Potential therapy paradigms for Marfan syndrome

Marfan syndrome is the most common genetic disorder of the connective tissue with an estimated prevalence of 1:10,000. The disease is characterised by manifestations in the cardiovascular, skeletal and ocular systems. The most severe manifestations are those of the cardiovascular system: mitral valve prolapse and dilation of the aortic root, which may progress to aortic dissection, a common cause of mortality in patients. Marfan syndrome is a dominant genetic disorder caused by mutations in the gene coding for fibrillin-1, the FBN1 gene. Fibrillin, a 347 kDa glycoprotein, is found in most connective tissues and is a major component of the extracellular microfibrils. More than 100 different FBN1 mutations have been identified in individuals with Marfan syndrome, the majority of which are unique missense point mutations. Evidence suggests a dominant-negative mechanism of pathogenesis for the disorder, that is, the presence of the mutant fibrillin molecule interferes with the function of the normal protein. Therapies for dominant disorders such as Marfan syndrome (MFS) are likely to require both suppression of the disease allele expression and maintenance of expression of its wild-type counterpart. Thus, dominant genetic disorders present a unique therapeutic challenge. One approach to developing a therapy would be to use catalytic nucleic acid molecules. Antisense catalytic RNAs, or ribozymes, have been widely used to down-regulate or repair targeted gene expression respectively through the cleavage or trans-splicing of messenger RNA. Similarly, antisense DNA molecules or DNAzymes have been shown to be capable of cleaving target RNA molecules in a highly specific manner. This review will discuss the potential of catalytic nucleic acid molecules as therapeutic agents for MFS.