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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 3  |  Page : 81-89

Progeria and accelerated cardiovascular aging


Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA

Date of Web Publication24-Sep-2018

Correspondence Address:
John P Cooke
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Tx 77030
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_26_18

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  Abstract 


Hutchinson–Gilford Progeria syndrome (HGPS) is characterized by accelerated aging leading to death in the teen years, usually due to severe coronary and/or carotid disease. The clinical presentation includes stunted growth, alopecia, loss of subcutaneous fat, osteoporosis, and cardiovascular disorders occurring in late childhood and the teen years including hypertension and accelerated vascular aging that precipitates myocardial infarction and cerebrovascular attacks. The disease is a nuclear laminopathy, due to a Lmna gene mutation. The aberrant protein (Progerin) accumulates in and distorts the nuclear envelope. We review the genetic and biochemical mechanism of HGPS; the clinical presentation with special attention to the cardiovascular pathology and complications; current therapeutic developments to address the disease; and the results of the clinical trials attempting to translate basic research insights into therapeutic benefit. An understanding of HGPS may lead to better treatment of other age-related disorders, particularly cardiovascular diseases.

Keywords: Atherosclerosis, cardiovascular aging, cardiovascular disease, nuclear lamina, progeria, progerin, telomere


How to cite this article:
Walther BK, Li Y, Thandavarayan RA, Cooke JP. Progeria and accelerated cardiovascular aging. Cardiol Plus 2018;3:81-9

How to cite this URL:
Walther BK, Li Y, Thandavarayan RA, Cooke JP. Progeria and accelerated cardiovascular aging. Cardiol Plus [serial online] 2018 [cited 2018 Dec 12];3:81-9. Available from: http://www.cardiologyplus.org/text.asp?2018/3/3/81/242082




  Introduction Top


Clinical presentation and epidemiology

Although it is a rare disease, Hutchinson–Gilford Progeria syndrome (HGPS) is of interest to cardiovascular clinicians and scientists as it is characterized by accelerated vascular aging leading to death in the teen years, usually due to severe coronary and/or carotid disease. As described below, an understanding of the cellular mechanisms of HGPS may provide insight into vascular aging that underlies more common causes of cardiovascular diseases.

The disease was first described in 1886 by Hutchinson, who described a child with a “peculiar…old-mannish look,” as well as “baldness,”[1] “tightness of the skin (especially of the scalp),” and the “slight muscular development” of a 3-year-old boy who despite the constellation of symptoms was “of cheerful disposition, and very intelligent.”[1] In a paper in 1896, Gilford details his correspondence with Hutchinson regarding a similar case, where he noted the close “likeness between” the patient and the paternal grandfather.[2] In addition, the child lacked superficial adipose tissue, had a “hydrocephalic” appearance of the cranium with visible veins, but with preservation of the intellect. Subsequently, Gilford coined the name “Progeria” to describe the condition.[3]

This rare disease has an estimated incidence from 1:20,000[4] to 1:4,000,000.[3] Progeria children have a failure to thrive from birth but are typically undiagnosed until roughly 3 years of age when other symptoms and signs begin to manifest.[3] Classically, these may include alopecia, scleroderma, lipodystrophy, distinct facies, osteolysis, locomotive impairment, stunted growth, and numerous cardiovascular problems occurring in late childhood and the teen years including hypertension, atherosclerosis, myocardial infarction, and cerebrovascular attacks.[1],[3],[4],[5],[6] Other impairments include corneal dryness,[6] decreased lingual strength,[6] delayed tooth eruption and impacted teeth,[6] and a conductive hearing loss.[6] Patients rarely live past the teenage years with an upper limit of around 20 years of age [4] and a median age of death at 13 years.[7] Approximately 90% succumb to atherosclerosis in the form of myocardial infarction, stroke, or other vascular/cardiac complications.[7]

Nonclassical HGPS [3],[8] differs from the previously described phenotype in a number of ways. Growth is less stunted with an average height of 130–145 cm3, onset of alopecia and lipodystrophy is late,[3] median age of survival is up to 20 years (compared to the classic HGPS, where the children succumb in their early or mid-teens),[3] autosomal recessive inheritance [6],[8] (as opposed to the sporadic mutations that typically cause classic HGPS), and osteolysis is significantly more severe.[3]

There are a number of systems and tissues in HGPS which are unaffected by the disease. Merideth et al. reported a normal intraocular pressure [6] and Hennekam reports that cataracts are uncommon.[3] Hematologic and chemistry panels are typically normal, although serum phosphorus and platelet counts may be elevated and prothrombin time prolonged.[6] Serum hormone levels were overall within normal limits,[6] and renal function is conserved.[6] The mental acumen of children with HGPS is unaffected by the disease, and they retain the optimism and cheerfulness of youth.

Cardiovascular complications in Hutchinson-Gilford progeria syndrome

A variety of cardiovascular problems may be associated with HGPS. About a one-third of patients have elevated systolic and/or diastolic blood pressure readings and/or tachycardia.[6] About 15% of patients have an abnormal ankle–brachial index consistent with the peripheral arterial disease.[6] A long QT syndrome (>440 ms) is not uncommon.[6] Dyslipidemia is often observed and may be represented by an elevated low-density lipoprotein cholesterol, a reduced high-density lipoprotein, and/or elevated triglycerides.[6]

Gerhard-Herman et al. extensively characterized the cardiovascular profile of 26 HGPS patients.[9] Of 26 patients, 22 had a normal EKG profile, 2 met the criteria for the left ventricular hypertrophy, and 2 had a left ventricular strain pattern.[9] Blood pressure readings were abnormal in about a third of patients, with 7/26 or 9/26 having elevated systolic or diastolic pressures (>95th percentile for age).[9] Evidence of vascular aging was common, manifested by increased pulse wave velocity (PWV), and increased internal carotid artery flow velocity in over 80% of the cohort.[9] Each of the patients had normal carotid intima-media thickness, but also had carotid artery echodensity probably reflecting fibrosis and calcification.[9] Most patients (21/26) had an abnormal ankle–brachial index in one or both limbs,[9] reflective of peripheral arterial disease.

At the time of death, HGPS patients have severe coronary and carotid artery disease.[5] The composition of the intimal lesions is variable with a range of cellularity, calcification, and cholesterol content.[5] In general, however, the vascular lesions are acellular with a depletion of vascular smooth muscle cells.[10] Morphological studies may reveal plaques similar to atherosclerosis in adults, with a necrotic core, needle-shaped cholesterol crystals, and inflammation.[5] Typically, there is substantial intimal fibrosis as well as medial thinning.[5] In contrast to vascular aging in adults, there is a greater amount of adventitial fibrosis and calcification.[5] This perivascular thickening is most evident in the aorta but is disseminated with the involvement of vessels of the salivary glands, lymph nodes, lungs, and liver.[5] Vascular inflammation is also observed, with macrophages and foam cells in the vascular lesions.[5] Intimal smooth muscle cells, if present, express high levels of progerin.[5] In view of the severity of the vascular disease, it is notable that the plasma concentrations of the usual atherosclerosis biomarkers are often within normal range in HGPS patients.[11]

In 1969 Reichel et al. and Garcia-Bunuel described two patients, both of which had extensive myocardial fibrosis,[12] ventricular dilatation,[12] and extensive lipofuscin accumulation.[12] In addition, one of the patients had a heavily calcified posterior mitral valve leaflets.[12] A subsequent case study described a patient with a thickened mitral valve, severe aortic calcification, subaortic stenosis, and myocardial fibrosis.[13] Two subsequent clinical series have reported patients with varying degrees of aortic or mitral valve thickening and calcification, in some cases with valvular regurgitation, together with subaortic vascular stenosis and myocardial fibrosis.[5],[6] These findings may be related to high levels of progerin and proteoglycans which have been found in the mesenchymal cells within the valves.[5]

Genetic basis for the disease

HGPS [1] causes accelerated aging and death in the teen years, usually due to heart attack or stroke. This disease is related to an abnormal Lamin A protein. Lamins are structural proteins in the nucleus of the cell [14],[15],[16],[17] and are classified into two categories: A (containing the A and C isotypes) and B.[17] The nuclear lamin proteins participate in chromatin organization/interaction, mitotic division, and epigenetic regulation [14],[15],[16],[18],[19],[20] Lamin gene mutations are termed laminopathies and are linked to genetic instability and elevated DNA damage.[15],[19],[21]

The Lmna gene encoding Lamin A consists of 12 exons [7] and is expressed in differentiated cells of mesodermal/mesenchymal origin.[22],[23] The gene encodes for two nuclear lamina proteins, lamin-A and lamin-C, through alternative splicing. HGPS is usually due to a de novo mutation (G608G GGC-> GGT)[24],[25],[26] of the Lmna gene that introduces a cryptic splice site on exon 11. This results in a truncated prelamin protein that is missing a cleavage site that is required for the action of a metallopeptidase ZMPSTE24.[4],[27] Normally, ZMPSTE24 cleaves the farnesyl group from prelamin to complete the nuclear lamin-A synthesis. However, because it is missing the cleavage site, the mutant protein remains permanently farnesylated (and is known as progerin).[7],[24],[28] Progerin thus remains permanently bound to the nuclear lamina [18],[24],[27] which disrupts genomic architecture and normal epigenetic interactions [16],[19],[20],[28] including interaction of the nuclear lamina with the telomeres. It is believed that the accumulation of progerin at the nuclear envelope [4],[27] is responsible for the aberrant nuclear lobulation [27],[28] [Figure 1]. Not surprisingly, this alteration in the nuclear architecture is associated with decreased genomic stability [5],[6],[13],[14] and accelerated senescence.[25],[29],[30],[31]
Figure 1: Left depicts the biochemical pathway resulting in progerin accumulation. Progerin lacks the splice site recognizable by the metalloprotease ZMPSTE24, resulting in a protein with a permanently attached farnesyl group. The protein remains lodged in the nuclear membrane and can polymerize aberrantly. Top right depicts the normal nuclear architecture in an endothelial cell iPSC model, and the subsequent nuclear abnormalities in a progeria endothelial cell iPSC model. Bottom right is the common clinical manifestations of Hutchinson–Gilford Progeria Syndrome

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Notably, B-type lamins are expressed during the embryonic stem cell stage [17] and the A/C-types expressed mainly in differentiated tissues.[17],[22],[32],[33],[34] Furthermore, the highest levels of expression of lamin A/C occurs in mesenchymal tissues.[22],[23] These differences in expression may explain the observation that induced pluripotent stem cells (iPSCs) generated from Progeria fibroblasts have a normal nucleus and normal function;[22],[33] and may determine why certain organ systems in HGPS patients are unaffected.

Cellular mechanisms of accelerated aging

Disruption of nuclear morphology

An understanding of the cellular mechanisms in progeria may provide some insights into accelerated vascular aging. In this regard, we all accumulate small amounts of nuclear progerin over time, because of a low amount of alternative splicing of lamin A in normal cells.[5],[10],[18],[25],[29] An age-related decrease in ZMPSTE24[25] may also contribute.

In cultured somatic cells from HGPS patients, a characteristic feature of the cells is nuclear blebbing. The nuclear blebbing is thought to be due to the accumulation of progerin in the nuclear envelope, due to its retained farnesyl group and pathological lipid interaction.[35],[36] Kalinowski et al. proposed that electrostatic interactions contribute to the association of progerin with the nuclear membrane and nuclear blebbing.[37] Interestingly, the group reported that WT lamin-A also associates with the nuclear membrane through similar interactions;[37] however, it only forms a monolayer.[37]

Qin et al. studied the structure of the lamin-A tail to investigate how the altered structure may contribute to the nuclear blebbing in HGPS. Combining computational methods with experimental techniques, they showed that the tail of progerin is more compact and stable than the WT lamin-A tail structure (an intrinsically disordered protein structure).[38] Notably, the stochastic folding nature of the WT protein is lost with the mutation.[38] This may explain why progerin continues to cause cellular harm whether it is farnesylated or not [39] (though the phenotype is milder).

Telomere interaction with nuclear lamin proteins

Telomeres are found at the end of a chromosome, and consist of thousands of hexanucleotide (TTAGGG) repeats.[19],[40],[41],[42] The telomeres terminate in a single-stranded, 3' guanine-rich repeat which arches backward and into the dsDNA strand upstream, to form a T-loop.[40],[42] The T-Loop is stabilized through a protein complex known as shelterin (composed of proteins: TRF1/2, PO1, RAN1, TIN2, TPP1; discussed in more depth in [40]) which shields the telomere complex from DNA repair mechanisms.[40]

An important function of the telomere is to buffer the chromosome from the loss of DNA that occurs with every cell division (known as the “end-replication problem”).[19],[40],[41],[43],[44] With each cell division, there is loss of some telomeric DNA at the end of the chromosome.[40],[42],[45] Loss of telomeric DNA may be accelerated by oxidative stress or radiation injury. Notably, the telomere length is typically reduced in cells of mesodermal lineage in Progeria patients.

Telomeres also participate in chromatin organization through their interactions with lamins.[40],[42] Telomeres interact with the nuclear matrix (Lamins-A and-B as well as lamin-associated proteins such as LAP2α) through the TTAAGG repeats [46] and TRF1/2 of the shelterin complex.[40] The interaction of lamins with the chromosome seems important during mitosis, as Lamin-B closely associates with chromosomes during the mitotic migration, and lamin-A follows when the nuclear architecture has reformed (around early G1 phase).[47] Lamin-C2 interactions are necessary for chromosomal rearrangement during meiosis whereby lamin-C2 is responsible for chromosomal repositioning and homologous recombination while also facilitating dsDNA break repair.[48] Kinetic studies indicate that lamin-A improves chromatin migration through the cell.[49] Finally, lamins stabilize expression of the genome.[15],[50] The lamina-associated domains (LADs) most often associate with chromosomal segments with low transcriptional activity.

The mutated lamin-A in HGPS causes defective protein-protein and protein-genome interactions The interaction of LAP2α-telomere and LAP2α-progerin are reduced by comparison to cells expressing normal Lamin A.[51] Strikingly, simply overexpressing LAP2α rescued the cells as well as telomerase expression.[51] The nuclear scaffolding protein SUN1 accumulates in HGPS. Knocking down SUN1 was sufficient to rescue the HGPS phenotype.[52] In this regard, the closely related SUN2 is a telomeric binding protein [53] and both SUN1 and SUN2 are involved in the DNA damage response.[54] Accordingly, an aberrant interaction of these proteins with the telomere in HGPS may contribute to the pathobiology.

While the mechanism is not entirely clear, telomeres are typically shortened in HGPS cells.[15],[19],[26],[30],[31] Notably, transduction with a retroviral vector encoding telomerase restored the replicative capacity of HGPS cells.[55] Although these authors did not observe a restoration of nuclear morphology by overexpression of hTERT,[55] others have reported that telomerase activity could reduce the number of lobulated nuclei in HGPS [51],[56] Harkening back to the dichotomy of cellular problems presented by HGPS (both genomic and proteomic), In the ZMPSTE24-/- mouse model of progeria, p53 activation is observed.[57] In this model, inhibition of p53 improves replicative capacity in a similar fashion as overexpression of telomerase,[55] suggesting that the HGPS cells are under genomic stress that could be contributing to telomere erosion. In this regard, Wallis et al. observed despite retroviral transfection with telomerase HGPS fibroblast lines continue to senesce,[30] indicating that progerin accumulation confers harm independently of telomere erosion.

Altered gene expression and senescence-associated secretory phenotype

Aged cells typically manifest a senescence-associated secretory phenotype (SASP), which is characterized by the secretion of inflammatory cytokines.[58] Cells subject to significant DNA damage also share a similar phenotype [58],[59] Accordingly, it is not surprising that HGPS cells have up-regulated inflammatory pathways, including significant increases in the expression of S100a8/9, Sprr2d, IL-1A, IL-1f5, and IL-1f8.[60] The inflammatory cytokine IL-1A activates mammalian target of rapamycin (mTOR)[61] which activates MAPKAPK2.[62] In this regard, inhibition of the mTOR pathway by rapamycin prolongs cell life in Drosophila by promoting autophagy and clearance of misfolded proteins.[63],[64] The role of mTOR in the SASP phenotype has sparked interest in targeting mTOR [65] for HGPS.

Current preclinical models

The first murine model of Progeria was generated by introducing a splicing defect on exon 9 of Lmna.[66] The homozygous mutant mice (denoted LmnaL530P/L530P) have a severe phenotype with a lifespan of 4–5 weeks.[66] These mice display restricted growth; gross gait abnormalities; and cutaneous abnormalities characterized by hyperkeratosis, excessive collagen deposition, dermal thinning, decreased follicular density, and subcutaneous adipose tissue loss.[66] Heart and myocyte mass is reduced, and bone architecture is characteristic of osteoporosis with decreased trabecular number and size.[66] Heterozygotes displayed similar characteristics with a delayed onset at 6 months of age.[66] A related approach is to delete the Lmna introns 10 and 11 as well was the last 150 bases of exon 11,[67],[68] removing lamin C as a genetic product.[68] The mutated gene exclusively generates progerin. Homozygous mice do not live past weaning, and heterozygous mice display growth retardation and bone pathology by 4 months of age.[67]

Another model is that of the ZMPSTE24 deficient mice (Zmpste24-/-).[57],[69],[70] These mice produce a WT Lamin-A, however, are unable to process it, much like HGPS cells. These mice displayed significant weight loss compared to WT mice [70] and had impaired overall grip strength (hanging grid test).[70] Osteolytic lesions develop in the mice by 4 months of age,[70] and fractures (measured by total rib fracture count) were significantly increased. The 20-week survival rate of the knock-out mice was roughly 57%, with 6/14 mice dying.[70]

Possibly, the best animal model in terms of a phenocopy of the human disease is that developed by Varga et al. They developed a murine model for HGPS using a bacterial artificial chromosome containing the gene encoding the human G608G Lmna mutant.[71] This transgenic mouse model is notable for its vascular phenotype, displaying VSMC loss and significant aortic and carotid artery fibrosis and calcification, similar to the vascular abnormalities in HGPS patients.[5] The mouse model deviates from human disease in that it did not display intimal thickening to any significant degree, and is devoid of many of the other systemic disorders seen in HGPS.

Oishi et al. details a unique case study of a spontaneous phenotype in a female Japanese monkey (referred to as N416) that displayed symptoms of accelerated aging such as premature wrinkling of the skin and bilateral cataracts.[72] N416 displayed longer cell division time periods,[72] accelerated fibroblast senescence,[72] and deficient DNA repair.[72] Differing from classical HGPS, however, was a neurological degeneration manifested in brain tissue and a lack of hair loss, growth reduction, sclerosis, osteolytic lesions, and joint dysfunction.[72] Sequencing of genomic DNA did not reveal a known mutation underlying progeroid syndromes, limiting the utility of this case.

Hutchinson-Gilford progeria syndrome-induced pluripotent stem cells for disease modeling and mechanistic studies

Much mechanistic work has been conducted in tissues or cultured fibroblasts from HGPS patients provided by the Progeria Research Foundation Cell and Tissue Bank. In partnership with the University of Toronto, the PRF also offers patient-derived iPSCs. The HGPS iPSCs are an invaluable resource, as they can be differentiated into any somatic cell to study the effect of the mutation in multiple lineages. Intriguingly, when HGPS fibroblasts are reprogrammed to iPSCs, these pluripotent stem cells appear to be normal, with a normal nuclear architecture, and normal functions for an iPSC, most importantly the ability to replicate indefinitely and to generate somatic cell derivatives. Notably, the iPSCs do not express progerin, having downregulated the mutated Lamin A gene.[33] This cellular resource has accelerated research into the mechanisms of pathobiology in HGPS. Using HGPS iPSCs, Zhang et al. derived multiple somatic cell lineages. They discovered significant pathobiology in mesodermal derivatives (mesenchymal stem cells, vascular smooth muscle cells, and fibroblasts having the highest progerin burden respectively), consistent with the tissues and organs that are most afflicted in HGPS patients.[22]

As first described by Hutchison, cognitive function is unaffected by HGPS. Two recent studies used iPSCs from HGPS to document the cellular protection afforded by a neuronal miRNA, miR-9.[73],[74] This miRNA targets mRNA encoding lamin-A/progerin, reducing its expression in neuronal cells. The existence of this neuronal miRNA may explain the preservation of intelligence in HGPS that has been previously documented. Thus, the derivatives of HGPS iPSCs may be used to further document pathobiological mechanisms; to perform high throughput screening for new therapies for progeria; and a model for testing such novel therapies. New therapeutic approaches are desperately needed, as the current therapies have limited benefit, as discussed below.

Therapeutic approach to Hutchinson-Gilford progeria syndrome

The current therapeutic recommendations for HGPS are based in part on the known benefits of therapies for adult cardiovascular disease, for example, aspirin and statins, exercise and nutritional recommendations. There are currently no drug therapies that have been specifically approved for HGPS. However current and past clinical trials have tested FDA approved drugs which have a mechanistic basis for ameliorating the disease as described below.

Farnesyltransferase inhibitors

Farnesyl is an isoprenoid derivative of the HMG coA reductase pathway. Farnesylation of proteins is important for targeting them to lipid membranes. As previously mentioned, Lamin A is farnesylated to localize it to the nuclear membrane, where the farnesyl group is removed. As previously mentioned, the mutation in Lamin A that creates progerin removes the splice site so that farnesyl cannot be removed. Thus, progerin is permanently farnesylated and accumulates in the nuclear membrane. The first generation of pharmacological treatment for HGPS involved inhibition of the farnesylation of progerin.[6],[21],[28],[75] Initial cellular studies revealed that inhibition of farnesylation prevented the accumulation of nuclear lamin proteins in the nuclear membrane.[28] In addition, inhibition of farnesylation rescued HGPS phenotype fibroblasts from nuclear damage.[28] Inhibition of farnesylation does not completely abolish accumulation of progerin the nuclear envelope however. An alternate pathway of geranylgeranylation which is resistant to farnesyltransferase inhibitors (FTIs) can lead to residual progerin accumulation in the nuclear envelope.[28]

The first clinical trial for HGPS was a prospective single-arm clinical study involving 25 patients who each received treatment with the FTI lonafarnib for at least 2 years. Primary outcome success was defined as a 50% increase in the annual rate of weight gain by comparison to the period before therapy, or a change from weight loss to on-study weight gain. Overall the therapy was well-tolerated, and no child had to cease therapy because of toxicity. Nine patients experienced a ≥50% increase in the annual rate of weight gain whereas six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. The dual X-ray absorptiometry and strength testing studies suggested that the weight gain was due to an increase in muscle and bone, not fat.

Secondary outcomes included decreases in carotid-femoral PWV and carotid wall echodensity. Before treatment, 18 subjects possessed a PWV which was 3.5 times the expected pediatric value, consistent with increased vascular stiffness. Treatment reduced PWV by 35%. Carotid intimal-medial thickness was normal in these HGPS patients, but echodensity of the carotid artery was increased by comparison to the expected pediatric values. During therapy, echodensity decreased to values that were within normal range.[75]

Previous studies have shown that HGPS is associated with a skeletal dysplasia manifested by reductions in bone mineral density (BMD), as well as reductions in bone rigidity. The latter is assessed by peripheral quantitative computed tomography to assess the resistance of the metaphysis and diaphysis of the radius to compressive, bending, and torsional loads.[76] With treatment, an increase in BMD of 3% or more was observed in 19 subjects at one or more of the specific sites tested, whereas a loss of BMD at one or more of the tested sites was observed in 10 patients. Furthermore, an improvement in bone rigidity was observed in the subset of 11 patients that could be tested.

With respect to auditory acuity, for the 18 subjects that could be tested, hearing was in the normal to low-normal range. Lonafarnib therapy was associated with an improvement in auditory acuity with eight children experiencing >10 dB improvement in low-frequency sensorineural hearing.[75] However, other features of HGPS such as insulin resistance (IR), lipodystrophy, joint contractures, and skin abnormalities were not ameliorated by lonafarnib therapy.

Nevertheless, every child completing the course of lonafarnib therapy manifested an improvement in one or more of the outcome measures of weight gain, vascular stiffness, bone structure or auditory acuity. These promising results encouraged a subsequent trial which tested a combination therapy of lonafarnib, pravastatin, and zoledronate.[77] The triple combination was based on preclinical data supporting inhibition of progerin prenylation upstream of its farnesylation step using combination therapy with pravastatin and zoledronic acid.[78],[79] Accordingly, a single-arm clinical trial assessed the benefit of triple therapy with lonafarnib, pravastatin, and zoledronic acid (triple therapy) in 37 patients with HGPS. The therapy was well-tolerated, and weight gain was observed in the majority of patients. Furthermore, triple therapy generated a greater improvement in bone density than observed in the prior trial. However, no improvement in vascular compliance or carotid echodensity was observed. Most concerning was an increase in the number of carotid and femoral artery plaques as assessed by duplex ultrasound. Because most of the morbidity and mortality in HGPS is due to cardiovascular disease, the triple combination therapy was judged to be inferior to lonafarnib alone.[77]

Future therapies

Rapamycin is an inhibitor of the mTOR signaling pathway [63],[80] and is known to enhance autophagy and thereby accelerate the clearance of abnormal proteins.[6],[65],[80],[81],[82] Preclinical studies revealed that rapamycin reduces the accumulation of progerin in HGPS cells, and normalizes nuclear morphology and gene expression.[64] These studies have provided the theoretical foundation for the current ongoing clinical trial of pharmacotherapy for HGPS which will test the benefit of rapamycin paired with lonafarnib. It began in April of 2016 and is currently in phase 2.

Resveratrol is an activator of SIRT1 and is known to increase life-span in yeast, worms, and flies and to enhance the health of rodents.[32] Resveratrol has also shown a beneficial effect in Zmpste24−/− mice.[83] In the presence of prelamin A, the association of the nuclear matrix with SIRT1 was reduced, and deacetylase activity was decreased, associated with a rapid depletion of adult stem cells in the murine Progeria model. Resveratrol increased SIRT1 deacetylase activity, slowed body weight loss, improved trabecular bone structure and BMD, and significantly extended the life-span of Zmpste24−/− mice.[83] Resveratrol also reversed the dental phenotype of overgrown and laterally displaced lower incisors in a mouse model with the osteoblast-and osteocyte-specific Lmna 1824 C->T expression.[84]

JH4 was discovered in a high throughput screen to detect small molecules which would prevent progerin from binding to lamin A/C, an interaction that disrupts the normal functions of lamin A/C.[85] The treatment of cells from LmnaG609G/G609G mice or HGPS patients improved nuclear morphology and attenuated senescence markers.[86] Subsequently, JH4 was shown to extend life-span of LmnaG609G/G609G mice by 4 weeks as well as reverse senescence as manifested as a gain of body weight and increase in muscle strength. Another small molecule of interest is Methylene blue. This agent might have utility in HGPS because of its antioxidant activity. This characteristic of methylene blue might ameliorate the known mitochondrial dysfunction in HGPS, as documented in the mouse LmnaG609G/G609G model.[87] Treatment of HGPS cells with methylene blue partially reverses the senescent phenotype.[88]

Genetic and cellular therapies. Neural-specific miR-9 downregulates lamin-A (and consequently progerin) expression and improves the HGPS phenotype, which may account for the preservation of cognitive function in Progeria.[3],[6],[73] Overexpression of miR-9 in HGPS cell lines reversed much of the cellular pathobiology.[73] This beneficial effect is in part due to the specificity of miR-9 for lamin-A and not lamin-C.[74]

The use of antisense oligonucleotides to block the aberrant splicing of mutant Lmna has also shown promise in preclinical studies.[89],[90],[91] The treatment of HGPS fibroblasts with antisense oligonucleotides reduced the expression of progerin, improved normal nuclear morphology, and reversed genetic dysregulation.[91] The administration of the antisense oligonucleotides to LmnaG609G/G609G mice markedly reduced the accumulation of progerin in vivo and resultant nuclear defects, leading to a significant amelioration of the aging phenotype and an extended life-span.[89],[90]

One of the features of HGPS is genomic instability and accelerated telomere erosion.[19],[26],[32],[43],[51] Although the loss of telomeric length is secondary to progerin expression, recent studies indicate that treatment directed toward restoration of the telomere length can reverse senescence in aged human cells, as well as in HGPS cells. Transfection of aged human fibroblasts, endothelial cells or myoblasts with mRNA encoding human telomerase (hTERT) reverses markers of senescence (e.g., beta-galactosidase expression) and increases replicative capacity.[92] Similar results have been obtained with fibroblasts from patients with HGPS.[56] The advantage of using mRNA is that the transcript is short-lived, but the protein telomerase is expressed for a sufficient time (48–72 h) to appreciably increase telomere length.

These genomic interventions will require an improvement in the methods to deliver the nucleic acid therapies to the target tissues that are most affected by Progeria.[93] Lipid nanoparticles, biomimetic nanovectors, microvesicles, and silicon-based vehicles are potential approaches. An alternative approach would be to use cell therapy to deliver the regenerative solution. For example, one might generate autologous iPSCs from patients, genetically engineer them with Crispr-CAS technology so as to correct the Lamin A mutation. One could then generate iPSC derivatives (e.g., adult mesenchymal stem cells) that could restore aged tissues in the children. However, much remains to be learned regarding the delivery of cell therapies, and how to sustain the viability, phenotype, and function of the regenerative cells in vivo.


  Conclusion Top


Although Progeria is a rare disease, it has many of the features of normal aging, in an accelerated form. Much has been learned about the pathobiology of Progeria in the past 20 years, due to the commitment of a small community of dedicated scientists knitted together by the Progeria Research Foundation. We now understand the genetic foundation of HGPS and have characterized the associated disruption of genomic architecture and gene expression that underlie the pathological processes of accelerated senescence. Murine and human cellular models of Progeria are furthering the work. Early clinical trial results show that the disease can be modified, providing hope that these children will have more definitive therapy in the future. What we continue to learn in this work may have implications for understanding other age-related diseases, and deriving novel therapies to slow or even reverse senescence.

Acknowledgments

This work was supported in part by a grant to JPC from the NHLBI R01 HL133254 and the Progeria Foundation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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