TERT mRNA lipid nanoparticles to extend telomeres to treat pulmonary fibrosis
TERT mRNA 脂质纳米颗粒延长端粒以治疗肺纤维化
基本信息
- 批准号:10547485
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-25 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAGTR2 geneAdvocateAffectAlveolarAmericanArchitectureAsphyxiaBiologicalBiological AssayBiological MarkersBleomycinBloodCell AgingCell DensityCell divisionCellsCessation of lifeChromosomesChronicCollagenComparative StudyDNADefectDiagnosisDiseaseDoseDrug KineticsEncapsulatedEnzymesEpigenetic ProcessEpithelial CellsEtiologyExhibitsExtracellular MatrixFDA approvedFamilyFibroblastsFibrosisFrequenciesGene ExpressionGene Expression ProfileGenomicsGrantHalf-LifeHumanImmunologic MarkersInflammationInflammation MediatorsInterstitial Lung DiseasesIntravenousKnockout MiceLegal patentLengthLungMaximum Tolerated DoseMedicalMessenger RNAMethodsModelingMolecularMusMyofibroblastOncogenesOxygenPathogenicityPatientsPharmaceutical PreparationsPharmacologyPharmacology StudyPharmacology and ToxicologyPhasePirfenidonePneumoniaPredispositionProductionPrognosisProteinsPulmonary EmphysemaPulmonary FibrosisRNA-Directed DNA PolymeraseRattusRejuvenationRespiratory FailureRiskRoleS-Phase FractionSafetyScientistSerumSilicon DioxideTechnologyTelomeraseTelomere ShorteningTestingTherapeuticTimeToxicokineticsTransforming Growth Factor betaTranslatingTumor-infiltrating immune cellsUniversitiesValidationWorkalveolar epitheliumanti-cancerarmbrief interventioncell typecommercializationdelivery vehicledensityeffective interventionepithelial stem cellfibrotic lungfirst-in-humanidiopathic pulmonary fibrosisimprovedimproved outcomein vivoindium-bleomycinlipid nanoparticleloss of function mutationlung healthlung preservationmanufacturing scale-upmeetingsmouse modelnanoparticlenintedanibnonhuman primatenovel strategiespharmacodynamic biomarkerpulmonary functionsenescenceside effectsingle-cell RNA sequencingstandard of carestem cellstelomere
项目摘要
Abstract
Short telomeres, the DNA tips of chromosomes, drive multiple key pathogenic mechanisms identified in
idiopathic pulmonary fibrosis (IPF) patients. Rejuvenation Technologies is developing the first safe and effective
intervention to extend short telomeres in lung and thereby extend IPF patient survival. IPF is characterized by
progressive scarring of lung tissue, leading to a lack of oxygen in the blood, and ultimately resulting in respiratory
failure. IPF affects up to 200,000 Americans, with up to 50,000 new cases each year. IPF patients have a median
survival of less than 5 years from the time of diagnosis, even with standard of care treatment. Increasing
evidence, however, points to a causative role of shortened telomeres in the etiology of IPF. Loss-of-function
mutations in telomerase are found in 2–5% of IPF patients and up to 15% of familial PF patients. Mice with
shortened telomeres exhibit increased susceptibility to fibrosis in a mouse model of IPF. Moreover, telomere
extension in mice using TERT DNA (which is not safe for humans due to the risk of genomic integration) reduces
fibrosis and improves lung function. Several key pathogenic mechanisms identified in IPF patients are also
consequences of critically short telomeres, including cellular senescence, elevated TGFβ and other inflammatory
mediators, chronic inflammation, myofibroblast activation, loss of progenitor cells, and reduced proliferative
capacity of remaining progenitor cells. These findings provide a strong rationale for developing a safe method to
extend telomeres to treat IPF. RTI proposes to use lipid nanoparticles (LNPs) encapsulating TERT mRNA (TERT
LNPs) to extend telomeres in the lung to treat IPF. RTI’s proprietary LNP lung delivery vehicle transfects >90%
of lung epithelial cells, and a single intravenous dose of TERT mRNA in mice extends telomeres in vivo by an
average of 230 bp, reversing the equivalent of years of telomere shortening in humans. Importantly for safety,
TERT mRNA only increases telomerase activity for about a day, after which the extended telomeres resume
shortening at their normal rate, leaving the important anti-cancer telomere shortening mechanism intact. RTI
demonstrated that i.v.-injected TERT mRNA LNPs increase survival by 210%, reduce fibrosis by 68%, and
improve lung function by 58% in the humanized telomere length (TERT KO) mouse bleomycin model of IPF. To
advance to IND approval, this Fast Track project will complete the following Specific Aims. Phase I: 1)
Pharmacokinetics (PK) and dose determination of i.v.-injected TERT mRNA LNPs. 2) Pharmacodynamics (PD),
biomarker, and comparative studies to FDA approved IPF drugs. 3) Pharmacology in IPF patient cells. Phase II:
4) Determine efficacy in second mouse model (silica). 5) CMC activities for manufacturing and scale-up of TERT
mRNA LNP production. 6) Perform IND-enabling toxicology and pharmacology studies. If successful, these
studies will provide proof of concept of a novel approach to preserve lung function, reduce fibrosis, and extend
survival in IPF. Commercialization of TERT LNPs will give IPF patients and clinicians a much-needed therapeutic
option to improve outcomes and survival.
摘要
项目成果
期刊论文数量(0)
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John Ramunas其他文献
John Ramunas的其他文献
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{{ truncateString('John Ramunas', 18)}}的其他基金
TERT mRNA lipid nanoparticles to extend telomeres to treat alcoholic hepatitis
TERT mRNA脂质纳米粒子延长端粒治疗酒精性肝炎
- 批准号:
10761603 - 财政年份:2020
- 资助金额:
$ 30万 - 项目类别:
Preventing liver fibrosis in alcoholic hepatitis by enhancing liver regenerative capacity via transient telomere extension using lipid nanoparticle-encapsulated TERT mRNA
使用脂质纳米颗粒封装的 TERT mRNA 进行短暂端粒延伸,增强肝脏再生能力,从而预防酒精性肝炎中的肝纤维化
- 批准号:
10082259 - 财政年份:2020
- 资助金额:
$ 30万 - 项目类别:














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