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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1)
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Wong, Renee P
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Enable Therapeutics LLC
United States
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