Therapies for Rare & Ultra-Rare Neuromuscular Diseases
What is DMD and BMD? Duchenne muscular dystrophy (DMD) is a neuromuscular condition with a prevalence of 1 in 3,500 male births that is caused by a mutation in the dystrophin gene. Becker muscular dystrophy (BMD) is another form of muscular dystrophy that impacts 1 in every 30,000 male births. Like DMD, BMD is caused by a mutation in the dystrophin gene. The mutation causes the patient to produce a shorter version of the dystrophin protein that does not function properly. Dystrophin is a protein that protects muscle fibers from breaking down, so the absence or deficiency of dystrophin caused by these mutations leads to muscle weakness and loss.
How is DMD and BMD acquired? DMD and BMD are genetic conditions that have an X-linked recessive inheritance pattern, meaning that the mutated dystrophin gene will always occur on the X-chromosome and all copies of the gene must be mutated for a person to have these disorders. This leads to predominantly males being affected by the conditions as females will nearly always have at least one functional copy of the dystrophin gene. DMD and BMD can be passed down from parent to child or can occur through a random mutation of the dystrophin gene.
What are some symptoms of DMD and BMD? Though DMD is progressive, early symptoms can be seen at only a few years of age. Early signs include difficulty going up stairs or standing up, facial weakness, delayed speech or language development, and leg pain. As the disease progresses, most experience decreases in cardiac and lung function. The overall symptom of DMD is muscle weakness and eventually loss of muscle function, though this can manifest in a variety of ways and have impacts outside of muscle function. Symptoms of BMD begin later than DMD, usually in the teens to late twenties. These signs include cramping and fatigue when exercising. Over time, patients will experience muscle breakdown in the hips, pelvis, thighs, and shoulders as well as decreased cardiac function. BMD progresses slower than DMD but patients often use a wheelchair or other mobility aids as the disease advances.
What is CRD doing to treat DMD and BMD? In partnership with labs in the United States and Canada, including Yale School of Medicine and SickKids Hospital, CRD is developing gene editing therapies using CRISPR technology to treat multiple different mutations of the dystrophin gene that manifest in DMD and BMD.
Learn more about the progress we are making to treat DMD and BMD.
What is ADSSL1? Adenylosuccinate synthase 1 (ADSSL1) is a gene that codes for an enzyme in skeletal muscle that aids in the production of adenosine monophosphate (AMP). AMP is a precursor to adenosine triphosphate (ATP), an energy-carrying molecule that is used for many processes in the body. Mutations in this gene cause the condition ADSSL-1 gene related myopathy, which has a prevalence of less than 1 in 1,000,000.
How is ADSSL1 acquired? ADSSL1 gene related myopathy is a genetic condition with an autosomal recessive inheritance pattern. This means that for a person to acquire the condition, they must inherit one copy of the mutated gene from each parent.
What are some symptoms of ADSSL1? ADSSL1 gene related myopathy is characterized by progressive muscle weakness, typically beginning sometime in childhood. As the condition progresses, weakness of the lower extremities is common, causing difficulty running and climbing stairs. Later in the progression of the condition, facial muscle weakness is also commonly experienced.
What is CRD doing to treat ADSSL1? Currently, CRD is developing gene replacement therapies to treat ADSSL1.
Learn more about the progress we are making to treat ADSSL1.
What is SCA3? Spinocerebellar ataxia type 3 (SCA3) is caused by a mutation in the ATXN3 gene, which codes for the enzyme ataxin-3. Ataxin-3 is found in cells throughout the body and is involved in the process that destroys and removes damaged or extra proteins. It is believed that ataxin-3 is also involved in transcription, the first stage of protein synthesis. The disease has a prevalence of 1 to 5 in 100,000 people.
How is SCA3 acquired? SCA3 is a genetic disorder that has an autosomal dominant inheritance pattern but can also occur through a randomly-occurring mutation in the ATXN3 gene. Having an autosomal dominant inheritance pattern means that a person only needs one copy of the mutated gene in order to inherit the condition. The specific mutation that causes SCA3 is a repetition of the nucleotide triplet C-A-G. A normal C-A-G segment is repeated 12 to 43 times within the gene. However, in people with SCA3, the C-A-G segment is repeated more than 50 times. SCA3 can also occur with no family history of the disease, meaning that the person had the mutation occur randomly.
What are some symptoms of SCA3? There are a variety of symptoms of SCA3 that vary greatly person to person and can appear at nearly any age from childhood to late adulthood. Symptoms can include clumsiness in the arms and legs and when walking, along with difficulty swallowing or speaking. People with SCA3 may also experience impaired eye movement or vision, nerve damage, twitching in the face and tongue, muscle spasms, and/or abnormal posture due to abnormal muscle tone.
What is CRD doing to treat SCA3? CRD is developing an ASO therapeutic for SCA3 in collaboration with Leiden University Medical Center that will skip the mutated part of the gene to allow for the correct, functional expression of the gene.
Learn more about the progress we are making to treat SCA3.
What is LGMD2b? Limb-girdle muscular dystrophy type 2b (LGMD2b) is caused by a mutation in the DYSF gene, which codes for a protein called dysferlin. Dysferlin is found in the sarcolemma, a membrane that surrounds muscle fibers in the body. The protein helps repair the sarcolemma and may also play roles in inflammation and in forming new muscle fibers. It has a prevalence of about 7.4/1,000,000.
What are symptoms of LGMD2b? The age of symptom onset is between 20 and 30 years but it can vary. Symptoms include muscle weakness in the pelvis and shoulder areas. In later stages of LGMD2b, breathing difficulties have been observed, but these are usually not as severe as in other types of muscular dystrophy. Because of this and the fact that the heart muscles are not generally impacted by this subtype, life expectancy usually falls within a normal range.
How is LGMD2b acquired? LGMD2b is a genetic disorder, meaning the mutated gene is passed down through family members. It is also autosomal recessive: to inherit it, an individual needs to have two copies of the mutated gene (one from each parent). So far, researchers have discovered over 140 mutations in the DYSF gene that cause LGMD2b. The disease is more common in individuals of Libyan Jewish descent.
What is CRD doing to treat LGMD2b? CRD is developing a treatment for this condition with recombinant protein therapeutics. This process involves inserting the DNA that codes for a specific protein in a bacterial or mammal cell so that those cells can produce the protein. Due to the large size of the DYSF gene, gene replacement therapy is not a viable option.
Learn more about the progress we are making to treat LGMD2b.
What is LGMD2g? Limb-girdle muscular dystrophy type 2g (LGMD2g) is caused by a mutation in the TCAP gene. The gene codes for telethonin, a protein that helps to regulate the assembly of muscle cells. LGMD2g has an estimated prevalence of 0.040/1,000,000.
How is LGMD2g acquired? LGMD2g is a genetic, autosomal recessive disease, so an individual must inherit one copy of the mutated gene from each parent.
What are symptoms of LGMD2g? The age of onset varies greatly: symptoms have emerged as early as infancy to as late as adolescence. Scapular winging (weakness of the muscles of the shoulder blade) and calf hypertrophy (enlargement of the calf muscle) are common symptoms. Respiratory and cardiac issues are not typically seen in this subtype.
What is CRD doing to treat LGMD2g? CRD is developing a gene replacement therapy to treat the condition in partnership with academic collaborators.
Learn more about the progress we are making to treat LGMD2g.
What is LGMD2i? Limb-girdle muscular dystrophy type 2i (LGMD2i) results from mutations in the FKRP gene. This gene carries the code for fukutin-related protein, which is found throughout the body but especially in the brain, heart muscles, and skeletal muscles. FKRP helps add sugars to alpha-dystroglycan, which is a protein that protects muscles during the cycle of contraction and relaxation and helps move nerve cells in the brain during early stages of development. Due to the mutation, the FKRP protein cannot add the sugars, so alpha-dystroglycan does not function properly. This disease has a prevalence of around 4.48/1,000,000.
How is LGMD2i acquired? LGMD2i is a genetic, autosomal recessive disease. People who have the disorder inherited one copy of the mutated gene from each parent. Out of all of the subtypes of LGMD, this is one of the more common ones, particularly in Northern Europe.
What are symptoms of LGMD2i? Some of the symptoms are: weakness in the upper arms and thighs, difficulty walking and climbing stairs, trouble balancing, calf muscle enlargement (calf hypertrophy), cardiomyopathy (stretching of the heart chambers), and respiratory difficulties. Some patients have also reported mild intellectual disabilities. The average age of symptom onset is around 11.5 years but ranges from 10 to 20 years old. People usually rely on a wheelchair 23 to 26 years after their first symptoms begin.
What is CRD doing to treat LGMD2i? CRD is currently developing a gene-replacement therapeutic to treat LGMD2i.
Learn more about the progress we are making to treat LGMD2i.