Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ∼1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients.

Introduction

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare genetic disease affecting ∼1 in 18 million children all over the world, characterized by multiple features of premature aging [1]. While children with HGPS do not usually display any clinical signs of disease at birth, they gradually develop an appearance often referred to as aged-like within their first years of life as the disease progresses. Progeria is clinically manifested as severe growth retardation and failure to thrive, where the skin is affected with alopecia, loss of subcutaneous adipose tissue, and scleroderma-like skin changes (Figure 1) [25]. The skeleton shows a unique skeletal dysplasia, with reduced bone mineral density (BMD), joint stiffness, and abnormal and delayed dentition (Figure 1) [26]. The cardiovascular system is affected by loss of arterial vascular smooth muscle cells (VSMCs), vascular calcification, and atherosclerosis with cardiovascular decline (Figure 1) [2,4,5]. Many of these symptoms are also found in normal aging (Figure 2). However, other age-associated features such as cancer, cataract, Alzheimer's disease, and senility are absent in HGPS (Figure 2), and the children show no alterations in their mental and intellectual abilities [2,4]. It is believed that a microRNA (miR9) is protecting neural cells of HGPS patients from accumulating progerin, thus preventing patients from developing brain-associated disorders [7]. Death occurs prematurely, with a median age of 14.6 years, and the most common causes of death are due to complications from cardiovascular disease and atherosclerosis [2,8].

Hallmarks of HGPS.

Figure 1.
Hallmarks of HGPS.

HGPS can be diagnosed based on four main hallmarks: 1. A very characteristic external phenotype including growth retardation, prominent scalp veins, characteristic facial features, and a high-pitched voice. 2. A skin-related phenotype such as alopecia, loss of subcutaneous fat, and changes related to scleroderma. 3. A fragile skeleton showing a unique dysplasia, acro-osteolysis, and joint contractures. 4. A cardiovascular system affected by loss of smooth muscle cells, calcification, and atherosclerosis.

Figure 1.
Hallmarks of HGPS.

HGPS can be diagnosed based on four main hallmarks: 1. A very characteristic external phenotype including growth retardation, prominent scalp veins, characteristic facial features, and a high-pitched voice. 2. A skin-related phenotype such as alopecia, loss of subcutaneous fat, and changes related to scleroderma. 3. A fragile skeleton showing a unique dysplasia, acro-osteolysis, and joint contractures. 4. A cardiovascular system affected by loss of smooth muscle cells, calcification, and atherosclerosis.

Comparisons of HGPS and normal aging.

Figure 2.
Comparisons of HGPS and normal aging.

Progeria and physiological aging share several common features such as alopecia, loss of subcutaneous fat, osteolysis, and cardiovascular complications. Other typical aging symptoms like cancer, neurodegeneration, or senility are not present in HGPS. Complications related to the cardiovascular system are the most common causes of death in HGPS.

Figure 2.
Comparisons of HGPS and normal aging.

Progeria and physiological aging share several common features such as alopecia, loss of subcutaneous fat, osteolysis, and cardiovascular complications. Other typical aging symptoms like cancer, neurodegeneration, or senility are not present in HGPS. Complications related to the cardiovascular system are the most common causes of death in HGPS.

HGPS is usually caused by a de novo single-point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G). The LMNA gene encodes the A-type lamins (lamin A, AΔ10, C and C2), which are generated through alternative splicing and together with the B-type lamins form the nuclear lamina [9,10]. In the case of HGPS, the mutation results in the increased activation of a cryptic splice site and generation of a truncated prelamin A precursor protein, containing a 50 amino acid internal deletion, called progerin or lamin AΔ50 [11,12]. Through this deletion, the recognition site for the final cleavage step by ZMPSTE24 has been removed, resulting in a partially processed prelamin A protein that remains permanently farnesylated and carboxymethylated in its 3′-terminal end (Figure 3) [13]. The farnesylation of progerin enables the protein to stay more tightly associated with the inner nuclear membrane, causing major impairments of the nuclear structure with blebbing of the nuclear envelope, a thickened nuclear lamina, mislocalization and clustering of nuclear pore complexes, and loss of heterochromatin anchoring [14,15]. In addition, progerin expression has also been shown to cause epigenetic changes and genomic damage [1619], as well as mitochondrial morphological and behavioral defects [20,21].

Localization of targeted mechanisms of candidate treatment strategies for HGPS.

Figure 3.
Localization of targeted mechanisms of candidate treatment strategies for HGPS.

Schematic cartoon representing several selected treatment strategies that have been developed for HGPS. The depicted treatments target diverse mechanisms occurring either in cytoplasmic components including prelamin A processing in the endoplasmic reticulum, autophagy in the lysosomes, and mitochondrial function and biogenesis, or in the nucleus including access of the splicing machinery and the interaction between progerin and lamin A. To target the prelamin A processing, statins or bisphosphonates (BPs) have been used to block the mevalonate pathway, as well as FTIs or shICMT to inhibit the farnesyltransferase (FTase) and ICMT activity, respectively. Treatment with Mono-APs has also been found to interfere with prelamin A processing by blockage of both the farnesyl-PP synthase and FTase. The autophagy pathway has been found to be triggered by administration of rapamycin, sulphoraphane, all-trans retinoic acid or MG132, resulting in the lysosomal degradation of progerin. To target the splicing machinery, other methods have been developed, involving the use of morpholinos (MmEx10 and MmEx11) or antisense oligonucleotides (ASO E11–31), inhibiting the LMNA mRNA splicing responsible for production of lamin A and progerin. The interaction between progerin and lamin A has also been investigated and the JH4 compound was found to successfully sequester progerin from lamin A. Finally, mitochondrial function and biogenesis have been targeted by drugs with antioxidant effects such as Metformin, NAC, or methylene blue, which resulted in improved mitochondrial function and reduction of ROS. Usage of FTI or a combination of Pravastatin and Zolenodrate has also been shown to improve mitochondrial function.

Figure 3.
Localization of targeted mechanisms of candidate treatment strategies for HGPS.

Schematic cartoon representing several selected treatment strategies that have been developed for HGPS. The depicted treatments target diverse mechanisms occurring either in cytoplasmic components including prelamin A processing in the endoplasmic reticulum, autophagy in the lysosomes, and mitochondrial function and biogenesis, or in the nucleus including access of the splicing machinery and the interaction between progerin and lamin A. To target the prelamin A processing, statins or bisphosphonates (BPs) have been used to block the mevalonate pathway, as well as FTIs or shICMT to inhibit the farnesyltransferase (FTase) and ICMT activity, respectively. Treatment with Mono-APs has also been found to interfere with prelamin A processing by blockage of both the farnesyl-PP synthase and FTase. The autophagy pathway has been found to be triggered by administration of rapamycin, sulphoraphane, all-trans retinoic acid or MG132, resulting in the lysosomal degradation of progerin. To target the splicing machinery, other methods have been developed, involving the use of morpholinos (MmEx10 and MmEx11) or antisense oligonucleotides (ASO E11–31), inhibiting the LMNA mRNA splicing responsible for production of lamin A and progerin. The interaction between progerin and lamin A has also been investigated and the JH4 compound was found to successfully sequester progerin from lamin A. Finally, mitochondrial function and biogenesis have been targeted by drugs with antioxidant effects such as Metformin, NAC, or methylene blue, which resulted in improved mitochondrial function and reduction of ROS. Usage of FTI or a combination of Pravastatin and Zolenodrate has also been shown to improve mitochondrial function.

In cells from HGPS patients, previous studies have shown that the levels of progerin are increased with increasing age, likely being the cause of the progressive nature of the disease [14,22]. Progerin has also been found at lower levels in cells from non-progeria individuals [23,24], and as in HGPS cells, the levels of progerin have been shown to increase with cellular aging also in the unaffected cells, supporting the hypothesis of a common underlying mechanism for HGPS and normal aging [22,24]. Similarly, low levels of progerin have also been found in several tissues, including skin, arteries, and adipose tissue, from apparently healthy individuals [2527].

Since the genetic cause for HGPS was discovered in 2003, numerous potential treatment options have rapidly emerged and been evaluated both in progeria patient cell lines and in mouse models, and some candidate drugs have also been assessed in clinical trials of HGPS patients. The treatment strategies have generally been developed to either directly target the HGPS mutation, the different lamin A post-translational processing steps, or progerin function and turnover. Here, we give an up-to-date resume of the growing list of different candidate treatment strategies that have been studied during the past decade.

Targeting prelamin A processing

Since progerin was early suggested to remain permanently farnesylated due to the lack of the RSYLLG motif that is the recognition motif for the ZMPSTE24 endoprotease [13], the initial treatment strategies focused on farnesyltransferase inhibitors (FTIs), drugs that were initially developed as anticancer agents functioning by inhibiting protein farnesylation (Figure 3). In HGPS, FTIs would inhibit farnesylation of the prelamin A precursor protein, resulting in its mislocalization away from the lamina into nucleoplasmic foci. Previous in vitro studies using HGPS patient cell lines and cells from progeroid mice showed vast improvements in nuclear morphology (Table 1) [2831]. In vivo studies using two different HGPS mouse models (LmnaHG/+ and BAC LMNA G608G) and Zmpste24-deficient mice (that accumulate prelamin A [32,33]) also showed improved disease symptoms after FTI treatment, including lifespan extension, improved skeletal properties, increased body weight and adipose tissue, and delayed onset of the cardiovascular phenotype as well as delayed disease progression (Table 2) [3437].

Table 1
In vitro evaluation of potential treatment strategies for HGPS
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
Cytoplasmic localization of target 
 Aminobisphosphonates + statins1 Geranylgeranylation Prelamin A farnesylation HGPS patient dermal fibroblasts Improved nuclear morphology [38
LmnaG609G/G609G and Zmpste24−/− mouse fibroblasts Restored mitochondrial function [20
 FTIs1 Prelamin A processing Prelamin A farnesylation HGPS patient dermal fibroblasts, Zmpste24−/− or LmnaHG/HG mouse MEFs Improved nuclear morphology [2831
LmnaG609G/G609G and Zmpste24−/− mouse fibroblasts Restored mitochondrial function [20
ICMT knockdown1 (shICMT) Prelamin A processing ICMT HGPS patient dermal fibroblasts Increased proliferation, delayed senescence [39
 NAC Oxidative stress ROS HGPS patient dermal fibroblasts Increased proliferation, reduced levels of DNA damage [73
 Metformin Activation of AMPK Hepatic gluco-neogenesis HGPS patient dermal fibroblasts Improved nuclear morphology, reduced progerin expression, reduced ROS, and DNA damage levels, reduced senescence, improved mitochondrial function [74
 Methylene blue Mitochondrial biogenesis Mitochondria function HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, nuclear membrane progerin release, reduced ROS levels, reduced senescence, restored mitochondrial defects, rescued heterochromatin loss, corrected gene expression [21
 Mono-AP Prelamin A processing Prelamin A farnesylation (FPPS + FT) HGPS patient iPSC–MSC Improved nuclear morphology, rescued premature osteogenic differentiation [40
Nuclear localization of target 
 All-trans retinoic acid Autophagy Progerin turnover HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin accumulation, and LMNA gene expression, recovered heterochromatin distribution, reduced DNA damage [56
 Antisense  oligonucleotide (ASO E11-31)1 Access of splicing machinery Lamin C/prelamin A splicing HGPS patient dermal fibroblasts Improved nuclear morphology, increased lamin C, and reduced lamin A/progerin expression [42
 caNRF2 NRF2 reactivation NRF2 HGPS patient dermal fibroblasts Reduced progerin accumulation, improved gene expression, and levels of nuclear architectural proteins, reduced ROS, and DNA damage levels [59
 DOT1L inhibitors1 Cell reprogramming DOT1L HGPS patient dermal fibroblasts Increased iPSC reprogramming efficiency [77
 JH41 Progerin–lamin A/C binding Progerin–lamin A/C binding HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin protein, reduced senescence, corrected gene expression [57
 MG1321 Autophagy Progerin turnover HGPS patient dermal fibroblasts, iPSC–MSC and iPSC–VSMC Improved nuclear morphology, increased proliferation, progerin clearance, reduced lamin A/progerin expression, improved gene expression, and levels of nuclear architectural proteins, reduced DNA damage, reduced senescence [58
 Morpholino antisense oligonucleotides1 Access of splicing machinery Abnormal Lmna splicing HGPS patient dermal fibroblasts, LmnaG609G/+ and LmnaG609G/G609G mouse fibroblasts Restored nuclear morphology, reduced progerin transcription and accumulation [41
 Rapamycin and analogs Autophagy Progerin turnover HGPS patient dermal fibroblasts Restored nuclear morphology, progerin clearance, delayed onset of cellular senescence [43
HGPS patient dermal fibroblasts Restored nuclear morphology, increased proliferation, progerin clearance, reduced levels of DNA damage [54
 Remodelin Microtubule NAT10 HGPS patient dermal fibroblasts Improved nuclear morphology and chromatin organization, increased proliferation, reduced DNA damage and signaling, reduced senescence [60
 Resveratrol1 SIRT1 activity SIRT1 Zmpste24−/− mouse MEFs and BMSCs Enhanced colony-forming capacity in adult stem cells [69
 Sulforaphane Autophagy Progerin turnover HGPS patient dermal fibroblasts Restored nuclear morphology, increased proliferation, progerin clearance, reduced levels of DNA damage [55
 Vitamin D Vitamin D receptor signaling Vitamin D receptor HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin and LMNA expression, reduced DNA damage, delayed onset of cellular senescence, increased Vitamin D receptor expression [64
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
Cytoplasmic localization of target 
 Aminobisphosphonates + statins1 Geranylgeranylation Prelamin A farnesylation HGPS patient dermal fibroblasts Improved nuclear morphology [38
LmnaG609G/G609G and Zmpste24−/− mouse fibroblasts Restored mitochondrial function [20
 FTIs1 Prelamin A processing Prelamin A farnesylation HGPS patient dermal fibroblasts, Zmpste24−/− or LmnaHG/HG mouse MEFs Improved nuclear morphology [2831
LmnaG609G/G609G and Zmpste24−/− mouse fibroblasts Restored mitochondrial function [20
ICMT knockdown1 (shICMT) Prelamin A processing ICMT HGPS patient dermal fibroblasts Increased proliferation, delayed senescence [39
 NAC Oxidative stress ROS HGPS patient dermal fibroblasts Increased proliferation, reduced levels of DNA damage [73
 Metformin Activation of AMPK Hepatic gluco-neogenesis HGPS patient dermal fibroblasts Improved nuclear morphology, reduced progerin expression, reduced ROS, and DNA damage levels, reduced senescence, improved mitochondrial function [74
 Methylene blue Mitochondrial biogenesis Mitochondria function HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, nuclear membrane progerin release, reduced ROS levels, reduced senescence, restored mitochondrial defects, rescued heterochromatin loss, corrected gene expression [21
 Mono-AP Prelamin A processing Prelamin A farnesylation (FPPS + FT) HGPS patient iPSC–MSC Improved nuclear morphology, rescued premature osteogenic differentiation [40
Nuclear localization of target 
 All-trans retinoic acid Autophagy Progerin turnover HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin accumulation, and LMNA gene expression, recovered heterochromatin distribution, reduced DNA damage [56
 Antisense  oligonucleotide (ASO E11-31)1 Access of splicing machinery Lamin C/prelamin A splicing HGPS patient dermal fibroblasts Improved nuclear morphology, increased lamin C, and reduced lamin A/progerin expression [42
 caNRF2 NRF2 reactivation NRF2 HGPS patient dermal fibroblasts Reduced progerin accumulation, improved gene expression, and levels of nuclear architectural proteins, reduced ROS, and DNA damage levels [59
 DOT1L inhibitors1 Cell reprogramming DOT1L HGPS patient dermal fibroblasts Increased iPSC reprogramming efficiency [77
 JH41 Progerin–lamin A/C binding Progerin–lamin A/C binding HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin protein, reduced senescence, corrected gene expression [57
 MG1321 Autophagy Progerin turnover HGPS patient dermal fibroblasts, iPSC–MSC and iPSC–VSMC Improved nuclear morphology, increased proliferation, progerin clearance, reduced lamin A/progerin expression, improved gene expression, and levels of nuclear architectural proteins, reduced DNA damage, reduced senescence [58
 Morpholino antisense oligonucleotides1 Access of splicing machinery Abnormal Lmna splicing HGPS patient dermal fibroblasts, LmnaG609G/+ and LmnaG609G/G609G mouse fibroblasts Restored nuclear morphology, reduced progerin transcription and accumulation [41
 Rapamycin and analogs Autophagy Progerin turnover HGPS patient dermal fibroblasts Restored nuclear morphology, progerin clearance, delayed onset of cellular senescence [43
HGPS patient dermal fibroblasts Restored nuclear morphology, increased proliferation, progerin clearance, reduced levels of DNA damage [54
 Remodelin Microtubule NAT10 HGPS patient dermal fibroblasts Improved nuclear morphology and chromatin organization, increased proliferation, reduced DNA damage and signaling, reduced senescence [60
 Resveratrol1 SIRT1 activity SIRT1 Zmpste24−/− mouse MEFs and BMSCs Enhanced colony-forming capacity in adult stem cells [69
 Sulforaphane Autophagy Progerin turnover HGPS patient dermal fibroblasts Restored nuclear morphology, increased proliferation, progerin clearance, reduced levels of DNA damage [55
 Vitamin D Vitamin D receptor signaling Vitamin D receptor HGPS patient dermal fibroblasts Improved nuclear morphology, increased proliferation, reduced progerin and LMNA expression, reduced DNA damage, delayed onset of cellular senescence, increased Vitamin D receptor expression [64

Abbreviations: MEFs, mouse embryonic fibroblasts; iPSC–MSC, mesenchymal stem cells derived from HGPS patient induced pluripotent stem cells; iPSC–VSMC, vascular smooth muscle cells derived from HGPS patient induced pluripotent stem cells; BMSCs, bone marrow stromal cells.

1Evaluated in vivo as well.

Table 2
In vivo evaluation of potential treatment strategies for HGPS
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
Cytoplasmic localization of target 
 Aminobisphosphonates + statins1 Geranylgeranylation Prelamin A farnesylation Zmpste24−/− mice2 Lifespan extension, reduced growth retardation and weight loss, reduced hair loss, improved bone density/bone mineralization/cortical thickness/kyphosis, increased adipose tissue [38
 FTIs1 Prelamin A processing Prelamin A farnesylation Zmpste24−/− mice2 Lifespan extension, improved grip strength and body weight, reduced rib fractures, improved pQCT measurements [34
LmnaHG/+ mice3 Lifespan extension, improved bone mineralization/cortical thickness/kyphosis/rib fractures, increased adipose tissue/body weight [35,36
BAC LMNA G608G mice4,5 Delayed onset of cardiovascular phenotype and delayed disease progression [37
 ICMT inhibition1 Prelamin A processing ICMT Zmpste24−/− mice2 Lifespan extension, increased body weight, normalized grip strength, reduced bone fractures [39
 Pyrophosphate Metabolism of extracellular pyrophosphate Calcium phosphate deposition LmnaG609G/G609G mice6 Reduced aortic vascular calcification [75
 Stem cell transplantation Stem cell function Tissue regeneration Ercc1−/−and Ercc1−/Δ mice7 Lifespan extension, health span extension (delayed phenotype onset) [76
Nuclear localization of target 
 Antisense oligonucleotide (ASO E11-31)1 Access of splicing machinery Lamin C/prelamin A splicing LmnaG609G/G609G mice8 Reduced progerin levels, improved aortic pathology and reduced loss of aortic arch VSMCs [42
 DOT1L inhibitors1 Cell reprogramming DOT1L Zmpste24−/− mice2 Lifespan extension, increased body weight, restored histology in intestines/skin/spleen/thymus, normalized skin cell proliferation rates, reduced senescence in kidneys, improved colony-forming capacity of bone marrow-derived MSCs [77
 JH41 Progerin–lamin A/C binding Progerin–lamin A/C binding LmnaG609G/G609G + LmnaG609G/+ mice6 Lifespan extension, improved nuclear morphology, increased tissue cell density, reduced senescence markers, restored gene expression, increased body weight, increased grip strength, suppressed hair loss [57
 MG1321 Autophagy Progerin turnover LmnaG609G/G609G Reduced progerin levels at injection site [58
 Morpholino antisense oligonucleotides (MmEx10/Ex11)1 Access of splicing machinery Abnormal Lmna splicing LmnaG609G/G609G mice6 Lifespan extension, reduced progerin transcription and accumulation, restored nuclear morphology, reduced senescence markers, improved body weights, reduced degree of kyphosis, normalized blood glucose [41
 OSKM induction Epigenetic remodeling Partial cellular reprogramming LmnaG609G/G609G mice6 Lifespan extension, restored nuclear morphology, reduced stress response/senescence markers, normalized histone markers, reduced degree of kyphosis, improved histology in gastrointestinal tract/kidney/skin/spleen and normalized cell proliferation rates, reduced loss of aortic arch VSMCs, reduced development of bradycardia, partial restoration of adult stem cell populations [78
 Resveratrol1 SIRT1 activity SIRT1 Zmpste24−/− mice2 Lifespan extension, rescued adult stem cell decline, slowed body weight loss, improved trabecular bone structure and mineral density [69
tetop-LAG608G+; Sp7-tTA+ mice5,9 Normalized external dental phenotype, reduction in ribcage fractures [70
 Sodium salicylate NF-κB signaling NF-κB inhibition LmnaG609G/G609G mice6 + Zmpste24−/− mice2 Lifespan extension, improved body weight, increased cell proliferation, increased subcutaneous fat layer, normalized skin hair follicles/spleen/thymus, improved cortical bone thickness [71
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
Cytoplasmic localization of target 
 Aminobisphosphonates + statins1 Geranylgeranylation Prelamin A farnesylation Zmpste24−/− mice2 Lifespan extension, reduced growth retardation and weight loss, reduced hair loss, improved bone density/bone mineralization/cortical thickness/kyphosis, increased adipose tissue [38
 FTIs1 Prelamin A processing Prelamin A farnesylation Zmpste24−/− mice2 Lifespan extension, improved grip strength and body weight, reduced rib fractures, improved pQCT measurements [34
LmnaHG/+ mice3 Lifespan extension, improved bone mineralization/cortical thickness/kyphosis/rib fractures, increased adipose tissue/body weight [35,36
BAC LMNA G608G mice4,5 Delayed onset of cardiovascular phenotype and delayed disease progression [37
 ICMT inhibition1 Prelamin A processing ICMT Zmpste24−/− mice2 Lifespan extension, increased body weight, normalized grip strength, reduced bone fractures [39
 Pyrophosphate Metabolism of extracellular pyrophosphate Calcium phosphate deposition LmnaG609G/G609G mice6 Reduced aortic vascular calcification [75
 Stem cell transplantation Stem cell function Tissue regeneration Ercc1−/−and Ercc1−/Δ mice7 Lifespan extension, health span extension (delayed phenotype onset) [76
Nuclear localization of target 
 Antisense oligonucleotide (ASO E11-31)1 Access of splicing machinery Lamin C/prelamin A splicing LmnaG609G/G609G mice8 Reduced progerin levels, improved aortic pathology and reduced loss of aortic arch VSMCs [42
 DOT1L inhibitors1 Cell reprogramming DOT1L Zmpste24−/− mice2 Lifespan extension, increased body weight, restored histology in intestines/skin/spleen/thymus, normalized skin cell proliferation rates, reduced senescence in kidneys, improved colony-forming capacity of bone marrow-derived MSCs [77
 JH41 Progerin–lamin A/C binding Progerin–lamin A/C binding LmnaG609G/G609G + LmnaG609G/+ mice6 Lifespan extension, improved nuclear morphology, increased tissue cell density, reduced senescence markers, restored gene expression, increased body weight, increased grip strength, suppressed hair loss [57
 MG1321 Autophagy Progerin turnover LmnaG609G/G609G Reduced progerin levels at injection site [58
 Morpholino antisense oligonucleotides (MmEx10/Ex11)1 Access of splicing machinery Abnormal Lmna splicing LmnaG609G/G609G mice6 Lifespan extension, reduced progerin transcription and accumulation, restored nuclear morphology, reduced senescence markers, improved body weights, reduced degree of kyphosis, normalized blood glucose [41
 OSKM induction Epigenetic remodeling Partial cellular reprogramming LmnaG609G/G609G mice6 Lifespan extension, restored nuclear morphology, reduced stress response/senescence markers, normalized histone markers, reduced degree of kyphosis, improved histology in gastrointestinal tract/kidney/skin/spleen and normalized cell proliferation rates, reduced loss of aortic arch VSMCs, reduced development of bradycardia, partial restoration of adult stem cell populations [78
 Resveratrol1 SIRT1 activity SIRT1 Zmpste24−/− mice2 Lifespan extension, rescued adult stem cell decline, slowed body weight loss, improved trabecular bone structure and mineral density [69
tetop-LAG608G+; Sp7-tTA+ mice5,9 Normalized external dental phenotype, reduction in ribcage fractures [70
 Sodium salicylate NF-κB signaling NF-κB inhibition LmnaG609G/G609G mice6 + Zmpste24−/− mice2 Lifespan extension, improved body weight, increased cell proliferation, increased subcutaneous fat layer, normalized skin hair follicles/spleen/thymus, improved cortical bone thickness [71

1Evaluated in vitro as well.

2Phenotype: prelamin A accumulation, reduced lifespan, growth retardation, weight loss, loss of adipose tissue, atrophic epidermis/hair follicles, muscular dystrophy, reduced grip strength, kyphosis, reduced BMD, bone fractures, micrognathia, and abnormal gait [32,33].

3Phenotype: progerin expression, misshaped nuclei, reduced lifespan, growth retardation, weight loss, loss of adipose tissue, kyphosis, osteolysis, reduced BMD, rib fractures, and micrognathia [35].

4Phenotype: progerin expression, loss of VSMCs, accumulation of acellular material, vascular calcification, and adventitial thickening [82].

5Transgene generated with human LMNA sequence.

6Phenotype: progerin expression, misshaped nuclei, reduced lifespan, growth retardation, weight loss, loss of adipose tissue, attrition of hair follicles, reduced grip strength, loss of aortic arch VSMCs, bradycardia, altered heart ventricular depolarization, lordokyphosis, reduced BMD/cortical thickness, increased bone porosity, involution of thymus/spleen, hypoglycemia, altered plasma hormone concentrations, increased senescence and DNA damage, and altered gene expression profile [41].

7Phenotype: reduced lifespan, premature aging of epidermal/hematopoietic/endocrine/hepatobiliary/renal/nervous/musculoskeletal/cardiovascular system [76].

8Phenotype: progerin expression, reduced lifespan, growth retardation, weight loss, loss of aortic VSMCs, adventitial thickening, and skeletal abnormalities [42].

9Phenotype: progerin expression in osteoblasts and osteocytes, growth retardation, reduced weight, irregular bone structure, impaired skeletal geometry, bone mineralization defects, loss of osteocytes, hypocellular bone marrow with adipocyte infiltration, reduced BMD/bone strength, bone fractures, irregular dentin formation, displaced incisors, imbalanced gait, abnormal osteoblast differentiation, reduced osteoclastic TRAP secretion, and increased DNA damage [83].

Table 3
Clinical trials of potential treatment strategies for HGPS.
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
FTI Prelamin A processing Prelamin A farnesylation 26 HGPS patients Improved estimated lifespan, reduced vascular stiffness/incidence of stroke/transient ischemic attack/headache, improved bone structure and audiological status, partially improved weight gain [8,79
FTI + statins + bisphosphonates Prelamin A processing + geranylgeranylation Prelamin A farnesylation 37 HGPS patients Compared with FTI treatment alone, increased arterial plaques and extraskeletal calcifications, increased bone mineral density [1
FTI + everolimus (rapamycin analog) Prelamin A processing + autophagy Prelamin A farnesylation + progerin turnover 17 HGPS patients enrolled to date Study initiated in April 2016 and ongoing [80
Treatment/drug Pathway Target Evidence Improvement(s) Ref. 
FTI Prelamin A processing Prelamin A farnesylation 26 HGPS patients Improved estimated lifespan, reduced vascular stiffness/incidence of stroke/transient ischemic attack/headache, improved bone structure and audiological status, partially improved weight gain [8,79
FTI + statins + bisphosphonates Prelamin A processing + geranylgeranylation Prelamin A farnesylation 37 HGPS patients Compared with FTI treatment alone, increased arterial plaques and extraskeletal calcifications, increased bone mineral density [1
FTI + everolimus (rapamycin analog) Prelamin A processing + autophagy Prelamin A farnesylation + progerin turnover 17 HGPS patients enrolled to date Study initiated in April 2016 and ongoing [80

Although treatment with FTIs prevents prelamin A farnesylation, an in vitro study showed that an alternative pathway (via geranylgeranyltransferase) allowed for prelamin A processing in HGPS patient fibroblasts despite the usage of FTIs [38]. The same study also showed that a combination of statins and aminobisphosphonates — drugs frequently used to reduce cardiovascular disease and to prevent loss of bone mass, respectively — inhibited both farnesylation and geranylgeranylation (Figure 3). As with FTIs, statin and aminobisphosphonate treatment improved the nuclear morphology in HGPS cells (Table 1), as well as provided phenotype improvements in Zmpste24-deficient mice, including lifespan extension, reduced growth retardation and weight loss, and improved skeletal properties (Table 2) [38].

Another potential target for the treatment of HGPS is the enzyme isoprenylcysteine carboxyl methyltransferase (ICMT), involved in the post-translational processing of prelamin A (Figure 3). A study from Ibrahim and colleagues using Zmpste24-deficient mice that harbored hypomorphic Icmt alleles, resulting in ICMT inhibition, showed beneficial effects including lifespan extension, increased body weight, and reduced frequency of bone fractures (Table 2) [39]. ICMT knockdown, using shICMT, was also evaluated in HGPS patient cells with beneficial results (Table 1) [39].

Taking advantage of induced pluripotent stem cell (iPSC) lines derived from HGPS patients, a large number of chemical compounds were screened to identify novel pharmacological farnesylation inhibitors [40]. The study identified mono-aminopyrimidines (Mono-APs), targeting the two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase (FPPS) and farnesyltransferase, hence acting like a combination of FTIs and bisphosphonates (Figure 3). In vitro experiments using these Mono-APs improved HGPS cell nuclear morphology and rescued premature osteogenic differentiation (Table 1) [40].

Blocking progerin and lamin A splicing

Antisense therapy is a promising treatment strategy, where blocking alternative LMNA gene splicing by targeting different parts of the gene using antisense oligonucleotides (Figure 3) have shown beneficial results both in vitro and in vivo. Using morpholino antisense oligonucleotides, the pathological splice site causing classical HGPS was directly targeted, which prevented production of the truncated HGPS prelamin A protein by blocking the splicing machinery access to the splice site [41]. In vivo treatment of HGPS mice (LmnaG609G/G609G) with morpholinos ameliorated the cellular HGPS phenotypes, as well as reduced the levels of progerin mRNA and protein, extended the lifespan, improved the body weights, and normalized the blood glucose of the mice (Table 2) [41]. Species-specific morpholinos were also evaluated in HGPS patient and mouse cells with beneficial results (Table 1) [41]. In another study, using the newly identified exon 11 antisense oligonucleotide ASO E11-31, that was suggested to inhibit binding of the exonic splice enhancer protein SRSF2 to exon 11 LMNA pre-mRNA, the balance of LMNA mRNA splicing was shifted towards lamin C transcripts and away from prelamin A transcripts [42]. This shift improved nuclear morphology and reduced lamin A/progerin expression in HGPS patient cells (Table 1), and in addition, improved the aortic pathology and improved the loss of VSMCs in LmnaG609G/G609G mice (Table 2) [42].

Modifying progerin interactions and turnover in the nucleus

One of the first treatment strategies shown to target progerin turnover was using the macrolide antibiotic drug rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), where the treatment of cells from HGPS patients showed autophagy-mediated progerin clearance (Figure 3), restored nuclear morphology, and delayed onset of cellular senescence (Table 1) [43]. mTOR is found in two signaling complexes, mTORC1 and mTORC2. mTORC1 is known to play an important role in many cellular processes, and especially in autophagy, and is thought to be an important modulator of aging [44]. Interestingly, numerous studies have shown that mTORC1 inhibition through rapamycin could extend the lifespan of healthy mice and improve age-associated disorders [4553]. However, the use of rapamycin or any other mTORC1 inhibitor to decelerate aging in humans remains to be determined. Studies using temsirolimus [54], a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin, and sulforaphane [55], an antioxidant derived from cruciferous vegetables, showed similar beneficial effects to rapamycin in treatments of HGPS cells (Table 1). In addition, these compounds increased cell proliferation and reduced DNA damage [54,55]. Similarly, in vitro treatment of HGPS cells with all-trans retinoic acid showed autophagy-mediated removal of progerin [56]. In addition to the benefits from using temsirolimus and sulforaphane, all-trans retinoic acid reduced total LMNA gene expression and recovered normal heterochromatin distribution (Table 1) [56].

It has also been shown that progerin binds lamin A/C and induces the nuclear deformations, with stronger binding affinity between progerin and lamin A/C than that between lamin A/C and lamin A/C [57]. Screening of chemical compounds identified JH4 as an inhibitor of progerin–lamin A/C interaction that improved HGPS cell nuclear morphology by selectively binding to progerin (Figure 3) [57]. In vivo treatment using JH4 in LmnaG609G/G609G and LmnaG609G/+ mice showed marked improvements in the HGPS phenotype, including lifespan extension, increased body weight, reduced senescence markers, increased tissue cell density, and restored gene expression (Table 2), and in vitro evaluation in HGPS patient cells showed equally beneficial results (Table 1) [57]. As a control, Zmpste24-deficient mice were also treated with JH4 but without any phenotype improvements, indicating progerin specificity of JH4 [57].

Another recently published study demonstrated that treatment using the proteasome inhibitor MG132 enhanced progerin clearance, mediated in part by macroautophagy, in HGPS patient fibroblasts as well as in HGPS patient iPSC-derived mesenchymal stem cells (MSCs) and VSMCs. Indeed, this compound was also found to indirectly reduce prelamin A aberrant splicing, and activation of these two pathways resulted in an improvement in the HGPS cellular phenotype (Table 1) [58]. Interestingly, in vivo treatment via intramuscular injections of MG132 in LmnaG609G/G609G mice also resulted in local clearance of progerin (Table 2) [58].

Targeting proteins in the nucleus affected by progerin

In vitro data suggest that progerin accumulation in the lamina sequesters NRF2, impairs its pathway, and blocks it from accessing target antioxidant genes. Reactivation of NRF2 using constitutively activated NRF2 (caNRF2) in HGPS cells reduced progerin accumulation, improved gene expression and levels of nuclear architectural proteins, as well as reduced reactive oxygen species (ROS) and DNA damage (Table 1) [59].

A screen for compounds that could improve the HGPS cellular phenotype discovered Remodelin, a small molecule targeting the lamina interacting SUN1-associated acetyl-transferase protein NAT10. In vitro treatment of HGPS cells with Remodelin mediated restoration of nuclear morphology via microtubule reorganization. Remodelin also improved chromatin organization, reduced DNA damage and signaling, increased cell proliferation, and reduced senescence (Table 1) [60].

Vitamin D is crucial for maintaining calcium and phosphate homeostasis, and most genomic activities of vitamin D are mediated by the nuclear vitamin D receptor (VDR) [61]. Expression of VDR in tissues unconnected to bone or calcium balance, however, suggests additional functions, and VDR knockout in mice induce premature aging symptoms similar to HGPS [62,63]. It was recently shown that accurate VDR function requires a correctly organized lamina, and that HGPS patient cells become VDR-deficient upon progerin accumulation [64]. In vitro supplementation of vitamin D counteracted VDR loss and ameliorated the HGPS phenotype, improving nuclear morphology, reduced progerin and total LMNA gene expression, reduced DNA damage, increased cell proliferation, and delayed onset of senescence (Table 1) [64].

There have been conflicting results regarding usage of resveratrol, a plant-produced antioxidant shown to activate SIRT1 and increase lifespan in yeast, worms, flies, and rodents [6568]. Lamin A was shown to directly interact with and activate SIRT1, a protein with deacetylase activity targeting a wide range of substrates regulating genomic stability, mitochondrial biogenesis, adipogenesis, inflammation, and stress response [69]. Both progerin and prelamin A reduced the activity of SIRT1, where resveratrol introduction enhanced the SIRT1–lamin A interaction to re-increase SIRT1 activity [69]. In vitro treatment using resveratrol showed enhanced colony-forming capacity of adult stem cells from Zmpste24-defecient mice (Table 1), and treatment of Zmpste24-deficient mice rescued adult stem cell decline, increased lifespan, slowed body weight loss, and improved bone properties (Table 2) [69]. In contrast, resveratrol treatment of a mouse model with bone-specific expression of the HGPS mutation (tetop-LAG608G+; Sp7-tTA+) showed no beneficial effects other than normalization of the external dental phenotype and reduced number of ribcage fractures [70]. These contradicting results might be caused by the fact that two different mouse models were used — one with systemic loss of ZMPSTE24, involved in prelamin A processing, and other with tissue-specific overexpression of human lamin A and progerin in differentiated osteoblasts and osteocytes.

Accumulation of prelamin A or progerin triggers a signaling pathway activating NF-κB, resulting in inflammation that contributes to the premature aging phenotypes in both Zmpste24-deficient and LmnaG609G/G609G mice [71]. Inhibition of NF-κB using sodium salicylate prevented these alterations, yielding lifespan extension, improved body weights, increased cell proliferation, and histological improvement of several tissues (Table 2) [71].

Targeting cytoplasmic functions affected by progerin

Mitochondrial dysfunction has been proposed as an important hallmark in the aging process that among other things results in increased production of ROS [72]. Innately elevated levels of ROS were shown to cause accumulation of unrepairable DNA damage in HGPS cells, and treatment with the ROS scavenger NAC (N-acetyl cysteine) reduced DNA damage and increased cell proliferation (Table 1) [73]. Recent studies demonstrated HGPS-specific mitochondrial defects, including mitochondrial dysfunction, an increased fraction of swollen and fragmented mitochondria, as well as reduced mitochondrial mobility [20,21]. Treatment with FTI-277 or with a combination of Pravastatin and Zolenodrate significantly improved mitochondrial function in progeroid fibroblasts obtained from LmnaG609G/G609G and Zmpste24-deficient mice (Table 1) [20]. Moreover, treatment with the mitochondrial-targeting antioxidant methylene blue significantly decreased the mitochondrial morphological and behavior defects and reduced ROS levels in vitro in HGPS patient cells (Figure 3), and rescued the HGPS nuclear abnormalities by increasing progerin release from the nuclear membrane (Table 1). In addition, rescued heterochromatin loss, corrected gene expression, increased cell proliferation, and reduced premature senescence as assessed by senescence-associated β-galactosidase assay and p16 expression analysis were seen [21]. Similar beneficial effects occurred when treating HGPS cells with metformin (Figure 3), a commonly used antidiabetic drug that was able to improve mitochondrial function and nuclear morphology, reduce levels of ROS, DNA damage, and progerin expression and senescence (Table 1) [74].

Recently, an in vivo study showed that excessive vascular calcification in LmnaG609G/G609G mice was caused by progerin expression, which impaired the metabolism of extracellular pyrophosphate via increased tissue-nonspecific alkaline phosphatase activity and reduced levels of ATP (the main source of extracellular pyrophosphate) caused by mitochondrial dysfunction in VSMCs [75]. Extracellular pyrophosphate is a major inhibitor of vascular calcification, and treatment with pyrophosphate inhibited aortic vascular calcification in the mice (Table 2) [75].

Cellular reprogramming and tissue regeneration

Among other features, aging is characterized by a decline in the regenerative potential of tissues; hence, stem cell exhaustion has been proposed as an important hallmark in the aging process [72]. Transplantation of wild-type muscle-derived progenitor cells delayed phenotype onset and extended lifespan in progeroid mouse models (Ercc1−/−and Ercc1−/Δ) with impaired muscle-derived progenitor cells [76]. The transplantation improved degenerative changes in tissues where donor cells were not detected, suggesting a systemic effect possibly originating from secreted factors [76].

Cellular reprogramming is a different way to promote tissue regeneration, as recently shown by NF-κB hyperactivation, that blocks cell reprogramming in HGPS and aging by eliciting the reprogramming repressor DOT1L [77]. Treatment with DOT1L inhibitors in HGPS patient cells increased iPSC reprogramming efficiency (Table 1), and inhibition of DOT1L in vivo ameliorated premature aging in Zmpste24-deficient mice, including lifespan extension, increased body weight, restored tissue histology, and improved colony-forming capacity of bone marrow-derived MSCs [77]. Another recently published study showed that cyclic in vivo induction of the Yamanaka factors OSKM (Oct 4, Sox2, Klf4, and c-Myc) in LmnaG609G/G609G mice ameliorated age-associated phenotypes, including lifespan extension, restored nuclear morphology and histone markers, reduced stress response and senescence markers, improved tissue histology, partial restoration of adult stem cell populations, and reduced loss of aortic arch VSMCs [78].

Clinical trials in HGPS patients

Based on the positive outcomes from the studies using statins, aminobisphosphonates and FTIs, two clinical trials have been performed in children with HGPS. The first trial enrolled 26 HGPS patients who were treated with the FTI Lonafarnib for a minimum of 2 years [79]. The results from this trial showed improvements in estimated lifespan [8], cardiovascular and audiological status, bone structure, and rate of weight gain in many of the patients [79] (Table 3). The second clinical trial added Pravastatin and the bisphosphonate Zoledronate to the treatment, and enrolled 37 HGPS patients who were treated with the three trial medications for 40–52 months [1]. Compared with the FTI monotherapy treatment trial, adding statins and bisphosphonates only improved the BMD. However, the percentage of patients having arterial plaques and extraskeletal calcifications substantially increased, suggesting that treatment with the two additional drugs might be less advantageous for HGPS [1] (Table 3).

With the positive outcomes from studies using rapamycin and similar compounds in mind, in April 2016, a third clinical trial using a combination of FTI and everolimus (a rapamycin analog) was initiated, and so far, 17 HGPS patients have been enrolled in the trial [80] (Table 3).

Conclusions

As summarized in this review, the development and testing of a substantial number of strategies to treat the very rare disease HGPS is remarkable. New strategies and refinement of existing strategies will likely be developed continuously, since clinical trials performed so far have generated encouraging results, including extension of lifespan and reduction of vascular stiffness in many of the patients [1,8,79]. However, there is still a need to gain a deeper understanding of the molecular mechanisms causing HGPS and to further evaluate other methods of treatment.

The possibility of treating disorders like HGPS is dependent not only on the drugs or ways of treatment used, but also on the actual ability of the affected tissues to recover. This is especially important in HGPS, since the clinical manifestations of the disease will always precede a therapeutic intervention due to the de novo origination and rarity of the disease. By using different conditional transgenic mouse models with inducible tissue-specific expression of the most common HGPS mutation, our laboratory has previously shown that both the HGPS skin and skeletal phenotypes are reversible if the progerin expression is silenced [70,81]. Importantly, in these studies, the disease phenotypes had been fully developed before the transgenic progerin expression was turned off, mimicking a real-life treatment precondition. When evaluating the results of candidate treatments performed in mouse models, it is therefore of importance to consider at which time point the treatment intervention was initiated — whether a disease phenotype had been developed or if the treatment was of prophylactic character. In many of the in vivo studies recapitulated here, treatment initiation time point preceded the onset of a visually pronounced disease phenotype [3436,39,42,57,69], or was not described [38,71], making it more difficult to draw conclusions if the treatments would show the same success in a clinical setting (where patients usually have a significantly developed phenotype).

Nevertheless, taken all together, the continuously growing list of emerging treatment candidates suggests several promising therapeutic approaches for future treatment of children with HGPS. The ultimate goal would be to remove or block the pathological mutation causing progerin expression; however, gene targeting and gene editing methods are not yet ready for clinical trials in patients due to the lack of methods for tissue-specific drug delivery and low efficiency of cellular uptake. Since cardiovascular disease is the primary cause of death in HGPS [2], the primary focus should be in finding a method to specifically target these tissues. In addition, since we have previously shown that both rapidly and slowly remodeling tissues like skin and bone can recover if progerin expression is halted [70,81], the prospect of future treatment of HGPS is promising. When the issues of drug delivery and cellular uptake efficiency have been resolved, and targeting the affected tissues in HGPS is possible and safely assessed in animal models, a gene therapy treatment approach will be more feasible.

Abbreviations

     
  • BMD

    bone mineral density

  •  
  • caNRF2

    constitutively activated NRF2

  •  
  • FPPS

    farnesyl pyrophosphate synthase

  •  
  • FTI

    farnesyltransferase inhibitor

  •  
  • HGPS

    Hutchinson-Gilford progeria syndrome

  •  
  • ICMT

    isoprenylcysteine carboxyl methyltransferase

  •  
  • iPSC

    induced pluripotent stem cell

  •  
  • Mono-AP

    mono-aminopyrimidine

  •  
  • MSC

    mesenchymal stem cell

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NAC

    N-acetyl cysteine

  •  
  • ROS

    reactive oxygen species

  •  
  • VDR

    vitamin D receptor

  •  
  • VSMC

    vascular smooth muscle cell.

Author Contribution

C.S. wrote the first version of the manuscript and summarized the data for Tables 1–3. G.R. made Figure 3. All authors contributed with revisions.

Funding

Work in the M.E.'s laboratory is supported by grants from Vetenskapsrådet (M.E.), the Center for Innovative Medicine (M.E.), the Karolinska Institutet Faculty Funds for doctoral students (C.S. and G.R.), Stohnes Foundation (A.S.C.), and Osterman Foundation (A.S.C.).

Acknowledgments

We thank Mattias Karlén for the illustrations in Figures 1 and 2.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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