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Following acute injury, or as a consequence of many chronic diseases, fibrosis develops and replaces or interferes with the function of healthy tissue. The excess accumulation of extracellular matrix (ECM) components, including collagen, disrupts the physiological architecture of healthy tissue, leading to impaired muscle, heart, lung, liver, skin, and kidney function. Fibrosis is observed across many diseases, including muscular dystrophies.
During the physiological healing process, there is transient release and activation of TGF-β which promotes repair and recovery. Balancing the amount of active TGF-β is essential for regulating wound healing and fibrosis formation.
Many fibrotic diseases have excess TGF-β activity as a key component of the disease process. It is this TGF-β hyperactivation that leads to irreversible fibrosis deposition. Our technology uses novel antibodies to regulate active TGF-β release and reduce fibrosis formation in myopathies and other related diseases.
Following acute injury, or as a consequence of many chronic diseases, fibrosis develops and replaces or interferes with the function of healthy tissue. The excess accumulation of extracellular matrix (ECM) components, including collagen, disrupts the physiological architecture of healthy tissue, leading to impaired muscle, heart, lung, liver, skin, and kidney function. Fibrosis is observed across many diseases, including muscular dystrophies.
During the physiological healing process, there is transient release and activation of TGF-β which promotes repair and recovery. Balancing the amount of active TGF-β is essential for regulating wound healing and fibrosis formation.
Many fibrotic diseases have excess TGF-β activity as a key component of the disease process. It is this TGF-β hyperactivation that leads to irreversible fibrosis deposition. Our technology uses novel antibodies to regulate active TGF-β release and reduce fibrosis formation in myopathies and other related diseases.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are rare and debilitating neuromuscular disorders due to mutations the dystrophin gene. Dystrophin is a large protein that stabilizes muscle and heart cells. Dystrophin deficiency disrupts the dystrophin glycoprotein (DGC) complex, which results in increased fragility of muscle and heart cell membranes (leaky cells).
In DMD and BMD, ongoing muscle membrane disruption outpaces the capacity for repair, and muscles become replaced by fibrotic scarring. In DMD and BMD, excess TGF-β expression drives the accumulation of scar tissue. DMD/BMD patients lose muscle over time as muscle is replaced by fibrosis; this results in progressive muscle weakness. Along with skeletal muscle weakness, the heart muscle and respiratory muscles are also compromised. Targeting TGF-β regulators like LTBP4 is a novel therapeutic strategy to treat fibrotic disorders like DMD/BMD.
Limb-girdle muscular dystrophies (LGMD) are a group of genetic disorders characterized by muscle wasting and weakness in the voluntary muscles of the hip and shoulder areas (limb-girdle area).
The large number of different genetic mutations causing LGMDs share common mechanisms that render muscle, and sometimes heart muscle, dysfunctional because of fibrotic replacement. Many LGMDs also have impaired respiratory muscles due to excess fibrosis. Like in DMD and BMD, the excess fibrosis in LGMDs is driven by hyper-TGF-β activation.
Muscle fibrosis over time leads to muscle weakness and reduced function in the muscle, which limits many activities of daily living. Targeting fibrosis in a mutation-agnostic way to provide an intervention for LGMD patients.
Myopathies are defined as neuromuscular disorders whose primary symptom is muscle weakness due to muscle fiber dysfunction. Many myopathies are genetic disorders. The muscular dystrophies are a subset of myopathies where the muscle becomes replaced by fibrosis. Myopathic disorders, including muscular dystrophies, are caused by mutations in different genes that encode proteins responsible for diverse aspects of muscular structure and function. These mutations change the stability and overall health of the muscle fibers. In muscular dystrophies, over time, muscle is gradually replaced with fibrotic tissue, resulting in muscle weakness.
Latent TGF-β binding protein 4 (LTBP4) regulates the amount of active TGF-β and modulates muscle cell injury response and scarring. LTBP4’s role in modifying muscular dystrophies was discovered from a genome-wide screen.
Different genetic subtypes of muscular dystrophy can affect specific muscle groups with symptoms appearing at different ages and varying in severity.
Types of MD include:
• Duchenne/Becker MD
~ 14 in 100,000 males 5 – 24 years of age
• Myotonic (DM)
~ 8 in 100,000 people of all ages are affected
• Limb-Girdle (LGMD)
~ 4 in 100,000 people of all ages
• Oculopharyngeal (OPMD)
~ 1 in 100,000 people of all ages
• Congenital (CMD)
~ 1 in 100,000 people of all ages
• Distal Myopathy (DM)
Fewer than 1 in 100,000 people of all ages
• Emery-Dreifuss (EDMD)
Fewer than 1 in 100,000 people of all ages
Transforming growth factor beta (TGF-β) is involved in many aspects of tissue injury and repair beyond muscular dystrophies. This includes pulmonary fibrosis, radiation response to injury, resistance to chemotherapeutics, and a broader role in tumor microenvironments that impacts tumor growth and metastasis.
Idiopathic pulmonary fibrosis (IPF) is a serious chronic disease with limited standard of care therapies available. It is characterized by progressive worsening of dyspnea and lung function, with poor prognosis.
Genetic mutations as well as gene-environment interactions predispose certain individuals to develop pulmonary fibrosis. As a result, the air sacs in the lungs (alveoli) become damaged, increasing fibrotic tissue and making breathing more difficult. As the lungs stiffen with excess fibrosis, it becomes more difficult for oxygen to cross into the blood.
IPF fibroblasts have distinct phenotypic alterations that contribute to the development of lung fibrosis. The remodeled matrix may provide a feed-forward loop of profibrotic signaling, with TGF-β playing an essential role in modulating ECM gene expression during lung fibrogenesis. TGF-β also stimulates expression of fibrogenic cytokines, including TNF-α, PDGF, IL-1β, and IL-13, thereby further enhancing and perpetuating the fibrotic cascade.
Excess TGF-β signaling can promote cancer progression through its effects on the tumor microenvironment (TME), which dynamically interacts with tumor cells to promote cancer growth. Contribution of fibrotic signaling in the TME has recently been recognized and is suggested as a new therapeutic target for blocking cancer progression. Additionally, resistance to radiation and checkpoint therapies is associated with excess TGF-β activity and signaling.
Sarcopenia is the loss of skeletal muscle mass and strength that occurs with age, characterized by excess intramuscular fibrosis, poor quality of life, and physical disability.
Research has shown that sarcopenia and muscular dystrophy (MD) share some pathophysiological mechanisms. Dysregulation of TGF-β proteins and their associated signaling components has been implicated in muscle wasting associated with sarcopenia.
Liver fibrosis occurs in Nonalcoholic fatty liver disease (NAFLD) independent of obesity and insulin resistance. Patients with advanced fibrosis from Non-alcoholic Steatohepatitis (NASH) and NASH-related cirrhosis have been found to have significantly higher risks of developing sarcopenia.
