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Principal Investigator: Gary Liu
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $91,260
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
Chronic kidney disease (CKD) is an urgent health problem in the U.S., afflicting ~15% of Americans and
costing the healthcare system $120 billion/year. Despite the availability of glucose-normalizing drugs, diabetes
remains the leading cause of renal failure. Current treatments depend on glucose and hypertension control that
cannot completely prevent diabetic nephropathy and progressive renal dysfunction. A major feature of diabetic
nephropathy is inflammation, driven by the upregulation of adhesion proteins in renal endothelium and
subsequent recruitment of inflammatory immune cells into renal tissue. Previous work has shown that knockout
of the adhesion protein ICAM1 attenuates diabetic nephropathy in mouse models of type 1 and 2 diabetes.
However, there is a lack of clinically viable technologies that can act on these findings. An FDA-approved lipid
nanoparticle (LNP) siRNA drug, patisiran, is capable of safely inducing efficient (>80%) and durable (up to one
month) gene knockdown in humans. As LNPs typically accumulate in the liver, this approach has not been
broadly applicable to other tissues. This application seeks to develop new LNPs for efficient siRNA delivery to
renal endothelium, to test the hypothesis that knockdown of ICAM1 is protective against type 1 and 2 diabetic
nephropathy. The goal of Aim 1 (K99 phase) is to identify LNPs capable of efficient siRNA delivery to renal
endothelium through high-throughput in vivo screening. A panel of DNA-barcoded LNPs with varying
compositions will be screened for functional siRNA delivery to the renal endothelium using a new workflow.
Isolated barcodes will be analyzed by deep sequencing to deduce LNP parameters that mediate renal
endothelial delivery and inform subsequent, refined screens. Lead LNPs will be individually validated and
assessed for knockdown efficiency, duration, and safety. During the R00 phase, LNP efficacy will be tested in
multiple models of type 1 and 2 diabetic nephropathy. These models capture human diabetic nephropathy
features of ICAM1 upregulation, albuminuria, renal fibrosis, and macrophage infiltration into renal tissue. LNPs
carrying ICAM1 siRNA will be tested for efficacy in prophylactic (before disease onset) and therapeutic (after
disease onset) models. Successful completion of this work could enable new, precision medicine approaches
that target inflammatory drivers of diabetic nephropathy. The PI, Gary Liu, aims to lead a lab that develops new
renal therapeutics and arrest disease progression. A major focus will be gene therapies for kidney diseases.
To prepare him for this role, this K99/R00 application includes training and coursework in DNA barcoding, deep
sequencing, and bioinformatics; nephrology and diabetic nephropathy; LNP technology; and inclusive
mentoring. Moreover, this application will enable the PI to disseminate work at conferences, network, and
apply for faculty positions. Training will occur at the Koch Institute of MIT in the laboratories of Profs. Robert
Langer and Giovanni Traverso, which will provide the resources and intellectual expertise necessary to carry
out the work.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Accounting><Adhesions><Adult-Onset Diabetes Mellitus><Albumins><Albuminuria><American><Attenuated><BB2><Bar Codes><Bio-Informatics><Bioinformatics><Blood><Blood Reticuloendothelial System><Blood Serum><Body Tissues><Brittle Diabetes Mellitus><CD102><CD102 Antigen><CD31><CD54><CD54 Antigens><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cholesterol><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Complex><Creatinine><D-Glucose><DNA><DNA Therapy><Deoxyribonucleic Acid><Dextrose><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Dihydroxyethanes><Disease><Disease Progression><Disorder><Drugs><Endothelial Cells><Endothelium><Engineering><Ethanediols><Ethylene Glycols><Exhibits><Extravasation><FDA approved><Faculty><Fibrosis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Transfer Clinical><Genes><Genetic Intervention><Glucose><Goals><Health><Health Care Costs><Health Care Systems><Health Costs><Healthcare Costs><Healthcare Systems><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><ICAM-1><ICAM-1 Gene><ICAM-2><ICAM1><ICAM1 gene><ICAM2><ICAM2 gene><IDDM><Immune><Immunes><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><In Vitro><Individual><Infiltration><Inflammation><Inflammatory><Insulin-Dependent Diabetes Mellitus><Intercellular Adhesion Molecule 2><Intercellular adhesion molecule 1><Intervention><Intervention Strategies><Intravenous><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Kidney><Kidney Diseases><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Knock-out><Knockout><Laboratories><Lead><Leakage><Libraries><Lipids><Liver><Liver Cells><Lung><Lung Respiratory System><Macrophage><Maturity-Onset Diabetes Mellitus><Mediating><Medication><Mentors><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monoethylene Glycol><Murine><Mus><Mφ><NIDDM><Nephrology><Nephropathy><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Onset of illness><PECAM1><PECAM1 gene><Pb element><Pharmaceutical Preparations><Phase><Position><Positioning Attribute><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Property><Proteins><Public Health><RNA Interference><RNA Interference Therapy><RNA Silencing><RNA interference therapeutics><RNA interference-based therapy><RNAi><RNAi therapeutics><RNAi therapy><RNAi-based therapeutics><RNAi-based therapy><Renal Cell><Renal Disease><Renal Failure><Renal Insufficiency><Renal Tissue><Reporter><Reporting><Research Resources><Resources><Role><STZ><Safety><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Short interfering RNA><Slow-Onset Diabetes Mellitus><Small Interfering RNA><Specific qualifier value><Specified><Spillage><Spleen><Spleen Reticuloendothelial System><Stable Diabetes Mellitus><Streptozocin><Streptozotocin><Sudden-Onset Diabetes Mellitus><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Technology><Testing><Therapeutic><Tissues><Training><Treatment Efficacy><Tropism><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><United States><Up-Regulation><Upregulation><Urinalysis><Western Blotting><Western Immunoblotting><Work><Zanosar><adult onset diabetes><attenuate><attenuates><barcode><blood glucose regulation><cell sorting><chronic kidney disease><conference><convention><cost><deep sequencing><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><determine efficacy><diabetes><disease onset><disorder onset><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><empowerment><ethylene glycol><evaluate efficacy><examine efficacy><flow cytophotometry><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><glucose control><glucose homeostasis><glucose regulation><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><hypertension control><hypertension management><in vivo><insulin dependent diabetes><insulin dependent type 1><intervention efficacy><interventional strategy><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><kidney cell><kidney disorder><kidney dysfunction><kidney fibrosis><knock-down><knockdown><large data sets><large datasets><lipid based nanoparticle><lipid nanoparticle><mRNA><maturity onset diabetes><mouse model><murine model><nano particle delivery><nanoparticle delivered><nanoparticle delivery><nucleic acid delivery><precision medicine><precision-based medicine><prevent><preventing><prophylactic><protein blotting><pulmonary><recruit><renal><renal disorder><renal dysfunction><renal fibrosis><screening><screenings><short interfering RNA delivery><siRNA><siRNA delivery><siRNA therapy><siRNA-based therapeutic><siRNA-based therapy><small interfering RNA delivery><social role><summit><symposia><symposium><therapeutic efficacy><therapeutic siRNA><therapeutic small interfering RNA><therapy efficacy><type 2 DM><type I diabetes><type II DM><type one diabetes><type two diabetes>