Document text
Principal Investigator: Kenneth Ber Margulies
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $793,828
Funding agency: National Heart Lung and Blood Institute
The delivery of therapeutic nucleotides to the myocardium is notoriously challenging and remains an important
unmet clinical need. Based on the global success of mRNA vaccines, solid lipid nanoparticles are the most
widely used vehicle for RNA delivery. We recently identified species of lipid nanoparticles with unprecedented
cardiotropism (cLNPs) that are efficient at delivering inhibitory RNA cargos to the heart. This supports
development of cLNPs for the therapeutic inhibition of select cardiomyocyte targets. Our prior work suggests
that increases in stable, post-translationally detyrosinated microtubules, as mediated by vasohibins
(VASH1/2) in complex with their chaperone (SVBP), contribute to contractile dysfunction in human heart
failure and clinically relevant animal models. Accordingly, the proposed research tests the hypothesis that
cLNPs with inhibitory cargos that limit disease-associated microtubule network detyrosination can improve
contractile dysfunction in disease models where increased VASH1 or VASH2 expression has been linked to
systolic and/or diastolic dysfunction. To test this hypothesis, Aim 1 experiments will prioritize therapeutic
reagents by characterizing the extent and duration of on- and off-target effects of cLNPs with alternative
inhibitory cargos (siRNA, shRNA, and antisense oligonucleotides) against both constitutively expressed
transcripts or against Vash1, Vash2, or Svbp in healthy rats. Studies demonstrating functional inhibition will
be extended to human myocardium using ex vivo delivery of cLNPs to perfused cardiac wedge preparations
derived from heart transplant recipients. Aim 2 experiments will determine whether short-term inhibition of
Vash2 via delivery of cLNPs is sufficient to blunt contractile dysfunction in viable myocardium following acute
myocardial infarction. Aim 3 experiments test whether cLNPs achieving sustained delivery of Vash1 can delay
the progression of diastolic dysfunction in an animal model of heart failure with preserved ejection fraction.
Our overall study design uses novel and complementary experimental approaches that seek to rigorously
characterize inhibitory nucleic acid delivery via cLNPs, and then test them in clinically relevant models of
microtubule-dependent cardiac dysfunction. Use of both acute and chronic models of cardiac dysfunction,
and in turn acute and chronic therapeutic inhibition, respectively, exploits a range of therapeutic options of
cLNPs. Inclusion of delivery to human myocardium furthers ultimate clinical translation. Together this work
will establish whether inhibition of microtubule network remodeling is therapeutically beneficial in heart failure,
defne which molecular target is best suited for each of two therapeutic scenarios, and establish the versatility
of cLNP mediated delivery of inhibitory nucleic acids for the treatment of cardiac dysfunction.
Terms: <Acute><Acute myocardial infarct><Acute myocardial infarction><Affect><Age><Animal Model><Animal Models and Related Studies><Antisense Agent><Antisense Oligonucleotides><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Binding><Blood><Blood Reticuloendothelial System><Body Tissues><Cardiac><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Transplantation><Cardiac infarction><Cardiocyte><Cardiomyopathies><Cardiovascular Diseases><Cell Body><Cells><Chaperone><Chronic><Clinical><Closure by Ligation><Common Rat Strains><Complex><Coronary><DNA Therapy><Development><Disease><Disorder><Dysfunction><EFRAC><Ejection Fraction><Endothelium><Functional disorder><Gene Expression><Gene Transfer Clinical><Genes><Genetic Intervention><Grant><Heart><Heart Grafting><Heart Muscle Cells><Heart Transplantation><Heart failure><Heart myocyte><Hereditary><Human><Impairment><Inherited><Injections><Kinetics><Knock-out><Knockout><Ligation><Link><Liver><MALAT1><MALAT1 gene><Mechanics><Mediating><Medical><Methods><Mice><Mice Mammals><Micro-tubule><Microtubules><Modeling><Modern Man><Molecular Chaperones><Molecular Interaction><Molecular Target><Morphology><Motion><Murine><Mus><Myocardial><Myocardial Contraction><Myocardial Diseases><Myocardial Disorder><Myocardial Infarct><Myocardial Infarction><Myocardial depression><Myocardial dysfunction><Myocardiopathies><Myocardium><Non-Polyadenylated RNA><Nucleic Acids><Nucleotides><Obesity><Outcome><Outcome Measure><Perfusion><Physiopathology><Preparation><Proteins><RNA><RNA Gene Products><RNA based therapeutics><RNA based therapy><RNA delivery><RNA therapy><RNA vaccine><RNA-based vaccine><Randomized><Rat><Rats Mammals><Rattus><Reagent><Receptor Protein><Relaxation><Research><Research Design><Ribonucleic Acid><Sampling><Short interfering RNA><Single-Nucleus Sequencing><Slice><Small Interfering RNA><Small RNA><Solid><Structure><Study Type><System><Testing><Therapeutic><Tissues><Transcript><Transplant Recipients><Tubulin><Work><adiposity><ages><alpha Tubulin><antisense oligo><cardiac dysfunction><cardiac failure><cardiac graft><cardiac infarct><cardiac muscle><cardiomyocyte><cardiovascular disorder><cell type><clinical relevance><clinical translation><clinically relevant><clinically translatable><coronary attack><coronary infarct><coronary infarction><corpulence><delivery vector><delivery vehicle><developmental><disease model><disorder model><experiment><experimental research><experimental study><experiments><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><heart attack><heart contraction><heart dysfunction><heart infarct><heart infarction><heart muscle><heart transplant><hemodynamics><hepatic body system><hepatic organ system><improved><in vivo><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><mRNA vaccine><mRNA-based vaccine><measurable outcome><mechanic><mechanical><metastasis-associated lung adenocarcinoma transcript 1><model of animal><myocardium disease><myocardium disorder><nanoparticle therapy><novel><nucleic acid delivery><outcome measurement><pathophysiology><pharmacologic><preparations><preservation><randomisation><randomization><randomly assigned><receptor><restraint><sNuc-Seq><scaffold><scaffolding><shRNA><short hairpin RNA><siRNA><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><small hairpin RNA><snRNA sequencing><snRNA-seq><study design><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic RNA><therapeutic nanoparticles><therapeutic target><transcriptomics><transplant patient><uptake><viscoelasticity><α Tubulin>