*2.5. Inhibition of the mTOR Pathway and Antisense Oligo Nucleotide Mediated Exon Skipping Are Potential Therapies for TTNtv Related DCM*

Identification of TTNtv in DCM is helpful for prognosis; however, as targeted therapies for TTNtv become available, this may also change clinical management (Table 1). Given the association of TTNtv inducing upregulation of the mTOR complex, mTOR inhibitors such as rapamycin may be reasonable to consider for therapeutic trials of TTNtv DCM [52]. There have also been promising results in correcting the frameshift and early termination in TTNtv using antisense oligonucleotide (AON) mediated exon skipping. In this strategy, single stranded oligonucleotides are designed to bind pre mRNA either at the intron-exon border of the mutated exon, or to block exon splicing motifs. The goal is to skip the mutated exon that contains the frameshift mutation via alternative splicing and prevent early termination of titin during translation. This strategy has been successfully utilized in other genetic conditions such as Duchenne Muscular dystrophy with FDA approval of an AON molecule [53]. The advantage of this approach is that separate AONs can be designed for each exon containing a TTNtv allowing a targeted approach to therapy. Feasibility of this approach has been demonstrated in a mouse model with a TTNtv where AON exon skipping resulted in rescue of the DCM phenotype [54]. AON mediated exon skipping has also been tested in hiPSC-CMs derived from a patient with TTNtv, where treatment of cardiomyocytes with AON rescued defective myofibril assembly [55]. AON mediated exon skipping represents a viable treatment strategy for patients with TTNtv with DCM that is actively being pursued.


**Table 1.** Proposed Therapies For Treatment Of Heart Failure That Modify Titin.
