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Principal Investigator: Asuka Eguchi
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $157,516
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
The long-term objective of this study is to develop gene therapies that treat Duchenne muscular dystrophy (DMD)
cardiomyopathy. DMD cardiomyopathy, characterized by ventricular chamber enlargement and thinning of the
ventricular wall, ultimately leads to heart failure. Pathogenic features of DMD cardiomyocytes include contractile
dysfunction, poor calcium handling, elevated reactive oxygen species, telomere shortening, and premature cell
death. When a large number of cells die in the heart, scar tissue forms, increasing the stiffness of the heart.
Although there are treatments available to alleviate symptoms of dilated cardiomyopathy, there are currently no
therapies to prevent or delay the onset of this disease. Smaller versions of dystrophin amenable to gene therapy
have shown promise to treat DMD-associated severe skeletal muscle wasting; however, surprisingly little is
known about their effects in treating heart failure. This research plan will leverage bioengineered hydrogels of
tunable stiffness, human induced pluripotent stem cells (iPSCs) with dystrophin mutations, and biochemical
techniques to determine if full-length dystrophin can rescue DMD cardiomyocytes from their pathogenic demise.
During the K01 award period, Dr. Asuka Eguchi will train under the mentorship of Dr. Helen Blau, an expert on
DMD. By engineering hydrogels that mimic stiff, diseased heart tissue, Dr. Eguchi will be able to measure
parameters of contraction in cardiomyocytes differentiated from DMD iPSCs. Aim 1 will test if full-length
dystrophin can rescue DMD cardiomyocytes from contractile deficits, aberrant calcium handling, and premature
cell death. Aim 2 will determine if split vector or lipid nanoparticle approaches can deliver full-length dystrophin
to cardiomyocytes. Aim 3 will test whether this gene therapy strategy to deliver full-length dystrophin can delay
the onset of DMD cardiomyopathy in a mouse model. Gene therapy approaches targeting the root cause of
disease, the lack of dystrophin, is critical for extending lifespan and improving the quality of life of DMD patients.
The career development plan is designed to enable Dr. Eguchi to successfully transition to a career as
independent investigator. Her scientific advisory committee consist of Dr. Beth Pruitt, a bioengineer with
expertise in traction force microscopy, Dr. Joseph Wu, an expert on cardiovascular disease modeling, and Dr.
Daniel Bernstein, a pediatric cardiologist. Collectively, these collaborators will help Dr. Eguchi develop skills at
the interface of bioengineering, cell biology, and biochemistry to launch an independent research program in
cardiovascular research.
Terms: <AAV vector><AAV-based vector><Active Oxygen><Address><Adeno-Associated Viruses><Advisory Committees><Affect><Airway failure><Assay><Award><Bioassay><Biochemical><Biochemistry><Biological Assay><Biological Chemistry><Biomedical Engineering><Body Tissues><Calcium><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cardiomyopathies><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Death><Cell Survival><Cell Viability><Cell membrane><Cell-Extracellular Matrix><Cells><Cellular Morphology><Cellular biology><Cicatrix><Code><Coding System><Coloring Agents><Congestive Cardiomyopathy><Contracting Opportunities><Contracts><Cytoplasmic Membrane><Cytoskeletal Gene><Cytoskeletal Proteins><DMD cardiomyopathy><DNA Therapy><Data><Defect><Dependoparvovirus><Dependovirus><Development Plans><Dilatation><Dilatation - action><Dilated Cardiomyopathy><Disease><Disease Progression><Disorder><Duchene><Duchenne><Duchenne cardiomyopathy><Duchenne muscular dystrophy><Duchenne muscular dystrophy cardiomyopathy><Duchenne-Griesinger syndrome><Dyes><Dysfunction><Dystrophin><ECM><Echocardiogram><Echocardiography><Ellis-van Creveld (EvC) syndrome><Engineering><Ensure><Exhibits><Extracellular Matrix><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Functional disorder><Gene Transfer Clinical><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Heart><Heart Diseases><Heart Muscle Cells><Heart Vascular><Heart failure><Heart myocyte><Histology><Hydrogels><Image><Immunoblotting><Impairment><Increase lifespan><Investigators><K01 Award><K01 Mechanism><K01 Program><Leanness><Learning><Left Ventricles><Left ventricular structure><Length><Life><Luciferase Immunologic><Luciferases><Measures><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Mentored Research Scientist Development Award><Mentored Training Award><Mentors><Mentorship><Methods><Microscopy><Muscle><Muscle Tissue><Muscular dystrophy cardiomyopathy><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Onset of illness><Oxygen Radicals><Pathogenicity><Pathologic><Patients><Phenotype><Physiopathology><Plasma Membrane><Pro-Oxidants><Proteins><Pseudohypertrophic Muscular Dystrophy><QOL><Quality of life><Reactive Oxygen Species><Reporter><Research><Research Personnel><Research Scientist Development Award><Researchers><Respiratory Failure><Scars><Skeletal Muscle><Stroke Volume><Symptoms><Task Forces><Techniques><Telomere Shortening><Testing><Therapeutic Effect><Thinness><Tissues><Traction Force Microscopy><Training><Transthoracic Echocardiography><Variant><Variation><Ventricular><Voluntary Muscle><Western Blotting><Western Immunoblotting><X-linked dilated cardiomyopathy><X-linked muscular dystrophy><X-linked recessive muscular dystrophy><adeno associated virus group><adeno-associated viral vector><adeno-associated virus vector><advisory team><alleviate symptom><ameliorating symptom><benign X-linked recessive muscular dystrophy><bio-engineered><bio-engineers><bioengineering><biological engineering><cardiac failure><cardiac fibrosis><cardiac function><cardiomyocyte><cardiomyopathy in muscular dystrophy><cardiovascular disorder><career><career development><cartilage link protein><cell biology><cell morphology><childhood pseudohypertrophic muscular dystrophy><circulatory system><classic X-linked recessive muscular dystrophy><coronary fibrosis><decrease symptom><design><designing><determine efficacy><disease model><disease onset><disorder model><disorder onset><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elongating the lifespan><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><extend life span><extend lifespan><fewer symptoms><fibrotic heart><function of the heart><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><heart disorder><heart fibrosis><heart function><heart sonography><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><imaging><improved><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><innovate><innovation><innovative><intervention design><life span><lifespan><lifespan extension><link protein><lipid based nanoparticle><lipid nanoparticle><male><mild X-linked recessive muscular dystrophy><monogenic disease><monogenic disorder><mouse model><murine model><muscle degeneration><muscular><mutation correction><myocardial fibrosis><myocardium disease><myocardium disorder><nano particle delivery><nanoparticle delivered><nanoparticle delivery><necrocytosis><novel><pathophysiology><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><pediatric cardiologist><plasmalemma><premature><prematurity><prevent><preventing><programs><progressive muscular dystrophy of childhood><promoter><promotor><protein blotting><protein expression><pseudohypertrophic adult muscular dystrophy><pseudohypertrophic muscular paralysis><ratiometric><reduce symptoms><relieves symptoms><response><restoration><single-gene disease><single-gene disorder><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle protein loss><skeletal muscle wasting><skills><symptom alleviation><symptom reduction><symptom relief><telomere attrition><therapy design><treatment design><vector>