Soluble pre-amyloid oligomers (PAO) are the most potent mediators of cytotoxicity, despite common focus on autophagy as a means to clear larger misfolded protein aggregates. Specifically, PAO, rather than aggresomes, are most correlated with desmin-related cardiomyopathy (DRC) caused by an Arg120Gly missense mutation of ?B-Crystallin (CryABR120G). In addition to causing DRC, emerging evidence suggests that increased PAO and resulting proteotoxic stress play an important role in the progression from a large subset of heart diseases to heart failure, a common condition in the United States. Despite substantial progress in our understanding of PAO and related diseases, no experimental therapeutics exist that clear these toxic species from the cytoplasm. Notably, a recent study demonstrated that up-regulation of myocardial Neprilysin (NEP) protein levels was implicated as a major mediator for voluntary exercise to reduce misfolded cytotoxic protein levels and slow down disease progression in a model of DRC. Treatment of cardiac proteinopathies such as DRC by increasing cardiac NEP levels to reduce PAO levels appears to be a promising therapeutic strategy. In order to deliver NEP to the cytoplasm of heart muscle cells, Valerion Therapeutics uses a commercializable cell-penetrating 3E10 antibody Fab fragment that is uniquely capable of delivering full-length protein cargo to the cytoplasm. 3E10 gains entry to the cells via the equilibrative nucleoside transporter 2 (ENT2; SLC29A2), a receptor found in many cell types but is highly expressed in skeletal and cardiac muscle. We are currently testing several Fab fusions, including Fab-GAA (VAL-1221) that recently demonstrated positive Phase 1 clinical results in Pompe disease (NCT02898753). Valerion has recently developed a new Fab fusion protein with NEP (VAL- 0914) that is uniquely capable of penetrating cells and degrades overexpressed cytoplasmic beta-amyloid(1-42). Therefore, VAL-0914 presents an innovative therapeutic strategy to treat cardiac proteinopathies such as desmin-related cardiomyopathy by delivering active NEP to the cytoplasm of affected cells. The proposed research in phase I will focus on (Aim 1) in vitro characterization of VAL-0914 in cultured cardiomyocyte and mouse heart models of cardiac proteinopathy to establish mechanistic proof-of-concept and (Aim 2) in vivo characterization of VAL-0914 effects on heart function and misfolded protein clearance in a mouse model of cardiac proteinopathy to establish preclinical models for subsequent IND-enabling phase II studies. A successful outcome of this work will create an immediate actionable impact on underserved cardiac proteinopathy patient populations such as those with DRC and a subset of heart failure patients.
The proposal aims to establish key proof-of-concept data for a first-in-class treatment to reduce toxic cytoplasmic pre-amyloid oligomers in cardiac proteinopathies. The academic partner is an expert in the molecular pathogenesis of misfolded proteins, and the small business partner has developed a genetic fusion between a cell-penetrating antibody fragment and neprilysin (VAL-0914), which reduces levels of cytoplasmic misfolded protein levels. A successful outcome will enable subsequent IND-enabling studies to ultimately provide the first treatment of underlying cardiac proteinopathy to the clinic.