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Principal Investigator: Daniel John Siegwart
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $409,859
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Project Summary
CRISPR/Cas-based gene editing has ushered in a hopeful era that dreams of new therapies for currently
untreatable genetic diseases. Because mutated proteins are produced in specific cells, there is a critical need to
develop organ- and cell-specific delivery strategies to realize the full potential of genomic medicines. We recently
overcame this challenge through development of the first class of non-viral nanoparticles for tissue-specific
genome editing. Selective ORgan Targeting (SORT) lipid nanoparticles (LNPs) enable targeted intravenous
delivery of nucleic acids and proteins to the lungs, liver, and spleen, plus local delivery to the muscle, brain, and
skin. Tropism is driven by inclusion of SORT molecules, which create tissue-selective 5-component SORT LNPs
that are compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9
ribonucleoprotein (RNP) complexes. In this grant proposal, we Aim to (1) determine the mechanism of SORT,
(2) improve the efficacy and tolerability of liver-, lung-, and spleen-targeting SORT LNPs, and (3) determine the
cell-specific gene editing capabilities of SORT LNPs with the potential for expanded tropism. Results will
determine the fundamental mechanisms and structure-activity relationships (SAR) for non-viral nanoparticle
liver, lung, and spleen tropism. This will ultimately allow targeted and safer CRISPR/Cas gene editing in vivo.
We will determine these factors by adapting a unique class of LNPs, called SORT LNPs, that we developed. We
will employ human cells and genetically engineered mouse models that allow quantification of precise, cell
specific gene editing events. Completion of the proposed studies will (1) Elucidate the fundamental mechanisms
how and why SORT LNPs target extrahepatic tissues, (2) Determine how SORT molecules control efficacy and
tolerability for improved gene editing outcomes, and (3) Determine and control cell-type gene editing specificity
to expand targeted gene editing. Cumulatively, this will open new avenues for CRISPR/Cas-based correction of
genetic diseases by developing efficacious, safe, and clinically translatable nanoparticle carriers.
Terms: <Acceleration><Adsorption><Affect><Applications Grants><Binding><Biodistribution><Body Tissues><Brain><Brain Nervous System><COVID-19><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CV-19><Cas nuclease technology><Cell Body><Cells><Charge><Chemical Structure><Chemicals><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Coronavirus Infectious Disease 2019><Coupled><Dangerousness><Data><Development><Disease><Disorder><Dose><Dreams><Drug or chemical Tissue Distribution><Encapsulated><Encephalon><Endosomes><Endothelium><Epithelium><Event><Extrahepatic><Formulation><Funding><GEM model><GEMM model><Gene Delivery><Genes><Genetic Diseases><Genetically Engineered Mouse><Genomic medicine><Grant><Grant Proposals><Hepatic Cells><Hepatic Parenchymal Cell><Hepatic Tissue><Hepatocyte><Human><In Vitro><Intramuscular><Intravenous><Knowledge><Learning><Lipids><Liver><Liver Cells><Lung><Lung Respiratory System><Measures><Mediating><Messenger RNA><Modern Man><Molecular Interaction><Muscle><Muscle Tissue><Mutate><NIBIB><NIH><National Institute of Biomedical Imaging and Bioengineering><National Institutes of Health><Non-Polyadenylated RNA><Nucleic Acids><Organ><Outcome><Property><Proteins><RNA><RNA Gene Products><Receptosomes><Ribonucleic Acid><Ribonucleoproteins><Skin><Specificity><Spleen><Spleen Reticuloendothelial System><Structure><Structure-Activity Relationship><Therapeutic Gene Editing><Therapeutic Uses><Tissue Distribution><Tissues><Tropism><United States National Institutes of Health><Vaccines><Viral Vector><Work><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cell engineering><cell type><cellular engineering><chemical structure function><clinical translation><clinically translatable><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><developmental><efficacy validation><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene-editing approach><gene-editing therapy><genetic condition><genetic disorder><genetically engineered mouse model><genetically engineered murine model><genome editing><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genomic editing><hepatic body system><hepatic organ system><immunogenicity><improved><in vivo><insight><intravenous injection><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><muscular><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nucleic acid delivery><promoter><promotor><pulmonary><structure function relationship><success><therapeutic editing><therapeutic genome editing><tool><validate efficacy>