parent.
HbS beta thalassemia – In this form, individuals inherit one sickle cell gene (S) from one parent and another mutated gene for beta thalassemia, another type of anemia, from the other parent.
What is the life expectancy of SCD?
SCD is linked to a shortened lifespan, however the prognosis for those with the disease has shown to be positive in the past few years and is dependent upon individual factors. SCD is a life-long illness and severity varies. Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. There is no available cure currently, however there are treatments directed at symptoms and complications to improve the quality of life.
What is the status of research in SCD?
In 2009, the National Institute of Health discovered that transplanting blood stem cells could improve sickle cell disease in adults severely affected by the disease, representing a milestone in the search for a cure. Studies were then funded by the NIH to learn more about the physiology of pain in a sickle cell patient in order to develop effective medications for symptoms. The use of antibodies to prevent the sticking of cells to vessels and thereby eliminating pain crises symptoms was tested for successfully. Additionally, a study found results to suggest that the disease may affect the more of an effect on the brain than initially noted, and ongoing studies are trying to evaluate how new treatments affect brain function.
Other research efforts being undertaken to understand the disease include the study of regulation of hemoglobin production, hidden complications of sickle cell trait, and genetic factors affecting sickle cell symptoms.
A recent new gene replacement method is being explored that could potentially help patients produce more normal red blood cells versus sickle shaped cells. The treatment removes stem cells from the patient’s own bone marrow or blood and adds a beta globin gene to it before returning the cells to the patient. This will result in the production of an anti-sickling hemoglobin.
Research targets for therapeutics:
Development of drugs to increase Hemoglobin F production, such as hydroxyurea
Transplantation of blood-forming stem cells
Optimal uses of blood transfusion and management of iron overload associated with repetitive blood transfusions
The FDA approved a treatment L-glutamine which reduces the number of crises. Endari, a medication developed to decrease acute complications in patients with SCD was made available by prescription in the United States. Endari had been approved by the US Food and Drug Administration (FDA) back in July 2017 for pediatric patients aged 5 and older with SCD.
In February 2018, Imara Inc. announced the dosing of their first patient in their phase 2a clinical trial designed to evaluate the safety, pharmacokinetics and pharmacodynamics of escalating doses of IMR-687 in adult patients with SCD.
The drug was granted Rare Pediatric Disease Designation by the FDA in May 2017, making it the first drug candidate for SCD to receive the label. Investigators are developing the drug to be used as a highly-potent oral therapy to be dosed once-daily to address the underlying red and white blood cell pathologies associated with the condition.
In May 2018, Bioverativ, Inc. announced that the FDA accepted the company’s Investigational New Drug (IND) application for their gene-edited cell therapy candidate, BIVV003, for the treatment of those with SCD. The acceptance marked the second IND for a gene-editing approach in less than a year, as well as the first ever for a gene-edited therapy intended to fight SCD. Biovertaiv and Sangamo are working to progress and commercialize these therapies for SCD and beta thalassemia.
Rivipansel (GMI-1070) is a potential new treatment for the excruciating pain of vaso-occlusive crisis associated with sickle cell anemia. It is being developed by GlycoMimetics in partnership with Pfizer. Rivipansel is a pan-selectin inhibitor, a molecule that blocks the activity of cell adhesion molecules called selectins in the blood vessels. The Phase 3 trial investigating the lead molecule (rivipansel) for vaso-occlusive crisis is expected to be completed in early 2019.
Lastly, new data from a post hoc analysis of the Phase II SUSTAIN study of crizanlizumab — a once-a-month, humanized anti-P-selectin monoclonal antibody infusion being investigated for the treatment of SCD — shows greater reductions of vaso-occlusive crises (VOCs) in patients who were adherent to the treatment protocol.