Potential therapy paradigms for Marfan syndrome

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Medicine
• Biochemistry

Background:

• Marfan syndrome (MFS) is a prevalent genetic connective tissue disorder affecting cardiovascular, skeletal, and ocular systems.
• Cardiovascular manifestations, including aortic root dilation and mitral valve prolapse, are the most severe and life-threatening.
• MFS is caused by dominant mutations in the FBN1 gene, encoding fibrillin-1, leading to a dominant-negative pathogenetic mechanism.

Purpose of the Study:

• To review the potential of catalytic nucleic acid molecules as therapeutic agents for Marfan syndrome (MFS).
• To explore novel therapeutic strategies for dominant genetic disorders like MFS.

Main Methods:

• Discussion of antisense catalytic RNAs (ribozymes) for gene expression down-regulation or repair via mRNA cleavage or trans-splicing.
• Review of antisense DNA molecules (DNAzymes) for specific target RNA cleavage.
• Exploration of therapeutic approaches requiring suppression of disease allele expression and maintenance of wild-type gene expression.

Main Results:

• Over 100 unique FBN1 mutations identified in MFS patients, primarily missense point mutations.
• Dominant-negative mechanism implicated in MFS pathogenesis, where mutant fibrillin interferes with normal protein function.
• Catalytic nucleic acid molecules demonstrate specificity in targeting and modifying gene expression.

Conclusions:

• Dominant genetic disorders like Marfan syndrome pose unique therapeutic challenges.
• Catalytic nucleic acid molecules, including ribozymes and DNAzymes, represent a promising avenue for MFS therapy.
• These molecules offer a potential strategy to address the dual requirement of suppressing mutant alleles and preserving wild-type gene function.