Developmental Biology - Progeria|
Possible New Treatment For Progeria
Impaired function of telomeres, the "end caps" of chromosomes, may be able to be mediated...
Progeria is a very rare disease that affects about one in 18 million children and results in premature aging and death in adolescence from complications of cardiovascular disease. In a study on mice and human cells, researchers at Sweden's Karolinska Institute and IFOM, the FIRC Institute of Molecular Oncology in Italy, have identified how antisense oligonucleotide therapies could be used as a new possible treatment option for the disease.
These results are published in the journal Nature Communications.
Progeria, or Hutchinson-Gilford progeria syndrome, has genetic causes and is linked to progerin, a defective form of lamin A protein found in the cell nucleus. This mutation inhibits normal cell division - the basis of tissue growth and renewal.
This cell division failure was identified in 2003 by researcher Maria Eriksson PhD with the Department of Biosciences and Nutrition, at the Center for Innovative Medicine in the Karolinska Institutet, Sweden. Children affected usually die in early adolescence from cardiovascular diseases typically found in the elderly.
So far, more than a dozen treatments of progeria have been tested in different ways, but clinical trial results have been disappointing.
"We have seen positive effects in the treatment of mice, but in humans the effect has been too small. We therefore need to rethink and find new ways to treat the disease."
Maria Eriksson PhD, Professor, Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.
In the new study, researchers used cell samples from children with progeria and found an impaired function in the telomeres at the far end of the chromosomes — an accumulation of so-called telomeric non-coding RNA or tncRNAs. These tncRNAs control DNA damage response (DDR) to dysfunctional telomeres.
By adding antisense oligonucleotides, a treatment used to inactivate harmful genes, researchers were able to reduce the level of tncRNAs, leading to a more normalised cell division. This technique will likely improve patients' conditions by extending lifespan.
"In a gene altered mouse model of progeria treated in this same way, we saw a significant increase in both maximum life expectancy, up 44 percent, and average life expectancy, up 24 percent. Very promising results."
Agustin Sola-Carvajal PhD, former postdoc, Eriksson's research group and co-author of the study.
Progerin is also found in healthy subjects and has been observed to increase with age, suggesting the results may also be important in normal aging and age-related disease.
"More research is needed to assess how the relatively low levels of progerin seen in healthy individuals contribute to ageing and age-related disease," says Eriksson. "It is interesting to note that antisense oligonucleotides are now included as drugs in advanced clinical trials, some of which are already approved by the FDA in the U.S."
Maria Eriksson PhD
Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.
Julio Aguado, Agustin Sola-Carvajal, Valeria Cancila, Gwladys Revêchon, Peh Fern Ong, Corey Winston Jones-Weinert, Emelie Wallén Arzt, Giovanna Lattanzi, Oliver Dreesen, Claudio Tripodo, Francesca Rossiello, Maria Eriksson and Fabrizio d’Adda di Fagagna.
The authors thank Valentina Matti and Isabel Budenbender for technical help; Amanda Oldani and Sara Barozzi for providing assistance in image acquisition and analysis; Ylli Doksani for advice on telomere length assays; Ernst Wolvetang for support during the revision process of this paper; all F.d’A.d.F. laboratory members for discussions. J.A. was supported by Marie Curie Initial Training Networks (FP7 PEOPLE 2012 ITN (CodeAge Project No: 316354)). F.d’A.d.F. was supported by the Associazione Italiana per la Ricerca sul Cancro, AIRC (application-12971 and 21091), Cariplo Foundation (grant-2014-0812), Fondazione Telethon (GGP17111), Progetti di Ricerca di Interesse Nazionale (PRIN) 2010-2011 and 2015, the Italian Ministry of Education Universities and Research EPIGEN Project, InterOmics Project and AMANDA project Accordo Quadro Regione Lombardia–CNR, a European Research Council advanced grant (322726), AriSLA (project ‘DDRNA and ALS’) and AIRC Special Program 5 per mille metastases (Project-21091). Research in the M.E. laboratory was supported by the Swedish Research Council and the Center for Innovative Medicine, Karolinska Institute.
The study is a collaboration with researchers from Milan and Singapore and has been implemented with grants from the Swedish Research Council and Center for Innovative Medicine, CIMED, at Karolinska Institute, among others.
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