None approved for ASO; Losartan and beta-blockers used for symptom management
Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene, which encodes fibrillin-1 — the primary component of extracellular microfibrils. These microfibrils provide structural support in connective tissue throughout the body and regulate the bioavailability of transforming growth factor beta (TGF-β). Mutations in FBN1 disrupt microfibril assembly and lead to excessive TGF-β signaling, causing the multisystem features of Marfan syndrome.
The disease affects the skeletal system (tall stature, long limbs and fingers, joint hypermobility, scoliosis, chest wall deformities), the ocular system (lens subluxation, myopia, retinal detachment risk), and most critically, the cardiovascular system (aortic root dilation, mitral valve prolapse, aortic dissection). Aortic dissection is the leading cause of death in Marfan syndrome and can occur suddenly, making cardiovascular monitoring and management essential.
Over 3,000 different FBN1 mutations have been identified in Marfan syndrome patients. The disease mechanism varies by mutation type: some mutations cause haploinsufficiency (reduced fibrillin-1 production), while others produce a dominant-negative protein that disrupts microfibril assembly. This heterogeneity means that the optimal ASO strategy depends on the specific mutation.
For dominant-negative mutations, allele-selective gene silencing can reduce expression of the mutant FBN1 allele while preserving the normal allele. By targeting a sequence variant unique to the mutant allele (such as the mutation itself or a linked SNP), an ASO can selectively degrade the mutant mRNA without affecting the wild-type transcript. For mutations that cause aberrant splicing, splice-modulating ASOs can redirect splicing to produce functional or less harmful fibrillin-1 variants.
Current treatment for Marfan syndrome focuses on symptom management: beta-blockers and angiotensin receptor blockers (particularly losartan) to slow aortic dilation, regular cardiovascular imaging, and prophylactic aortic root surgery when dilation reaches a critical threshold. These treatments manage complications but do not address the underlying genetic cause.
Pequliar designs personalized ASO candidates for Marfan syndrome based on the patient’s specific FBN1 mutation. The platform determines the appropriate ASO strategy (allele-selective silencing, splice modulation, or other approaches), identifies optimal target sites, and provides synthesis-ready sequences with full chemistry assignment, thermodynamic scoring, and off-target screening for preclinical evaluation.
Describe your mutation and get ranked, synthesis-ready ASO candidates in minutes. $399 per design.
Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.