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主题文献:Progeria-- A Paradigm for Translational Medicine

主题文献:Progeria-- A Paradigm for Translational Medicine
主题文献:Progeria-- A Paradigm for Translational Medicine

Leading Edge

Essay

Progeria:A Paradigm

for Translational Medicine

Leslie B.Gordon,1,2,*Frank G.Rothman,3Carlos Lo′pez-Ot?′n,4and Tom Misteli5,*

1Department of Anesthesia,Boston Children’s Hospital and Harvard Medical School,Boston,MA02115,USA

2Department of Pediatrics,Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University,Providence,RI02912,USA 3Division of Biology and Medicine,Brown University,Providence,RI02912,USA

4Departamento de Bioqu?′mica y Biolog?′a Molecular,Instituto Universitario de Oncolog?′a(IUOPA),Universidad de Oviedo,33006Oviedo, Spain

5National Cancer Institute,NIH,Bethesda,MD20892,USA

*Correspondence:leslie_gordon@https://www.wendangku.net/doc/8a4968599.html,(L.B.G.),mistelit@https://www.wendangku.net/doc/8a4968599.html,(T.M.)

https://www.wendangku.net/doc/8a4968599.html,/10.1016/j.cell.2013.12.028

Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies.The progress made on the premature aging disorder Proge-ria is a shining example of the impact that studies of rare diseases can have.

The premature aging disorder Hutchin-son-Gilford progeria syndrome(HGPS, or progeria)is one of the rarest human diseases.Yet its study over the last decade has attracted attention from basic scientists,clinicians,the pharma-ceutical industry,and policy makers. Why is the scienti?c community intensely watching the activity surrounding a dis-ease that affects a mere350children worldwide(Gordon,2013)?There are two important reasons.First,progress in HGPS can be viewed as a paradigm of modern translational medicine:basic science informing clinical medicine in a bench-to-bedside approach to medical discovery.Second,discoveries in rare diseases often offer new possibilities for understanding of cellular and organismal mechanisms,such as normal aging and cardiovascular disease in the case of HGPS.This Essay summarizes advances made in the understanding of HGPS and discusses the implications of research into rare diseases on basic cell biology, understanding of physiological pro-cesses,drug discovery,and clinical trial design.

A Short History of HGPS

HGPS was?rst described by Drs.Jona-than Hutchinson and Hastings Gilford in 1886and1897,respectively(Gilford, 1904;Hutchinson,1886).For more than 100years,its cause was a medical mys-tery.The disease was designated as a premature aging syndrome by Gilford based on the overall resemblance of

patients to aged individuals and the pres-

ence of aging-associated symptoms,

including lack of subcutaneous fat,hair

loss,joint contractures,progressive car-

diovascular disease resembling athero-

sclerosis,and death due to heart attacks

and strokes in childhood(Merideth et al.,

2008)(Figure1).

The mapping of the disease gene re-

vealed that HGPS is a sporadic,auto-

somal dominant disease caused by a

mutation in LMNA(De Sandre-Giovannoli

et al.,2003;Eriksson et al.,2003).This

gene codes for the inner nuclear mem-

brane proteins lamins A and C,two

prominent structural components of the

eukaryotic cell nucleus.HGPS is a

member of a group of diseases called

laminopathies,resulting from mutations

throughout the LMNA gene that result

in a wide spectrum of overlapping

disorders.These include muscular dys-

trophies,a peripheral neuropathy,lipo-

dystrophy syndromes,and accelerated

aging disorders(Worman and Bonne,

2007).

The disease-causing mutation in

HGPS activates what is normally a only

sporadically used alternative splice site

in LMNA exon11,resulting in partial

deletion of the exon(Figure1).Although

the discovery of disease genes does

not always inform about disease mecha-

nism,the identi?cation of an LMNA

mutation as the cause of HGPS inspired

intense basic and clinical research into

this disease and its relationship to aging.

The reason for the rapid progress in our

understanding of HGPS was that the

gene identi?cation dovetailed with exten-

sive prior work by basic cell biologists on

the complex posttranslational processing

events of lamin A,which would turn out

to be key for understanding the HGPS

disease mechanism(Sinensky et al.,

1994).

Normally,lamin A is produced via a

prelamin intermediate whose C-terminal

cysteine residue is?rst modi?ed by farne-

sylation and carboxymethylation followed

by enzymatic cleavage of the terminal15

amino acids,including the farnesylated

cysteine,by the ZMPSTE24endopro-

tease.However,in the HGPS mutant prel-

amin A isoform,this cleavage site is

missing as a result of the aberrant splicing

event.Thus,the HGPS mutation leads to

the accumulation of a permanently farne-

sylated,uncleaved lamin A isoform

named progerin(Figure1).This aberrantly

modi?ed,lamin A intermediate triggers,

by yet-to-be discovered mechanisms,

the many cellular and organismal disease

symptoms.

A Rare Disease Provides Insight into

Fundamental Cell Biology

Elucidating the cascade of damaging

events is a critical step in the understand-

ing of any disease,and it is often crucial

for identifying candidate drug targets.

HGPS patient cells have numerous de-

fects,and studying them has become

a

400Cell156,January30,2014a2014Elsevier Inc.

powerful tool for both basic scientists and clinicians to ask questions about the roles of major cellular processes in health and disease (Figure 1).Nuclear Morphology and Function The most overt cellular defects in HGPS are dramatic changes in nuclear morphol-ogy (Eriksson et al.,2003),a phenotype that is not surpris-ing given the prominent archi-tectural role of lamin A in the nucleus.Whereas the lamin proteins in healthy cells move dynamically between the nuclear lamina polymer at the nuclear periphery and the nucleoplasm,they become immobilized in HGPS patient cells,leading to thickening of the lamina (Goldman et al.,2004;Dahl et al.,2010).Probably as a consequence of these structural changes,the mechanical properties of HGPS nuclei are altered and patient cells exhibit increased stiffness compared with cells from healthy individuals (Dahl et al.,2010).These alterations are likely relevant in disease pathology,as they might affect the response of cells in tissues that are particularly exposed to mechanical stress such as the vasculature,bone,and joints—three tis-sues that exhibit some of the most prominent symptoms in HGPS patients.These defects are of great interest to the study of lamin biology because despite the known major functions of the nuclear lamins,the structural properties of the nu-clear scaffold have remained elusive (Burke and Stewart,2013).For example,it is unclear precisely how lamins poly-merize and how they interact with a myriad of inner nuclear membrane complexes and chromatin or how they transmit mechani-cal signals to mechanosensitive https://www.wendangku.net/doc/8a4968599.html,min mutants such as the one causing HGPS are promising tools to begin to elucidate fundamental aspects of nuclear organization.DNA and Chromosome Function

Two other notable cellular defects in HGPS patient cells are widespread alter-ations of chromatin structure,such as the loss of heterochromatin domains,and changes in epigenetic https://www.wendangku.net/doc/8a4968599.html,ing HGPS cells as a model system,the nucleosome-remodeling and deacetylase complex NURD has been identi?ed as a mediator of both higher-order chromatin structure and maintenance of genomic integrity (Pegoraro et al.,2009).Using genome-wide studies in which the physical interac-tions of lamins with the genome are comparatively mapped in wild-type and patient cells,HGPS also provides an opportunity to probe lamin-genome interac-tions,which are increasingly recognized as key drivers of

overall genome organization (McCord et al.,2013).HGPS

patient cells also suffer DNA

repair defects due to both reduced recruitment of DNA damage response (DDR)fac-tors to sites of damage and slowed repair kinetics (Ben-son et al.,2010;Musich and Zou,2009).On the other hand,the xeroderma pig-mentosum group A (XPA)protein appears aberrantly recruited to replication forks,promoting replication fork stalling and activation of the DDR (Liu et al.,2006).Pro-gerin also appears to modu-late telomere function and to induce DDR signaling from

telomeres via activation of p53and Rb pathways (Ben-son et al.,2010).Interestingly,telomere dysfunction during senescence appears to feed back and promote pro-gerin expression (Cao et al.,2011a ).These studies have begun to uncover the elu-sive mechanisms that link nuclear structure and geno-mic instability.

Regulatory and Stress Response Functional studies using ani-mal and cellular models of

HGPS have facilitated the identi?cation of regulatory and stress-response path-ways involved in HGPS development.Of special interest is the hyperactivation of p53signaling in HGPS cells and in mouse models of HGPS (Kudlow et al.,2008;Liu et al.,2006;Varela et al.,2005).However,the fact that phenotype alterations in these progeroid mice are not completely rescued in a p53null background indi-cates that other pathways contribute to the generation of the observed

defects.

Figure 1.HGPS:From Genetics to Symptoms HGPS is caused by a spontaneous point mutation in the LMNA gene,coding

for the nuclear intermediate ?lament proteins lamin A and C.The disease mutation activates an alternative pre-mRNA splice site in exon 11that results

in removal of 150nt from the 30end of this exon and creates an internal deletion of 50aa in the translated lamin A protein.The mutant protein (red),referred to as progerin,is permanently farnesylated as the 50aa deletion includes an

endoproteolytic cleavage site,which normally removes the farnesylated C terminus from the wild-type protein.The farnesyl group is believed to facilitate

the association of the protein to the nuclear membrane,resulting in its accu-mulation at the nuclear periphery.Association of progerin with the lamina

interferes with normal lamina function and triggers,via yet unknown mecha-nisms,many of the commonly observed nuclear defects.HGPS cells also

exhibit nonnuclear defects,including altered signaling and metabolic prop-erties.It is assumed that these cellular defects and particularly the loss of stem cell function contribute to the prominent overt patient symptoms.(Left)Fluo-rescently tagged progerin (green)accumulates at the periphery of patient nuclei and alters nuclear morphology.(Right)Two progeria patients.Image

reproduced with permission,courtesy of The Progeria Research Foundation.Cell 156,January 30,2014a2014Elsevier Inc.401

These additional pathways may include the attrition of adult stem cells(Espada et al.,2008;Rosengardten et al.,2011; Scaf?di and Misteli,2008),the dysregula-tion of the somatotrophic axis and several miRNA-controlled circuits(Marin?o et al., 2010;Ugalde et al.,2011),the generation of profound changes in glucose and lipid metabolism(Marin?o et al.,2008),and the ATM-dependent activation of NF-k B signaling that links nuclear lamina defects to the systemic in?ammation observed in two different progeroid murine models (Osorio et al.,2012).

Induced Pluripotent Stem Cells and Their Potential

As in many diseases,tissue-speci?c cell lines from HGPS patients are not easily obtainable due to the dif?culty of performing biopsies on frail patients.The development of patient-derived induced pluripotent stem(iPS)cells provides powerful tools to study differentiation pathways of tissues affected by the dis-ease.HGPS iPS cells have been success-fully generated and differentiated along multiple lineages,including the particularly disease-relevant vascular smooth muscle cells(VSMCs)and mesenchymal stem cells(Zhang et al.,2011).Early experi-ments using these cells revealed height-ened sensitivity of HGPS mesenchymal stem cells to stress and aberrant differenti-ation of HGPS VMSCs(Zhang et al.,2011). Patient-derived iPS cells have also already been used to develop strategies that can successfully correct the HGPS muta-tion(Liu et al.,2011),and,as with many other diseases,they will also be invaluable in screening approaches to identify possibly tissue-speci?c drugs.Finally, normal and gene-corrected HGPS iPS-derived tissue-speci?c cells may in the future provide a foundation for cell replace-ment therapy approaches to HGPS. What Progeria May or May Not Teach Us about Normal Aging

Rare diseases often re?ect highly preva-lent pathological events and provide a unique opportunity to study physiological processes.In the case of HGPS,the obvious question is whether the disease provides insights into normal aging and, because cardiovascular failure is the source of signi?cant morbidity and mor-tality,into aging-related cardiovascular disease.

The similarities between HGPS and

normal aging extend to all levels,from

shared molecular features to similarities

in symptoms(Burtner and Kennedy,

2010;Lo′pez-Ot?′n et al.,2013).Notably,

progerin is produced in normally aging in-

dividuals as well as in HGPS patients.This

is because the classic HGPS mutation is a

pre-mRNA splicing mutation,which acti-

vates a weak,yet sporadically used,

intronic splice site that is present in wild-

type individuals(Rodriguez et al.,2009;

Scaf?di and Misteli,2006).Progerin RNA

and protein are detected in tissues from

healthy individuals,even before the

teenage years,albeit at levels 50-fold

lower than in HGPS cells.However,given

the dominant-negative nature of progerin,

these levels are likely suf?cient to elicit

limited cellular damage.In addition,there

is histological evidence that progerin

levels may increase with age and may

be responsible for some of the cellular de-

fects associated with aging,which are

reminiscent of those seen in HGPS pa-

tients(McClintock et al.,2007).In support

of a potential dosage effect of progerin,

nonclassical progeria mutations that

induce less frequent use of the internal

splice site and thus lower cellular levels

of progerin also cause a much milder

form of disease but still eventually pro-

duce atherosclerosis(Hisama et al.,

2011).The extent to which lower levels

of progerin relative to HGPS can affect

health and aging is undetermined,but

evidence is accumulating to suggest a

role of progerin in many aspects of gener-

alized aging and cardiovascular health.

Notably,the atherosclerotic plaques in

HGPS are similar to those found in aging

individuals(Olive et al.,2010).Addition-

ally,vascular stiffening in progeria is

much like that seen over a lifetime of aging

re?ected in each population by increased

pulse wave velocity(Gerhard-Herman

et al.,2012).

The cardiovascular system is of crucial

importance in HGPS,as cardiovascular

failure is the source of signi?cant

morbidity and almost all mortality.From

a clinical perspective,HGPS is a primary

vasculopathy,characterized by early and

pervasive accelerated vascular stiffening

followed by hypertension,vessel plaques,

angina,cardiomegaly,metabolic syn-

drome,and congestive heart failure

(Baker et al.,1981).Isolated from risk fac-

tors such as hypercholesterolemia and

increased C-reactive protein(Gordon

et al.,2005),early stage hypertension,

and smoking,the study of HGPS could

provide an opportunity to discover new

elements that may in?uence the vascular

disease component of aging.For

example,the abnormally dense vascular

adventitia observed in individuals with

HGPS may contribute to their vessel stiff-

ening,and the role of the adventitia in the

pathobiology of generalized CVD during

aging is just beginning to be explored(Ha-

velka and Kibbe,2011).Additionally,

HGPS has shed light on mechanisms of

vascular calci?cation in aging and athero-

sclerosis.Excess prelamin A or progerin

results in calcium dysfunction(Ragnauth

et al.,2010),and prelamin A promotes

VSMC calci?cation and aging by inducing

persistent DNA damage signaling(Liu

et al.,2013).HGPS patients suffer

from extraskeletal calcium phosphate

deposition,which potentially acts as an

important factor for vascular plaque

development(Cleveland et al.,2012).

These studies that show connections be-

tween cellular senescence,generalized

calcium dysfunction,vascular calci?ca-

tion,and atherosclerotic plaque formation

in both aging and HGPS represent

emerging areas of cross-discovery in

both basic and clinical research arenas

(Mackenzie and MacRae,2011).

Much like in normal aging,tissue stem

cell functions appear to be compromised

in HGPS(Espada et al.,2008;Rose-

ngardten et al.,2011;Scaf?di and Misteli,

2008).In a progeroid mouse model that

lacks the prelamin A endoprotease

ZMPSTE24and recapitulates some phe-

notypes seen in HGPS,the proliferative

potential of epidermal stem cells is greatly

reduced(Espada et al.,2008).Further-

more,expression of progerin in human

mesenchymal stem cells triggers prema-

ture expression of lineage markers,albeit

in the absence of differentiation,but at the

same time interferes with differentiation

along de?ned lineages,including adipo-

genesis and osteogenesis(Scaf?di and

Misteli,2008).

Notably,some key aspects of aging are

not recapitulated in HGPS.Most promi-

nent among these are the absence of

nervous system deterioration,including

dementia,and the lack of detectable im-

mune system de?cits.Recent studies

402Cell156,January30,2014a2014Elsevier Inc.

have shown that progerin levels in the brain are very low and that the microRNA miR-9downregulates lamin A synthesis in the brain (Jung et al.,2012;Nissan et al.,2012).These results suggest that the lack of symptoms in the CNS of HGPS patients may be due to an absence of pro-gerin in neural cells.This may also be the case for the absence of immune system de?ciencies.Moreover,the paucity of reports on tumors or cancers in HGPS patients implies low susceptibility of their cells to malignant transformation,in contrast to the strong increase in tumor susceptibility during normal aging.The lack of tumors in HGPS patients is even more surprising,given the persistently high levels of DNA damage in HGPS cell lines.Interestingly,recent studies using ZMPSTE24mosaic mice have revealed that prelamin A accumulation prevents cancer invasion and results in a decrease in the incidence of in?ltrating carcinomas in association with altered extracellular matrix components (de la Rosa et al.,2013).

Like any premature aging syndrome,HGPS is only a partial representation of the multifactorial process of normal aging.However,rather than using dis-crepancies as an argument to diminish the potential of HGPS to provide insight into normal aging,a more productive approach may be to carefully elucidate the intersections and distinctions be-tween HGPS and normal aging in order to gain new understanding within both ?elds.Progeria as a Testbed for Therapeutic Strategies

The development of therapeutic strate-gies for HGPS bene?ted from the con?u-ence of gene discovery and extensive prior knowledge of lamin A function at the time of the gene discovery.This made several therapeutic strategies immediately apparent.Remarkably,the time from gene discovery to the ?rst hu-man therapeutic trial for HGPS was just 5years (Kieran et al.,2007).In the wake of initial therapeutic trials,exponential increases in our understanding of the dis-ease mechanisms combined with techno-logical advances have broadened the scope of both the potential therapeutic targets and approaches (Figure 2).All of the therapeutic strategies applied to HGPS are under consideration for many other diseases,and it is likely that experi-ences with HGPS will prove relevant to the larger medical community.Drug Repurposing

Compared with developing any type of new medication,drug repurposing,which uses medications previously developed for other diseases,promises the shortest timeline from preclinical to clinical testing.Discovering that progerin is permanently farnesylated immediately opened the door for a candidate drug discovery approach using farnesyltransferase inhib-itors (FTIs),which had previously been developed as potential anticancer drugs and had acceptable side effects in chil-dren.FTIs were quickly and successfully tested preclinically in cell culture (Capell et al.,2005;Glynn and Glover,2005;Mal-lampalli et al.,2005;Toth et al.,2005;Yang et al.,2005)and animal models (Ca-pell et al.,2008;Fong et al.,2006;Yang et al.,2008),which showed improvement of disease symptoms upon FTI treatment.A prospective single-arm clinical trial was initiated in 2007with a cohort of 26HGPS patients between 3and 16years of age.Administration of the FTI lonafarnib for a minimum of 2years yielded improve-ments in weight gain,vascular stiffness,and bone structure in some patients (Gor-don et al.,2012)and provided evidence for decreased headaches and strokes (King and Heyer,2013;Ullrich et al.,2013),though the extent of improvements varied among patients.

Subsequent to initiation of the ?rst clin-ical trial,it was reported that progerin was partially modi?ed in cultured HGPS ?broblasts by geranylgeranylation after FTI treatment (Varela et al.,2008).This alternate modi?cation could be blocked by statins and aminobisphosphonates that prevent the production of both farne-syl and geranylgeranyl precursors (Varela et al.,2008).This result offered one possible explanation for why FTI treatment only modestly lengthened lifespan in a mouse model (Yang et al.,2008)and prompted several currently ongoing thera-peutic trials in which FTIs are combined with pravastatin (a statin)and zoledronic acid (an aminobisphosphonate).The development of combination therapies re?ects a potentially powerful iterative approach between basic and

clinical

Figure 2.A Spectrum of Possible HGPS Therapies

HGPS is amenable to a wide spectrum of cutting-edge therapeutic strategies.

Cell 156,January 30,2014a2014Elsevier Inc.403

sciences toward improving and optimizing therapeutic strategies.

The drug-repurposing approach for HGPS is still ongoing.One rationale is that treatments with putative prolongevity effects may also bene?t children with HGPS.For example,the macrolide antibi-otic rapamycin,which extends lifespan and improves stroke volume in several model organisms,including aging mice (Choi et al.,2012;Ramos et al.,2012), has been shown to abolish nuclear struc-ture defects and postpone senescence in HGPS?broblasts in cell culture by enhancing progerin clearance through autophagy(Cao et al.,2011b;Cenni et al.,2011).Another compound of inter-est is resveratrol,a SIRT1activator that interacts with lamin A(Liu et al.,2012).In the presence of progerin,SIRT1exhibits reduced association with the nuclear ma-trix and decreased deacetylase activity, leading to rapid depletion of adult stem cells in an HGPS model mouse.Treat-ment with resveratrol improved cellular phenotypes and extended lifespan in this mouse model(Liu et al.,2012).Other repurposed drug candidates are likely to emerge,for example,non-steroidal anti-in?ammatory drugs,which may be useful for blocking the NF-k B-signaling hyperac-tivation observed in progeroid cells and mouse models(Osorio et al.,2012).

New Drug Discovery Strategies

The HGPS etiology offers several points of entry for drug discovery(Figure2). One potential avenue is the identi?cation of small molecular inhibitors of the aber-rant pre-mRNA splicing event in HGPS. But this is a challenging undertaking,as no speci?cally acting small molecular regulators of pre-mRNA splicing have ever been reported.As a complementary approach,imaging-based high-content screens may be able to identify small molecules that prevent the formation,or promote the reversion,of HGPS cellular phenotypes.Aberrant nuclear mor-phology,DNA damage,or elimination of the progerin protein may serve as read-outs for these cell-based approaches in drug discovery.HGPS patient-derived iPS cells should prove a particularly useful tool for such screens.New candidate molecules from several such screens are likely to be forthcoming shortly.

Similar to the farnesylation inhibitor treatment strategy,another potential treatment avenue is based on our under-

standing of lamin A posttranslational

modi?cations.After farnesylation,the

last three amino acids of prelamin A and

progerin are cleaved,and the farnesylcys-

teine is methylated.Inhibition of the

posttranslational methylation step was

recently reported to improve HGPS

cellular senescence in vitro and amelio-

rated disease and early death in a proge-

roid mouse model(Ibrahim et al.,2013).

RNA Therapy

Because the HGPS mutation results from

the activation of an alternative pre-mRNA

splice site,HGPS is a prime candidate for

an RNA therapy approach via inhibition or

elimination of this site.Reversal of pheno-

type by inhibition of the altered splice site

was?rst achieved in HGPS?broblasts by

treatment with a morpholino antisense

oligonucleotide targeted to the activated

splice site(Scaf?di and Misteli,2005).

This strategy was successfully applied to

a knockin HGPS mouse model,resulting

in improved body weight,extended life-

span,and correction of several mutant

phenotypes(Osorio et al.,2011).An alter-

native approach is to eliminate the pro-

gerin mRNA using siRNA-based methods

(Huang et al.,2005).Although systemic

delivery of oligonucleotides and siRNAs

remains a challenge to these therapeutic

approaches,the availability of an appro-

priate animal model,an extensively clini-

cally characterized patient population,

and a clearly de?ned primary target tissue

(the vasculature)may make HGPS an

attractive case study for the development

of high-ef?ciency delivery methods for

these types of agents(Kole et al.,2012).

Stem Cell Treatment

Many of the alterations seen in HGPS are

consistent with stem cell dysfunction

(Halaschek-Wiener and Brooks-Wilson,

2007;Wenzel et al.,2012).In vitro,pro-

gerin affects the multipotency and differ-

entiation of human mesenchymal stem

cells(Scaf?di and Misteli,2008),and

HGPS patient-derived iPS cells exhibit

differentiation defects(Zhang et al.,

2011).Furthermore,in a HGPS-related

cellular model,the proliferative potential

of epidermal stem cells was reduced

(Espada et al.,2008),and in an inducible

HGPS mouse model that speci?cally ex-

presses progerin in skin,the epidermal

population of adult stem cells was

depleted and wound healing impaired

(Rosengardten et al.,2011).This involve-

ment of tissue-stem cells in the HGPS

phenotype opens the possibility of cell-

based replacement therapies using either

matching wild-type cells or tissue-stem

cells generated from genetically cor-

rected HGPS iPS cells.Cell replacement

approaches face many challenges,

particularly in systemic diseases such as

HGPS.However,the prominence of the

vascular defects in HGPS may provide

an interesting model system to explore

the effectiveness of tissue-targeted ap-

proaches in systemic diseases.

Gene Therapy Approaches

As the progerin protein acts in a dominant

fashion and its effects cannot be compen-

sated by introduction of wild-type lamin A,

gene therapy for HGPS focuses on tar-

geted gene correction.For example,

zinc-?nger,TALEN,or CRISPR-based ap-

proaches,in which the LMNA is repaired

ex vivo and corrected cells are re-intro-

duced into patients,is a possibility,albeit

a technically challenging one.As proof

of principle for the feasibility of this

approach,correction of the genetic defect

in HGPS patient-derived iPS cells and

their subsequent differentiation has been

achieved(Liu et al.,2011).

Challenges of Clinical Trials for

Rare Diseases

Rare diseases pose particular challenges

in designing and executing clinical trials.

Given that there are more than6,800

rare diseases—about80%of them with

a genetic basis—the lessons learned dur-

ing the rapid journey in HGPS from gene

identi?cation to clinical trial may be of

value to other disease populations.The

very limited pool of patients with HGPS

required worldwide recruitment and orga-

nized communication with patient families

and their physicians through programs

such as international patient registries,

diagnostics programs,and continued

outreach to the patient community.For

optimal trial execution,these processes

must precede clinical trials by several

years.For HGPS,this recruitment was

achieved through a patient advocacy or-

ganization(The Progeria Research Foun-

dation),and the?rst clinical trial was fully

enrolled in under4months.Hospital-

based centers of excellence with similar

programs can also be useful for recruiting

patients to trials.

404Cell156,January30,2014a2014Elsevier Inc.

Due in part to the100%fatality rate in HGPS and in part to the extremely small subject numbers(26in the published clinical trial),all human trials to date have used open label design with no pla-cebo control groups.In order to assess drug ef?cacy,primary outcome measures have relied upon a change in individual patient status using each patient as his or her own control(Gordon et al.,2012)(https://www.wendangku.net/doc/8a4968599.html, identi?er: NCT00425607).Designing appropriate outcome measures required intensive and ongoing natural history studies to establish robust baseline values for each clinical parameter in each individual pa-tient.For any disease,investment into natural history clinical trials,with the aim of identifying longitudinal trends in dis-ease-relevant and consistently evaluable clinical abnormalities for use as treatment trial outcome measures,is invaluable.In addition,natural history studies are remarkably insightful and powerful in un-covering disease characteristics.For example,some of the most relevant vascular defects in HGPS were discov-ered during baseline studies conducted as part of the?rst clinical trial(Gerhard-Herman et al.,2012;Gordon et al.,2011; Silvera et al.,2013),which precluded their inclusion as primary outcome measures for trial drug ef?cacy but led the way for improving detection of therapeutic ef?-cacy in future trials.The constraints and approaches seen in the HGPS trials are not unlike those in oncology trials for rare,fatal pediatric cancers,wherein similar challenges apply and similar trial designs are used(Pui et al.,2011). Future trials will need to grapple with how to reliably measure changes in dis-ease status in the face of combination therapies whose implementation will also further amplify the challenge of recruiting suf?ciently large patient popu-lations for each treatment combination. Although treatment outcomes have been published for HGPS monotherapy using lonafarnib(Gordon et al.,2012;Ull-rich et al.,2013),its effects on patient morbidity and mortality are not yet known and will require longer-term patient expo-sure.Given this,an important issue at hand is whether it will be ethical and statistically viable to conduct future trials using a control arm with farnesylation inhibitors and a treatment arm with farne-sylation inhibitors plus a new treatment of

interest.

Regulatory approval based on uncon-

trolled or small trials is a huge challenge,

as the U.S.Food and Drug Administration

(FDA)is responsible for evaluating safety

and ef?cacy and for weighing the risk-

to-bene?t ratio with much less data than

what is supplied for common diseases.

Rare disease applications are the fastest

growing area of pharmaceutical and

biotechnical development.Unlike only

5years ago,today there is an acute

awareness of rare diseases within the

FDA,which has identi?ed the rare disease

space as a priority area.As a result,the

FDA has proactively created the Center

for Drug Evaluation and Research specif-

ically for Rare Diseases Drug Develop-

ment.In addition,the FDA and European

Medicines Agency Orphan Drug status is

designed to fast track what is usually a

very long process,without compromising

the quality of the review process.

Although increasing patient numbers

may not be an option,there is now a

regulatory body that can be consulted

speci?cally on recommendations for rare

disease treatment trials.

Looking Back and To the Future

Progress in the HGPS?eld has been

remarkably rapid over the last decade,

and if the most recent Progeria Research

Foundation Workshop is any indication,

there is no sign of slowdown.Many of

the hot topics in the?eld have both a

basic and translatable clinical compo-

nent,and the basic-clinical connection

will be driving much of the future work.A

recurrent theme was the emergence of

various candidate small molecules for

consideration in clinical trials,which has

been driven by our growing understand-

ing of the molecular and cellular mecha-

nisms affected in the disease.

Everyone wants to get to the?nish

line—to cure patients with fatal diseases

and translate discoveries to the clinic.

Looking back over the past10years in

the progeria?eld,we see a roadmap for

how to optimize our chances of tackling

a disease once its molecular basis is un-

covered.Key elements to success are a

strong basic research foundation that

creates a detailed knowledge base of

the fundamental cellular disease process,

access to patient populations,and

intense crosstalk between basic and clin-

ical investigators.

We have learned many important

lessons from a very rare disease,and

they will undoubtedly be applicable to

many other diseases,especially as the

rate with which disease-causing genes

are being identi?ed is growing exponen-

tially due to the availability of powerful

genomic methods.Perhaps most impor-

tantly,the story of HGPS is yet another

example for how one can never predict

how scienti?c research on basic and

sometimes obscure-sounding topics,

such as farnesylation of a precursor to a

nuclear scaffold protein,may one day

become the key to better health for many.

ACKNOWLEDGMENTS

This Essay is based on inspiring discussions at The

Progeria Research Foundation workshop held in

April,2013in Bethesda,MD.

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Cell156,January30,2014a2014Elsevier Inc.407

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