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Principal Investigator: KENNETH E WHITE
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $431,771
Funding agency: National Institute on Aging
Abstract: The hallmarks of chronic kidney disease (CKD) include fibrosis, increased inflammatory
responses, and dysregulated mineral metabolism, which are all especially problematic in aged patients and
strongly associated with morbidity and mortality. Indeed, the fibrotic lesions arising in humans as well as CKD
rodent models cause dramatic decreases in renal function, leading to further cycles of inflammation and
activation of myofibroblasts with collagen accumulation. The bone-produced hormone fibroblast growth factor-
23 (FGF23) controls phosphate and vitamin D metabolism, and is markedly increased in late-stage CKD
(>1000-fold), in part due to loss of its co-receptor, Klotho (KL). The dysregulation of FGF23 results in severe
endocrine bone disease in aged patients whose musculoskeletal system is already compromised, and it is
not known whether this pathologic phenotype can be ameliorated with improvement of kidney function. There
are no direct therapies for CKD fibrosis, and it remains unclear whether targeting fibrosis using broad
spectrum drugs is feasible in clinical practice because most drugs that decrease fibrosis in pre-clinical models
target multiple essential pathogenic pathways (eg, renin-angiotensin-aldosterone system blockade).
Fibroblast activation protein (FAP) is a transmembrane serine protease expressed by activated fibroblasts in
wound healing and pathological conditions such as fibrosis and cancer. Our collaborator, Dr. Jonathan
Epstein, developed a transient anti-FAP Chimeric Antigen Receptor (CAR)-T cell mRNA therapy (or
‘FAPCAR’) which reduced cardiac fibrosis following infarction. FAP is an optimal target for CAR-T cell
targeting as it is a cell surface molecule only expressed during pathology and not at high levels under normal
conditions. To treat fibrosis, lipid nanoparticles (LNPs) designed to target CD5-positive T cells are
endocytosed, and the mRNA encoding FAPCAR translated within the cell. The advantage of this approach is
that the generated in vivo fibrosis-targeted CAR-T cells do not require individualized patient derived cells, and
there is no danger of random T-cell gene interruption as in standard CAR-T therapy. Our central hypothesis
is: CD5/LNP-FAPCAR pre-clinical therapy will directly target renal fibrosis and improve renal function and
mineral metabolism either alone or in combination treatment in aged mice with CKD. Considering the
magnitude of the negative effects of fibrosis on CKD outcomes in the aging population, and the fact there are
no FDA-approved therapies directly resolving fibrosis, our studies are important for the CKD field. Thus we
will address our hypothesis under Specific Aims: 1. To test preclinical CD5/LNP-FAPCAR therapy in
prevention and treatment of CKD fibrosis in aged and adult mice; and 2.To test FAP-expressing fibroblast
ablation as a combination therapy. Thus, our proposed studies are innovative as we will test for the first time
whether a novel transient LNP-FAPCAR therapy can be used to reduce CKD fibrosis in the aged, and whether
this treatment improves mineral metabolism, a key pathology that also has no adequate treatments.
Terms: <(TNF)-α><1H-Purin-6-amine><21+ years old><Ablation><Adenine><Adult><Adult Human><Affect><Aging><Anemia><Antibodies><Biochemical><Blood Plasma><Body Tissues><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><Cachectin><Cancers><Cell Body><Cell surface><Cells><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical Trials><Collagen><Combined Modality Therapy><Deposit><Deposition><Diet><Disease><Disease Outcome><Disorder><Drugs><Effectiveness><Enbrel><Endocrine Bone Diseases><Endocrine Gland Secretion><Esbriet><Etanercept><Evaluation><FDA approved><FGF23 gene product><Fibroblasts><Fibrosis><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Gene Expression><Genes><Histologic><Histologically><Histology><Hormones><Human><Immunofluorescence><Immunofluorescence Immunologic><Individual><Infarction><Inflammation><Inflammatory Response><Intermediary Metabolism><Interruption><Investigation><Kidney><Kidney Urinary System><Lesion><Lung Tissue Fibrosis><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Membrane><Messenger RNA><Metabolic Processes><Metabolism><Mice><Mice Mammals><Minerals><Modeling><Modern Man><Molecular><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Musculoskeletal System><Myofibroblast><Outcome><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Pharmaceutical Preparations><Phenotype><Phosphates><Pirfenidone><Plasma><Plasma Serum><Pre-Clinical Model><Preclinical Models><Preclinical Testing><Prevention><Proteins><Pulmonary Fibrosis><Receptor Protein><Renal function><Renin-Angiotensin-Aldosterone System><Reticuloendothelial System, Serum, Plasma><Rodent Model><Sampling><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Staining method><Stains><T cells for CAR><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic Hormone><Time><Tissues><Translating><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><VIT D><Vitamin B4><Vitamin D><Wild Type Mouse><Work><Wound Repair><adulthood><aged><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><aging population><bone><cardiac fibrosis><cardiac function><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><chronic kidney disease><clinical investigation><clinical practice><combination therapy><combined modality treatment><combined treatment><coronary fibrosis><design><designing><diets><drug/agent><elderly mice><fibroblast activating factor><fibroblast activation protein><fibroblast growth factor 23><fibroblast proliferation factor><fibroblast-activating factor><fibrosis in the lung><fibrotic heart><function of the heart><functional improvement><heart fibrosis><heart function><improve function><improved><improved functional outcomes><in vivo><infarct><innovate><innovation><innovative><inorganic phosphate><kidney fibrosis><kidney function><lipid based nanoparticle><lipid nanoparticle><locomotor system><lung fibrosis><mRNA><mRNA Expression><malignancy><membrane structure><mortality><multi-modal therapy><multi-modal treatment><myocardial fibrosis><neoplasm/cancer><novel><old mice><pathway><population aging><pre-clinical><pre-clinical testing><pre-clinical therapy><preclinical><preclinical therapy><receptor><renal><renal fibrosis><thymus derived lymphocyte><transcriptomics><wildtype mouse><wound healing><wound recovery><wound resolution>