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 Statement PROJECT NARRATIVE 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.
Project Terms: Affect ; Amyloid ; Amyloid Substance ; Antibodies ; Attention ; Autophagocytosis ; autophagy ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Crystallins ; lens protein ; Cytoplasm ; Desmin ; Skeletin ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exercise ; Face ; faces ; facial ; Foundations ; Glycogen storage disease type II ; Acid Maltase Deficiency Disease ; Generalized Glycogenosis ; Glycogenosis 2 ; Glycogenosis Type II ; Lysosomal alpha-1,4-Glucosidase Deficiency Disease ; Pompe Disease ; acid maltase deficiency ; alpha 1,4 glucosidase deficiency ; Goals ; Heart ; Heart Diseases ; Cardiac Diseases ; Cardiac Disorders ; heart disorder ; Heart failure ; cardiac failure ; Human ; Modern Man ; Immunoglobulin Fragments ; Antibody Fragments ; Fab Immunoglobulins ; Antigen Binding Fragment ; Fab Fragments ; Immunoglobulin, F(ab) Fragment ; In Vitro ; Incidence ; Neprilysin ; CD10 Antigens ; Enkephalinase ; Membrane Metalloendopeptidase ; Neutral Endopeptidase ; Mus ; Mice ; Mice Mammals ; Murine ; Muscle ; Muscle Tissue ; muscular ; Myopathy ; Muscle Disease ; Muscle Disorders ; Muscular Diseases ; Myopathic Conditions ; Myopathic Diseases and Syndromes ; Myopathic disease or syndrome ; muscular disorder ; Myocardium ; cardiac muscle ; heart muscle ; Patients ; Peptide Hydrolases ; Esteroproteases ; Peptidases ; Protease Gene ; Proteases ; Proteinases ; Proteolytic Enzymes ; Play ; Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Respiratory Insufficiency ; lung insufficiency ; Role ; social role ; South Dakota ; Stress ; Testing ; Translating ; Ubiquitin ; APF-1 ; ATP-Dependent Proteolysis Factor 1 ; HMG-20 ; High Mobility Protein 20 ; United States ; Universities ; Up-Regulation ; Upregulation ; Work ; Nucleoside Transporter ; Nucleoside Transport Proteins ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Businesses ; Muscle Weakness ; Muscular Weakness ; Chimeric Proteins ; Chimera Protein ; Fusion Protein ; base ; Benign ; Clinical ; Phase ; multicatalytic endopeptidase complex ; 20S Catalytic Proteasome ; 20S Core Proteasome ; 20S Proteasome ; 20S Proteosome ; Macropain ; Macroxyproteinase ; Multicatalytic Proteinase ; Prosome ; Proteasome ; Proteasome Endopeptidase Complex ; Proteosome ; Link ; Evaluation ; Physical activity ; Cardiac Myocytes ; Cardiac Muscle Cells ; Cardiocyte ; Heart Muscle Cells ; Heart myocyte ; cardiomyocyte ; heart function ; cardiac function ; function of the heart ; Disease Progression ; Skeletal Muscle ; Voluntary Muscle ; uptake ; Therapeutic ; Genetic ; Clinic ; Route ; cell type ; System ; Lytotoxicity ; cytotoxicity ; Receptor Protein ; receptor ; Missense Mutation ; trafficking ; transgenic ; Transgenic Organisms ; Orphan Disease ; Rare Disorder ; orphan disorder ; Rare Diseases ; novel ; Pathogenesis ; Modeling ; Myocardial Diseases ; Myocardial Disorder ; Myocardiopathies ; myocardium disease ; myocardium disorder ; Cardiomyopathies ; Experimental Therapies ; Investigational Treatments ; experimental therapeutic agents ; experimental therapeutics ; Investigational Therapies ; OMIM ; Online Mendelian Inheritance In Man ; Therapeutic Uses ; Mediator ; Mediator of Activation ; Mediator of activation protein ; Length ; cytotoxic ; Data ; Preclinical Models ; Pre-Clinical Model ; in vivo ; Clinical Treatment ; trial regimen ; trial treatment ; Transgenic Model ; transgenic trait ; Molecular ; Myocardial ; Cardiac ; protein aggregation ; insoluble aggregate ; protein aggregate ; Outcome ; Prevalence ; innovation ; innovate ; innovative ; clinically relevant ; clinical relevance ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; progenitor ; overexpression ; overexpress ; patient population ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; phase 2 study ; phase II study ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; misfolded protein ; proteotoxic protein ; proteotoxin ; proteotoxicity ; proteotoxic ;
