Portal de Periódicos da CAPES

An Encouraging Progress Report on the Treatment of Progeria and Its Implications for Atherogenesis

2014; Lippincott Williams & Wilkins; Volume: 130; Issue: 1 Linguagem: Inglês

10.1161/circulationaha.114.010648

1524-4539

Junko Oshima, Fuki M. Hisama, George M. Martin,

RNA modifications and cancer

HomeCirculationVol. 130, No. 1An Encouraging Progress Report on the Treatment of Progeria and Its Implications for Atherogenesis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAn Encouraging Progress Report on the Treatment of Progeria and Its Implications for Atherogenesis Junko Oshima, MD, PhD, Fuki M. Hisama, MD and George M. Martin, MD Junko OshimaJunko Oshima From the Department of Pathology (J.O., G.M.M.) and the Division of Medical Genetics (F.M.H.), University of Washington, Seattle, WA; and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA (G.M.M.). , Fuki M. HisamaFuki M. Hisama From the Department of Pathology (J.O., G.M.M.) and the Division of Medical Genetics (F.M.H.), University of Washington, Seattle, WA; and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA (G.M.M.). and George M. MartinGeorge M. Martin From the Department of Pathology (J.O., G.M.M.) and the Division of Medical Genetics (F.M.H.), University of Washington, Seattle, WA; and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA (G.M.M.). Originally published2 May 2014https://doi.org/10.1161/CIRCULATIONAHA.114.010648Circulation. 2014;130:4–6Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 1, 2014: Previous Version 1 There are no known human genetic syndromes that faithfully accelerate all of the common phenotypes associated with aging, but there are several striking disorders with multiple features (segmental progeroid syndromes). The suffix -oid is conceptually important, because it leaves open the possibility that the underlying mechanisms may differ to some extent from what is considered the usual pathogenesis. Two canonical examples are the Werner syndrome and the Hutchinson-Gilford Progeria Syndrome (HGPS). In both disorders, atherosclerosis is a particularly striking feature, causing the majority of deaths, usually via a myocardial infarction (although cancer is also a common cause of death in Werner syndrome, a later-onset disorder). Werner syndrome is an autosomal recessive disorder due to null mutations at a member of the RecQ family of DNA helicases and is associated with accelerated clonal senescence of somatic cells and genomic instability.1 HGPS is caused by a specific class of autosomal dominant mutations in lamin A, a component of the nuclear membrane. The causative mutations result in the synthesis of large amounts of an alternatively spliced toxic isoform known as progerin2–4; it is thus a gain-of-function mutation.Article see p 27During the maturation of prelamin A, a farnesyl group is added to a cysteine residue at the C terminus and subsequently removed by a proteolytic enzyme, Zmpste24, to produce mature lamin A. In progerin, the proteolytic site for Zmpste24 is deleted because of a cryptic splice site generated by the mutation.2,3 A mouse model expressing the nonfarnesylated progerin exhibited near-normal phenotypes, supporting the interpretation that progerin toxicity is mediated by the farnesyl moiety.5 The severities of the disease correlate with the amount of progerin, a function of the activity of the cryptic splice site.6 The size of the deletion also contributes to the severity of the phenotype. The majority of classical early-onset forms of HGPS result from a 50-amino-acid deletion. Attenuated forms of the disease have been associated with alternative deletions that lead to lesser amounts of the progerin isoform.7,8Of major biomedical interest have been reports that small amounts of progerin can be detected in human tissues, including human arteries, and that these amounts increase with age.9,10 These observations now raise the important question of the extent to which progerin contributes to human atherogenesis.In this issue of Circulation, Gordon et al11 describe small but robust increases in the survival of HGPS patients following treatments that interfere with the posttranslational farnesylation of lamin A proteins. Remarkably, given the extreme rarity of this disorder,12 this team, assisted by the efforts of a highly successful Progeria Research Foundation (http://www.progeriaresearch.org/), managed to assemble a cohort of 161 untreated control HGPS patients and 43 HGPS patients who were treated with either a single farnesyltransferase inhibitor, lonafarnib, or 2 additional agents that also inhibited farnesylation: a bisphosphonate (zoledronate), which inhibits the synthesis of farnesyl-pyrophosphate, and a statin (pravastatin), which inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (see Figure 111).Recruitment of control disease subjects did not require genotyping, although some are listed in Table III in the online-only Data Supplement.11 In contrast to the experience of our International Registry of Werner Syndrome, however, in which we could only provide a molecular diagnosis of ≈80% of clinical diagnoses, molecular confirmations of clinically diagnosed HGPS are much more robust, probably well in excess of 95%. Moreover, all treated subjects were in fact genotyped, some of whom had LMNA mutations that resulted in lower levels of progerin (see Table V in the online-only Data Supplement11).It is important to note that the treated group included patients with any duration of treatment, either during a previous 2-year trial of farnesyltransferase inhibitor monotherapy or during an ongoing 3.5-year trial of combination treatment. Given that feature of the study, the Kaplan-Meier curves of Figure 2B11 are even more impressive – 21/43 deaths in the untreated group versus 5/42 deaths in the treated group during the approximately 5-year period of this study.The authors suggest that the increased longevity of the treated HGPS patients was due to a reduction of cardiovascular pathology, a very plausible hypothesis. Investigators engaged in survival studies must always keep in mind, however, the possibility that any intervention with the potential to induce dietary restriction might have a more general effect on the pathophysiology of aging.13 This is extraordinarily unlikely in the present case, however, given the precise target of the interventional agents and the fact that there was no evidence of weight loss in a previous preliminary trial of monotherapy.14The authors point out that the present data now provide the best available baseline data of HGPS survival for use by interventional trials with other agents. Among these future potential interventions is research that uses a mouse model of HGPS to evaluate phenotypic improvements via the targeting of an enzyme, isoprenylcysteine carboxyl methyltransferase, which is responsible for the methylation of isoprenylcysteine.15 After farnesylation of prelamin A and progerin, farnesylcysteine is methylated by isoprenylcysteine carboxyl methyltransferase before cleavage by Zmpste24. Zmpste24-deficient mice expressing hypomorphic isoprenylcysteine carboxyl methyltransferase showed striking ameliorations of HGPS-like phenotypes and upregulation of mammalian target of rapamycin (mTOR) signaling.15 In contrast to those mTOR results, however, Cao et al16 showed that long-term treatment of HGPS cells with the mTOR inhibitor, rapamycin, facilitated the autophagic clearance of progerin and reversed cellular HPGS phenotypes. Therefore, mTOR inhibitors could prove to be useful in the treatment of age-related disorders, including the treatment of Werner syndrome.17 Since the advent of drug-eluting coronary stents that deliver sirolimus or everolimus to prevent restenosis, the use of systemic mTOR inhibitors has been approved by the Food and Drug Administration for the treatment of renal and brain manifestations of the genetic condition, tuberous sclerosis, and for the treatment of HER2-negative breast cancer, pancreatic neuroendocrine tumors, and advanced renal cell carcinoma, as well. There is also much current interest in the use of rapalogs, chemical agents that may have fewer side effects, for example, on immune suppression.18 Finally, there are reports of the use of RNAi against progerin mRNA that showed improvements of cellular HGPS phenotypes.19,20 Such gene therapy, however, may not be practical at this point because of the limitations of delivery systems.Returning to the consideration of the most biomedically significant HGPS phenotype, atherosclerosis, 2 issues remain to be resolved. The first is the histopathologic observations of apparent phenotypic discordances with atherosclerosis as it usually occurs. Of particular interest are the unusually extensive periarterial adventitial fibrosis and the involvement of vascular smooth muscle alterations.9 The latter issue has been addressed in part by in vitro studies indicating that aging normal vascular smooth muscle cells reiterate the aging phenotype of HGPS fibroblasts in culture and that this process of cell senescence is accelerated by the accumulation of prelamin A.21 The former observation will require more research, however.The second issue is the need for more robust animal models of HGPS that include atherosclerosis. To the best of our knowledge, atherosclerosis has yet to be demonstrated in any of the several published mouse models of HGPS. The use of alternative animal models, such as the miniature pig, would be highly desirable.22AcknowledgmentsWe dedicate this editorial to the memory of Sam Berns, a highly intelligent and heroic HGPS patient and the son of the first author of the article addressed by this editorial. For one of Sam's inspirational addresses, the reader is referred to the TED talk he presented shortly after his 17th birthday: https://www.youtube.com/watch?v=36m1o-tM05g.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Junko Oshima, MD, PhD, Department of Pathology, University of Washington, Box357470, HSB K-543B Seattle, WA 98195. E-mail [email protected]References1. Oshima J, Martin GM, Hisama FM. Werner syndrome., Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens KIn: Genereviews. Seattle, WA; 2014. http://www.ncbi.nlm.nih.gov/pubmed/20301687. Accessed April 26, 2014.Google Scholar2. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Lévy N. Lamin a truncation in Hutchinson-Gilford progeria.Science. 2003; 300:2055.CrossrefMedlineGoogle Scholar3. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature. 2003; 423:293–298.CrossrefMedlineGoogle Scholar4. Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.Proc Natl Acad Sci U S A. 2004; 101:8963–8968.CrossrefMedlineGoogle Scholar5. Yang SH, Chang SY, Ren S, Wang Y, Andres DA, Spielmann HP, Fong LG, Young SG. Absence of progeria-like disease phenotypes in knock-in mice expressing a non-farnesylated version of progerin.Hum Mol Genet. 2011; 20:436–444.CrossrefMedlineGoogle Scholar6. Hisama FM, Lessel D, Leistritz D, Friedrich K, McBride KL, Pastore MT, Gottesman GS, Saha B, Martin GM, Kubisch C, Oshima J. Coronary artery disease in a Werner syndrome-like form of progeria characterized by low levels of progerin, a splice variant of lamin A.Am J Med Genet A. 2011; 155A:3002–3006.CrossrefMedlineGoogle Scholar7. Fukuchi K, Katsuya T, Sugimoto K, Kuremura M, Kim HD, Li L, Ogihara T. LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome.J Med Genet. 2004; 41:e67.CrossrefMedlineGoogle Scholar8. Navarro CL, De Sandre-Giovannoli A, Bernard R, Boccaccio I, Boyer A, Geneviève D, Hadj-Rabia S, Gaudy-Marqueste C, Smitt HS, Vabres P, Faivre L, Verloes A, Van Essen T, Flori E, Hennekam R, Beemer FA, Laurent N, Le Merrer M, Cau P, Lévy N. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.Hum Mol Genet. 2004; 13:2493–2503.CrossrefMedlineGoogle Scholar9. Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L, Gerhard-Herman M, Machan JT, Kutys R, Virmani R, Collins FS, Wight TN, Nabel EG, Gordon LB. Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging.Arterioscler Thromb Vasc Biol. 2010; 30:2301–2309.LinkGoogle Scholar10. Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312:1059–1063.CrossrefMedlineGoogle Scholar11. Gordon LB, Massaro J, D'Agostino RB, Campbell SE, Brazier J, Brown WT, Kleinman ME, Kieran MW. Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome.Circulation. 2014; 130:27–34.LinkGoogle Scholar12. Hennekam RC. Hutchinson-Gilford progeria syndrome: review of the phenotype.Am J Med Genet A. 2006; 140:2603–2624.CrossrefMedlineGoogle Scholar13. Speakman JR, Mitchell SE. Caloric restriction.Mol Aspects Med. 2011; 32:159–221.CrossrefMedlineGoogle Scholar14. Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.Proc Natl Acad Sci U S A. 2012; 109:16666–16671.CrossrefMedlineGoogle Scholar15. Ibrahim MX, Sayin VI, Akula MK, Liu M, Fong LG, Young SG, Bergo MO. Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria.Science. 2013; 340:1330–1333.CrossrefMedlineGoogle Scholar16. Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells.Sci Transl Med. 2011; 3:89ra58.CrossrefMedlineGoogle Scholar17. Saha B, Cypro A, Martin GM, Oshima J. Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts.Aging Cell. 2014; 13:573–575.CrossrefMedlineGoogle Scholar18. Blagosklonny MV. Immunosuppressants in cancer prevention and therapy.Oncoimmunology. 2013; 2:e26961.CrossrefMedlineGoogle Scholar19. Huang S, Chen L, Libina N, Janes J, Martin GM, Campisi J, Oshima J. Correction of cellular phenotypes of Hutchinson-Gilford Progeria cells by RNA interference.Hum Genet. 2005; 118:444–450.CrossrefMedlineGoogle Scholar20. Scaffidi P, Misteli T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.Nat Med. 2005; 11:440–445.CrossrefMedlineGoogle Scholar21. Ragnauth CD, Warren DT, Liu Y, McNair R, Tajsic T, Figg N, Shroff R, Skepper J, Shanahan CM. Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.Circulation. 2010; 121:2200–2210.LinkGoogle Scholar22. Al-Mashhadi RH, Sørensen CB, Kragh PM, Christoffersen C, Mortensen MB, Tolbod LP, Thim T, Du Y, Li J, Liu Y, Moldt B, Schmidt M, Vajta G, Larsen T, Purup S, Bolund L, Nielsen LB, Callesen H, Falk E, Mikkelsen JG, Bentzon JF. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant.Sci Transl Med. 2013; 5:166ra1.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Orriss I (2020) Extracellular pyrophosphate: The body's "water softener", Bone, 10.1016/j.bone.2020.115243, 134, (115243), Online publication date: 1-May-2020. Atchison L, Zhang H, Cao K and Truskey G (2017) A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells, Scientific Reports, 10.1038/s41598-017-08632-4, 7:1, Online publication date: 1-Dec-2017. Orriss I, Arnett T and Russell R (2016) Pyrophosphate: a key inhibitor of mineralisation, Current Opinion in Pharmacology, 10.1016/j.coph.2016.03.003, 28, (57-68), Online publication date: 1-Jun-2016. Root A (2015) Editorial comments, Current Opinion in Pediatrics, 10.1097/MOP.0000000000000248, 27:4, (492-495), Online publication date: 1-Aug-2015. Bachmann H, Meier W, du Bois A, Kimmig R, Kuhlmann J, Siffert W, Sehouli J, Wollschlaeger K, Huober J, Hillemanns P, Burges A, Schmalfeldt B, Aminossadati B and Wimberger P (2015) The FNTB promoter polymorphism rs11623866 as a potential predictive biomarker for lonafarnib treatment of ovarian cancer patients, British Journal of Clinical Pharmacology, 10.1111/bcp.12688, 80:5, (1139-1148), Online publication date: 1-Nov-2015. July 1, 2014Vol 130, Issue 1 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.010648PMID: 24795391 Originally publishedMay 2, 2014 KeywordsfarnesyltransferaseEditorialsclinical trialatherosclerosisgeneticshumansprogeriaPDF download Advertisement SubjectsGeneticsPharmacology