Telomerase mRNA Reverses Senescence in Progeria Cells

Li, Yanhui; Zhou, Gang; Bruno, Ivone G.; Cooke, John P.

doi:10.1016/j.jacc.2017.06.017

Cited by 14 publications

(14 citation statements)

References 5 publications

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“…The telomeres of HGPS patients are generally shorter for their chronological age (Decker et al, ). However, there is heterogeneity in average telomere length among HGPS patients, with ~29% of patients having normal or even longer telomeres (Li, Zhou, Bruno, & Cooke, ) (Figure ). We explored the telomere length variations in HGPS fibroblast cells.…”

Section: Resultsmentioning

confidence: 99%

Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

Zhou

Bruno

et al. 2019

Aging Cell

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Hutchinson–Gilford progeria syndrome (HGPS) is characterized by accelerated senescence due to a de novo mutation in the LMNA gene. The mutation produces an abnormal lamin A protein called progerin that lacks the splice site necessary to remove a farnesylated domain. Subsequently, progerin accumulates in the nuclear envelope, disrupting nuclear architecture, chromatin organization, and gene expression. These alterations are often associated with rapid telomere erosion and cellular aging. Here, we further characterize the cellular and molecular abnormalities in HGPS cells and report a significant reversal of some of these abnormalities by introduction of in vitro transcribed and purified human telomerase (hTERT) mRNA. There is intra‐individual heterogeneity of expression of telomere‐associated proteins DNA PKcs/Ku70/Ku80, with low‐expressing cells having shorter telomeres. In addition, the loss of the heterochromatin marker H3K9me3 in progeria is associated with accelerated telomere erosion. In HGPS cell lines characterized by short telomeres, transient transfections with hTERT mRNA increase telomere length, increase expression of telomere‐associated proteins, increase proliferative capacity and cellular lifespan, and reverse manifestations of cellular senescence as assessed by β‐galactosidase expression and secretion of inflammatory cytokines. Unexpectedly, mRNA hTERT also improves nuclear morphology. In combination with the farnesyltransferase inhibitor (FTI) lonafarnib, hTERT mRNA promotes HGPS cell proliferation. Our findings demonstrate transient expression of human telomerase in combination with FTIs could represent an improved therapeutic approach for HGPS.

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Section: Resultsmentioning

confidence: 99%

Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

Zhou

Bruno

et al. 2019

Aging Cell

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“…[35][36][37] We have previously shown that transient delivery of modified mRNA encoding human telomerase (hTERT) in aged human cells can extend telomere length, reverse features of senescence and restore replicative capacity. [38][39][40] Similarly, telomerase gene therapy has been shown to augment myocardial regeneration and revascularization by rejuvenating ageing stem cells. [41][42][43] Here, we show that hTERT treatment of HGPS ECs extends telomere length, restores endothelial function and gene expression, increases sirtuin 1 (SIRT1) expression, reduces markers of DNA damage, and reverses adverse paracrine effects on VSMCs.…”

Section: Translational Perspectivementioning

confidence: 99%

Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice

Mojiri

Walther

Jiang

et al. 2021

European Heart Journal

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Aims Hutchinson-Gilford progeria syndrome (HGPS) is an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke. In HGPS a mutation in lamin A (progerin) alters nuclear morphology and gene expression. Current therapy increases the lifespan of these children only modestly. Thus, greater understanding of the underlying mechanisms of HGPS is required to improve therapy. Endothelial cells (ECs) differentiated from induced pluripotent stem cells (iPSCs) derived from these patients exhibit hallmarks of senescence including replication arrest, increased expression of inflammatory markers, DNA damage, and telomere erosion. We hypothesized that correction of shortened telomeres may reverse these measures of vascular ageing. Methods and results We generated ECs from iPSCs belonging to children with HGPS and their unaffected parents. Telomerase mRNA (hTERT) was used to treat HGPS ECs. Endothelial morphology and functions were assessed, as well as proteomic and transcriptional profiles with attention to inflammatory markers, DNA damage, and EC identity genes. In a mouse model of HGPS, we assessed the effects of lentiviral transfection of mTERT on measures of senescence, focusing on the EC phenotype in various organs. hTERT treatment of human HGPS ECs improved replicative capacity; restored endothelial functions such as nitric oxide generation, acetylated low-density lipoprotein uptake and angiogenesis; and reduced the elaboration of inflammatory cytokines. In addition, hTERT treatment improved cellular and nuclear morphology, in association with a normalization of the transcriptional profile, effects that may be mediated in part by a reduction in progerin expression and an increase in sirtuin 1 (SIRT1). Progeria mice treated with mTERT lentivirus manifested similar improvements, with a reduction in inflammatory and DNA damage markers and increased SIRT1 in their vasculature and other organs. Furthermore, mTERT therapy increased the lifespan of HGPS mice. Conclusion Vascular rejuvenation using telomerase mRNA is a promising approach for progeria and other age-related diseases.

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“…In addition, RNA-enhanced cell therapies and bioengineering are on the horizon. As one example, we have shown that mRNA encoding human telomerase can extend telomeres in senescent human cells, increase replicative capacity, reverse the senescence associated secretory phenotype, reduce DNA damage, and restore normal cellular functions (Ramunas et al 2015;Li et al 2017Li et al , 2019Mojiri et al 2021). This promising work has stimulated pre-clinical studies to assess the benefit of this mRNA therapy to enhance an FDA-approved cell therapy product for burn patients.…”

Section: Applications Of Rna Therapeuticsmentioning

confidence: 99%

Hospital-based RNA Therapeutics

Damase¹,

Sukhovershin²,

Zhang³

et al. 2022

Preprint

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Hospital-based programs democratize mRNA therapeutics by facilitating the processes to translate a novel RNA idea from the bench to the clinic. Because mRNA is essentially biological software, therapeutic RNA constructs can be rapidly developed. The generation of small batches of clinical grade mRNA to support IND applications and first-in-man clinical trials, as well as personalized mRNA therapeutics delivered at the point-of-care, is feasible at a modest scale of cGMP manufacturing. Advances in mRNA manufacturing science and innovations in mRNA biology, are increasing the scope of mRNA clinical applications.

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Telomerase mRNA Reverses Senescence in Progeria Cells

Cited by 14 publications

References 5 publications

Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

Transient introduction of human telomerase mRNA improves hallmarks of progeria cells

Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice

Hospital-based RNA Therapeutics

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