Marfan Syndrome
Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 (FBN1) gene, leading to abnormalities in the synthesis and organization of elastin fibers. With our expertise in Marfan syndrome drug and therapy development, our company is at the forefront of a full range of therapeutic development services.
Introduction to Marfan Syndrome
Marfan syndrome (MFS) is a genetic disorder that affects the connective tissue, primarily in the cardiovascular, skeletal, and ocular systems. The pathogenesis of Marfan Syndrome revolves around the dysfunction of the extracellular matrix (ECM) due to mutations in the FBN1 gene. Fibrillin-1 is a major component of microfibrils, which provide structural support to elastic fibers. The mutations disrupt the assembly and function of fibrillin-1, leading to abnormal tissue development and increased TGF-β signaling.
The dysregulated TGF-β signaling pathway plays a central role in the pathogenesis of MFS. Excessive TGF-β signaling contributes to the overproduction of matrix metalloproteinases (MMPs) and the degradation of elastin fibers, resulting in tissue fragility and aortic aneurysm formation. Other signaling pathways, including the Notch and Wnt pathways, also play a role in the pathogenesis of MFS.
Fig.1 Pathogenetic variants in FBN1. (Milewicz D. M., et al., 2021)
Therapeutics Development for Marfan Syndrome
Beta-blockers, such as propranolol and atenolol, are commonly prescribed as the first-line therapy for individuals with Marfan syndrome. These drugs help reduce the heart rate and blood pressure, thereby reducing the stress on the weakened aorta and slowing down its dilation. Moreover, angiotensin II receptor blockers (ARBs), such as losartan, have shown promise in the therapeutics of Marfan syndrome. They block the effects of angiotensin II, a hormone that promotes vascular inflammation and fibrosis. ARBs have been shown to reduce aortic root dilation rates and improve aortic stiffness in individuals with MFS.
At our company, we harness cutting-edge techniques and technologies to meticulously identify and develop groundbreaking therapeutics for Marfan syndrome. We invite you to explore the links provided below to gain further insight into our comprehensive range of therapeutic development solutions.
Our Services
Harnessing cutting-edge technological platforms, our company delivers a comprehensive solution for the development of therapies targeting Marfan syndrome. Our state-of-the-art technologies enable us to provide a seamless, all-encompassing approach to therapy development, ensuring that we can effectively address the specific challenges posed by Marfan syndrome.
In conjunction with our exceptional therapy development services, our organization places significant emphasis on the development of robust animal and in vitro models that faithfully recapitulate the pathogenesis and manifestations of Marfan syndrome. These meticulously designed models serve as invaluable tools in advancing our therapeutic solutions.
Fbn1mgΔ/mgΔ Mouse Models
In Fbn1mgΔ/mgΔ mouse model, exons 19-24 of the Fbn1 gene are replaced with a neomycin-resistant expression cassette, resulting in a substantial reduction in fibrillin-1 protein levels. These mice exhibit normal elastin levels and do not show overt phenotypic abnormalities at birth.
Fbn1mgR/mgR Mouse Models
The Fbn1mgR/mgR mouse models have an aberrant recombination event that replaces exons 20-24 of the Fbn1 gene, while retaining exon 19. As a result, they exhibit reduced fibrillin-1 protein levels, leading to skeletal abnormalities such as progressive kyphosis, rib overgrowth, and elongation of long bones.
Fbn1C1039G/+ Mouse Models
These mice harbor a heterozygous C to G cysteine substitution in a calcium binding EGF-like domain of the Fbn1 gene. As a result, they exhibit a 50% reduction in fibrillin-1 protein levels at birth, recapitulating various phenotypic features observed in human MFS cases.
In Vitro Models
Our cell-based model development service focuses on utilizing patient-derived cells, such as fibroblasts or smooth muscle cells. In addition, our organoid model development service focuses on generating organoids that mimic the affected tissues in Marfan syndrome, such as the aorta or the ocular system.
Our company offers a range of preclinical research services to evaluate the safety and efficacy of potential therapeutics for Marfan syndrome. We take pride in our state-of-the-art approach, which allows us to stay at the forefront of therapeutic development in this field. If our comprehensive suite of services has sparked your interest, we wholeheartedly encourage you to connect with us without any hesitation.
References
- Milewicz Dianna M., et al. "Marfan syndrome." Nature reviews Disease primers 7.1 (2021): 64.
- Zeigler Sanford M., Brandon Sloan, and Jeffrey A. Jones. "Pathophysiology and pathogenesis of Marfan syndrome." Progress in Heritable Soft Connective Tissue Diseases (2021): 185-206.