cells

Review
Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential
Therapeutic Target for HGPS
Bae-Hoon Kim 1 , Yeon-Ho Chung 1 , Tae-Gyun Woo 1 , So-Mi Kang 2 , Soyoung Park 2 and Bum-Joon Park 1,2, *

1 Rare Disease R&D Center, PRG S&T Co., Ltd., Busan 46274, Republic of Korea; [email protected] (B.-H.K.);
[email protected] (Y.-H.C.); [email protected] (T.-G.W.)
2 Department of Molecular Biology, College of Natural Science, Pusan National University,
Busan 46231, Republic of Korea; [email protected] (S.-M.K.); [email protected] (S.P.)
* Correspondence: [email protected]

Abstract: Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder

caused by the mutant protein progerin, which is expressed by the abnormal splicing of the LMNA
gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children,
showing that cellular aging can occur in the short term. Studying progeria could be useful in
unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear
cause of HGPS or the development of a therapeutic medicine could improve the quality of life and
extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered
as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary
neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin
and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS
and introduce clinical trials for its treatment.

Keywords: Hutchinson–Gilford progeria syndrome; progerin; nuclear lamina

Citation: Kim, B.-H.; Chung, Y.-H.;

1. Introduction
Woo, T.-G.; Kang, S.-M.; Park, S.; Hutchinson–Gilford progeria syndrome (HGPS; OMIM#176670) was first reported
Park, B.-J. Progerin, an Aberrant more than 100 years ago by Hutchinson and Gilford in 1886 and 1897, respectively [1]. The
Spliced Form of Lamin A, Is a condition was designated as a premature aging syndrome by Gilford based on the fact
Potential Therapeutic Target for that the symptoms associated with aging are similar to the changes seen in older people in
HGPS. Cells 2023, 12, 2299. general, including a lack of subcutaneous fat, hair loss, joint contractures, a progressive
https://doi.org/10.3390/ cardiovascular disease similar to atherosclerosis, and death from heart attacks and strokes
cells12182299 in childhood. As patients typically live to their teens or early 20s and usually die before
Academic Editor: Ursula Stochaj reaching reproductive age, this syndrome is not inherited. Diagnosis can be achieved
within the first 6 months of age, although prominent and noticeable symptoms may be
Received: 8 August 2023 observed later [2–8]. This fatal pediatric disease remained a medical mystery until genetic
Revised: 14 September 2023
mapping revealed that 90% of patients have a de novo point mutation in the LMNA gene
Accepted: 15 September 2023
that replaces cytosine with thymine [9,10].
Published: 18 September 2023
Nuclear membrane proteins (lamins A and C), encoded by the LMNA gene, are struc-
tural components of the nuclear lamina, a network of proteins underneath the nuclear
membrane that determines the shape and size of the nucleus [11,12]. LMNA produces four
Copyright: © 2023 by the authors.
proteins as a result of alternative splicing: lamin A and lamin C as major products, and
Licensee MDPI, Basel, Switzerland. lamin C2 and lamin A delta 10 as minor products. Lamins A and C are similar through the
This article is an open access article first 566 amino acids (encoded by exons 1–10) but deviate at the carboxyl terminus [3,13,14].
distributed under the terms and Prelamin A, but not lamin C, contains a CaaX motif at its C-terminus and undergoes farne-
conditions of the Creative Commons sylation and methylation (Figure 1). Lamin A is synthesized as a precursor (prelamin A)
Attribution (CC BY) license (https:// and matures through four sequential post-translational processing steps [15]. First, farne-
creativecommons.org/licenses/by/ syltransferase (FTase) adds a 15-carbon farnesyl moiety to the carboxyl-terminal cysteine.
4.0/). Second, the Zmpste24 endopeptidase cleaves the last three amino acids of prelamin A.

Cells 2023, 12, 2299. https://doi.org/10.3390/cells12182299 https://www.mdpi.com/journal/cells

Cells 2023, 12, x FOR PEER REVIEW 2 of 19
Cells 2023, 12, 2299 2 of 17

terminal cysteine. Second, the Zmpste24 endopeptidase cleaves the last three amino acids
ofThird,
prelamin
the A. Third,
newly the newly
exposed exposed
farnesyl farnesyl
cysteine cysteine is carboxyl-methylated
is carboxyl-methylated by a
by a prenyl protein-
specific
prenyl methyltransferase.
protein-specific Finally, the endopeptidase
methyltransferase. Finally, theremoves 15 carboxyl-terminal
endopeptidase removes 15 amino
car-
acids from theamino
boxyl-terminal protein, resulting
acids in the
from the release
protein, of mature
resulting lamin
in the A. of mature lamin A.
release

Figure 1. A
Figure 1. schematic representation
A schematic of of
representation thethe
post-translational
post-translationalprocessing of of
processing lamin A and
lamin progerin
A and progerin
and the effect of progerin inhibition on cells. Spontaneous mutations in LMNA (c.
and the effect of progerin inhibition on cells. Spontaneous mutations in LMNA (c. 1824C>T)1824C>T) in in
eggs, sperm, embryos, or during aging cause alternative splicing of the LMNA gene, leading to
eggs, sperm, embryos, or during aging cause alternative splicing of the LMNA gene, leading to the the
accumulation of progerin in the nuclear layer. Consequently, the accumulation of progerin renders
accumulation of progerin in the nuclear layer. Consequently, the accumulation of progerin renders
the cell unhealthy in a mechanophysiological manner. Inhibiting progerin by several methods
the cell unhealthy in a mechanophysiological manner. Inhibiting progerin by several methods (small
(small molecules, ASOs, base editors) can restore damaged cells (See table 1 for detail).
molecules, ASOs, base editors) can restore damaged cells (See Table 1 for detail).
It has been questioned whether the post-translational processing steps of prelamin A
It has been questioned whether the post-translational processing steps of prelamin A
areare
essential
essential inin
targeting
targeting the protein
the proteintotothethenuclear
nuclear envelope
envelope [16]. Mice
[16]. Micethat could
that coulddirectly
directly
produce mature lamin A without going through the usual
produce mature lamin A without going through the usual prelamin A synthesis prelamin A synthesis and pro-
and
cessing steps were created. However, no detectable disease phenotype
processing steps were created. However, no detectable disease phenotype was observed was observed in in
thethe
mice
mice andandthethe
nuclear
nuclear membrane
membrane ofof
mature
mature lamin
laminAA appeared
appeared normal
normal [16], suggesting
[16], suggesting
that prelamin A processing is minimally important for the
that prelamin A processing is minimally important for the nuclear targeting nuclear targeting ofof
mature
mature
lamin A and is independent of lamin B in laboratory
lamin A and is independent of lamin B in laboratory mice. mice.
HGPS
HGPS belongs
belongs toto
a group
a group of of
diseases
diseases called laminopathies,
called laminopathies, in in
which
which mutations
mutations across
across
thethe
LMNA gene result in a wide range of overlapping disorders
LMNA gene result in a wide range of overlapping disorders [17]. Genetic mapping[17]. Genetic mapping of
theofgenome
the genomefrom from
patients elucidated
patients that a sporadic,
elucidated autosomal-dominant
that a sporadic, autosomal-dominantde novode point
novo
mutation, c.1824C>T
point mutation, (p.G608G)
c.1824C>T (NM_170707.3)
(p.G608G) in exonin
(NM_170707.3) 11exon
of the
11human LMNA LMNA
of the human gene, me-
gene,
diates abnormal
mediates abnormalalternative
alternativesplicing [9,10],
splicing which
[9,10], produces
which produces an an
abnormal
abnormal variant
variantprotein
protein
called
calledprogerin,
progerin, which
which is is
responsible
responsible forfor
this accelerated
this accelerated aging
aging disease
disease[18–20]
[18–20](Figure
(Figure1).1).
The current review describes the discovery of progerin as a
The current review describes the discovery of progerin as a causative agent causative agent ofof
HGPS
HGPS
and
and provides
provides evidence
evidence of of
itsits
deleterious
deleterious effects when
effects when expressed
expressed intracellularly,
intracellularly,andandthe
the
benefits of inhibiting its expression. Additionally, it introduces efforts to develop therapies
and clinical trials for HGPS.
Cells 2023, 12, 2299 3 of 17

2. Absence of Primary Neurological Disease in HGPS

Extensive studies have been conducted to examine mutations in the LMNA gene
encoding prelamin A and lamin C, which result in distinct muscular dystrophy, cardiomy-
opathy, partial lipodystrophy, and progeroid syndromes. These laminopathies mostly
affect mesenchymal tissues (e.g., the myocardium, skeletal muscle, adipose tissue, fibrous
connective tissue, and bone tissues). However, one confusing observation in patients with
HGPS is that they generally show fundamental and dramatic premature aging but do not
exhibit any noticeable cognitive damage. For many years, it has been puzzling that patients
with HGPS do not have any primary neurological disease. However, recent research has
confirmed a lack of lamin A expression, the major isoform of LMNA, in HGPS patient-
driven induced pluripotent stem cells (iPSCs) [21–24]. In most tissues, the amounts of
lamins A and C are approximately equal; however, the brain mostly generates lamin C and
very little lamin A [21,25]. Immunohistochemistry has indicated that lamin C is expressed
at high levels in the neurons and glia of the brain, but the expression of prelamin A and
lamin A is restricted to the vascular endothelial cells [25]. Further studies have shown that
the expression of prelamin A in the brain is downregulated by miR-9, a microRNA highly
expressed in the brain that binds to a single site in the 30 untranslated region of prelamin
A [21,22,25,26]. The ectopic expression of miR-9 in fibroblasts or HeLa cells decreases the
levels of prelamin A and lamin A proteins but does not influence lamin C expression [25].
In lamin-A-only knock-in mice, where there is no alternative splicing and the output of
all genes is directed to the prelamin A transcript, high levels of lamin A are found in the
peripheral tissues, but very little lamin A is found in the brain [25]. Likewise, a knock-in
mouse was created to direct the production of LMNA towards the progerin transcript. In
this model, high levels of progerin were expressed in peripheral tissues, while minimal
levels were observed in the brain [25], demonstrating that the unique expression pattern
of lamin A/lamin C in the brain is not the result of alternative splicing. This regulation
of lamin A in the brain provides us with a basis to further study improperly processed
progerin and toxic lamin A. Children with HGPS have aging-like phenotypes in many
tissues but lack common features of physiological aging in the central nervous system
(CNS), such as senile dementia. Therefore, progerin accumulation in cells is considered a
pathology-inducing factor.
Additionally, several studies have highlighted the important role of nuclear lamins in
the CNS, indicating that type B lamins, lamins B1/B2, play an important role in neuronal
migration in the developing brain [27–29]. Duplication of the LMNB1 gene encoding
lamin B1 has been shown to cause autosomal-dominant leukodystrophy (ADLD) [30,31].
More recently, both LMNB1 deficiency and overexpression have been reported to inhibit
proliferation, but only LMNB1 overexpression induces senescence, which is prevented
by telomerase expression or p53 inactivation. A concomitant decrease in lamin A/C
levels aggravates this phenotype. These findings show that changes in the expression of
LMNB1 inhibit proliferation and are potentially relevant in understanding the molecular
pathophysiology of ADLD [32], suggesting the possibility that a distinct spectrum of “brain
laminopathies” might eventually be mapped to missense mutations in LMNB, not in LMNA.

3. Dysfunctional Progerin Expression

a. Effect of progerin at the cellular level
Notably, the expression levels of progerin and lamins A and C (lamin A/C) were
significantly reduced in iPSCs derived from patients with HGPS [21–24]. Moreover, these
cells showed decreased patterns of cellular senescence markers, including nuclear deforma-
tion, histone H3 trimethyl Lys9 (H3K9-Me3), and senescence-associated β-gal (SA–β-gal).
In contrast, HGPS cells differentiated from iPSCs start expressing progerin and lamin
A/C and re-expressing senescence markers [23]. This implies that the expression of the
LMNA gene is tightly regulated at an early developmental stage; therefore, progerin is
expressed in differentiated HGPS cells and its expression drives the cells to a pathological
state. Twenty years ago, Collins et al. proved that progerin is the main factor inducing a
Cells 2023, 12, 2299 4 of 17

premature aging phenotype in HGPS by the disruption of lamin-related functions ranging

from the maintenance of nuclear shape to the regulation of gene expression and DNA
replication [18].
A correlation between progerin levels and the severity of HGPS phenotypes has
been reported. Progerin levels in HGPS fibroblasts increase with the culture passage
number [19,33,34]. Recently, Gordon et al. developed a plasma assay to assess the amount of
progerin in response to progerin-targeted therapy and its correlation with patient survival.
The extent of the survival improvement was related to both the magnitude and duration
of progerin reduction at low levels, demonstrating that the level of plasma progerin is a
biomarker of HGPS that enables the short- and long-term assessment of progerin-targeted
therapeutic efficacy through progerin reduction [35].
The arrangement of chromatin in the nucleus is crucial in regulating many aspects of
nuclear function and protecting nuclear integrity. The nuclear envelope (NE) is an essential
factor in the dimensional scattering of these chromosomes. It binds to and ties a wide range
of chromatin domains by interacting with the nuclear lamina and other associated proteins.
Progerin sequesters NRF2 at the NE site, causing a subnuclear localization mismatch
that impairs NRF2 transcriptional activity and consequently increases chronic oxidative
stress [36]. Progerin also induces altered 3D telomere organization between telomeres
and the nuclear lamina, and an altered telomeric chromatin state [37]. Overexpression
of telomerase reverse transcriptase (TERT) enhances the proliferative capability of HGPS
fibroblasts and repairs progerin-induced DNA damage [38,39]. Chojnowski et al. [40]
suggested a controllable cellular model of progeria and showed that exogenous TERT
prevents proliferation deficiency, DNA damage, lamin B1 reduction, and gene expression
differences induced by progerin, suggesting that progerin disturbs the interaction between
LAP2α and telomeres. However, TERT could not restore defects in nuclear morphology or
altered H3K27me3 deposition [40]. Other reports have indicated that progerin expression
is sufficient to cause heterochromatin loss by inducing DNA damage [41,42].
ER stress can be induced by the disruption of cellular energy levels, such as the redox
status or Ca2+ concentration, leading to the accumulation and aggregation of unfolded
proteins [43,44]. Progerin expression disrupts calcium homeostasis and whole-body en-
ergy consumption. A mouse model (CAG-Progerin+ and MCK-Cre+) was developed
to investigate the role of human progerin in sarcoplasmic reticulum function [45]. The
study demonstrated that the conditional overexpression of progerin in muscle tissue is
sufficient to provoke premature death and impair the regulatory control of the expression
of thermogenesis-related genes.
It has been found that the abnormal expression of progerin could aggravate the
defenestration of liver sinusoidal endothelial cells (LSEC) during liver fibrosis, whereas the
knockdown of progerin expression could attenuate premature liver senescence [46,47]. It
has been proposed that in response to DNA damage, the binding between LC3 and UBC9-
sumoylated lamin A/C enables autophagy to specifically mediate the disruption of lamins
A/C and leaky nuclear DNA, suggesting that, in response to cancer-promoting stresses such
as DNA damage, autophagy breaks down nuclear material to prevent tumor formation [48].
Another study has shown that progerin is involved in nucleophagy [49]. It was indicated
that deficient nucleophagy due to progerin expression caused oxidative stress presumably
due to the decomposition of basal lamin B1. Furthermore, the acetylation of nuclear LC3
was responsible for the unusual deposition of progerin, whereas its deacetylation promoted
progerin removal, thus suggesting a potentially novel approach to maintaining the LSEC
phenotype [50].
Progerin-mediated functions at the protein level and their relationship with miRNA
expression have also been described in recent studies [51–53]. A structure-based study has
revealed that unfarnesylated progerin can form a disulfide bond with an Ig-like domain in
the nuclear lamina. The Alphafold2-assisted docking structure showed that disulfide bond
formation was promoted by a weak interaction between the groove of the Ig-like domain
and the unfarnesylated C-terminal tail region of progerin, providing molecular insights
Cells 2023, 12, 2299 5 of 17

into the abnormal interactions caused by progerin [51]. The evaluation of miRNA expres-
sion profiles in HGPS and normal fibroblasts revealed an enriched set of overexpressed
miRNAs belonging to the 14q32.2–14q32.3 miRNA cluster and showed that inducing their
overexpression in normal fibroblasts reduced cell proliferation and increased senescence,
whereas inhibiting them in HGPS fibroblasts alleviated proliferation defects and senes-
cence and reduced progerin accumulation [52]. Progerin overexpression induced notable
changes in miRNA expression and confirmed that has-miR-59 (miR-59) was markedly
upregulated in cells from patients with HGPS and in multiple tissues of an HGPS mouse
model (LmnaG609G/G609G ) [53].
In this report, we describe the relationship between progerin and cellular homeostasis,
and its role in inducing premature aging in most cells. Several groups have examined
progerin as a biomarker of aging and indicated that it may be one of the few known
biological indicators that initiate the aging process at a certain age [54–57]. Recently,
fibroblasts cultured from older individuals were shown to have nuclear features similar
to HGPS cells [54]. Notably, although these cells expressed progerin mRNA transcripts
at barely detectable levels [54], they contained several abnormal nuclei that were clearly
positive for progerin-specific antibodies after prolonged culture [58,59], indicating that
progerin can be expressed in normal cells. To further investigate the biological relationship
between progerin expression and aging in normal humans, Djabali et al. examined skin
biopsies from 150 unaffected individuals. They found that similar splicing events occurred
in vivo at low levels in the skin of individuals of all ages [60]. Although the mRNA
expression level of progerin is low, it accumulates with age in a subpopulation of skin
fibroblasts and terminally differentiated keratinocytes [60,61], suggesting that research on
HGPS may improve our knowledge of physiological aging.
b. Systemic effect of progerin or effect of progerin on tissues
Over the last 20 years, several types of mice have been developed as animal models to
investigate diverse aspects of HGPS as follows: the knock-out or transgenic mice affecting
the whole-body level are Zmpste24−/− [62,63], transgenic G608G BAC [64], LmnaG609G [65],
Apo−/− LmnaG609G/G609G [66], Ldlr−/− , and LmnaG609G/G609G [67]; the mice affecting spe-
cific tissues or cells are LmnaLCS/LCS SM22αCre [66], Apoe−/− LmnaLCS/LCS SM22αCre [66],
LmnaLCS/LCS Tie2Cre [68,69], Lmnaf/f ; TC [70], and Prog-Tg [71]—see reference [72] for
further details. The limited number of patients with HGPS worldwide renders it difficult
to conduct longitudinal studies and clinical trials, and there is also a scarcity of human
samples available for ex vivo analyses. Therefore, the use of animal models and their
derived cell lines has contributed to the understanding of progeria phenotypes and is
particularly important in developing therapeutic reagents for the disease. The current
section aims to examine how progerin affects the phenotypes of various cell types and
mouse models by compiling research carried out by various experts.
Blood vascular diseases are the predominant cause of death in classical HGPS [73].
As childhood progresses, other symptoms appear, including hair loss, joint stiffness, body
fat loss, osteoporosis, and other aspects of physiological aging. The most clinically rel-
evant aspect of HGPS is the hardening of the arteries (atherosclerosis), which leads to
premature death from cardiovascular disease or stroke at an average age of approximately
15 years [74]. In HGPS, atherosclerosis is accompanied by pathological changes in the aortic
wall, including severe vascular smooth muscle cell (VSMC) depletion in the media, extracel-
lular matrix deposition, calcification, and early thickening of the aortic wall [61,75,76]. Skin
tissue sections from patients with HGPS have shown that progerin accumulates primarily
in the nuclei of vascular cells, suggesting that its accumulation has a direct association with
vascular diseases in progeria [19]. Similarly, several reports have suggested that progerin
in vascular muscles could accelerate atherosclerosis by inducing endoplasmic reticulum
(ER) stress, DNA damage, wound healing impairment, mislocalization of a myocardin-
related transcription factor, and replication stress [77–81]. Recently, Hamczyk et al. (2018)
produced the first mouse model (Apoe–/– LmnaLCS/LCS SM22αCre) with progerin-induced
atherosclerosis acceleration expressing progerin specifically in VSMCs and demonstrated
Cells 2023, 12, 2299 6 of 17

that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis,

trigger plaque vulnerability, and reduce lifespan [66]. Moreover, they succeeded in develop-
ing CRISPR-Cas9 technology to generate HGPSrev mice (LmnaHGPSrev/HGPSrev ), engineered
to express progerin throughout the body while lacking lamin A and allowing progerin
suppression and the restoration of lamin A in a temporal and cell-type-specific manner
upon Cre recombinase activation. Regardless of the broad expression of progerin and
its pathological effects in several organs, restricting its suppression to VSMCs and car-
diomyocytes is adequate to ameliorate vascular diseases and extend the lifespan of mouse
models [82].
Progerin accumulation is associated with fat tissue disorders [83–85] and its expression
decreases the capacity for adipocyte differentiation in both iPSCs and human mesenchymal
stem cells (hMSCs) derived from patients with HGPS [57,86]. Mateos et al. [87] performed
quantitative proteomics to study the effect of progerin accumulation in a preadipocyte
cell line, 3T3L1 cells. They reported that progerin accumulation in adipocytes contributed
to the generation of reactive oxygen species and premature aging features, establishing a
relationship between mitochondrial malfunction and proteostasis failure in HGPS [87].
Patients with HGPS exhibit unique skeletal dysplasia with bone morphological abnor-
malities and short stature. The HGPS mouse model (homozygous transgenic G608G BAC)
also shows a similar bone structure pattern [88–90]. The cartilage abnormalities observed
in this HGPS mouse model were similar to those observed in age-matched WT controls,
including the premature loss of glycosaminoglycans and decreased cartilage thickness
and volume. These alterations may mimic degenerative joint diseases prevalent in the
elderly [89]. The Zmpste24−/− HGPS and progeria mouse model showed the development
of kyphosis and spontaneous bone fractures in multiple locations [91]. More recently, the
LmnaG609G/G609G mouse model exhibited joint immobility and skeletal deformities in the
vertebral column and skull [90].
Several studies have examined the relationship between progerin and inflammatory
responses [92,93]. Endothelial cells expressing progerin recapitulate some characteristics of
aging-associated cell dysfunction, including pro-inflammatory features, oxidative stress,
DNA damage, increased expression of cell cycle arrest proteins, and cellular senescence [92].
Using HGPS fibroblasts, it was shown that progerin-induced replication stress causes ge-
nomic instability by stalling the replication fork and nuclease-mediated degradation, along
with the upregulation of the cGAS/STING cytosolic DNA sensing pathway and the ac-
tivation of a robust STAT1-regulated interferon (IFN)-like inflammatory response [93].
Hamczyk et al. (2018) also showed that exogenously expressed progerin increased inflam-
mation [66]. A significant correlation was observed between chronic inflammation and
ZMPSTE24 levels. Additionally, patients with cardiovascular diseases showed abnormal
lamin A/C expression associated with progerin levels [94]. The pro-atherogenic role of
progerin in HGPS-related early atherosclerosis was proposed by Bidault et al. [92]. They
found that progerin overexpression increased the expression of pro-inflammatory cytokines
IL-6 and IL-1β, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion
molecule-1 (VCAM-1), enhancing inflammation along with oxidative stress [92]. González-
Dominguez et al. (2021) recently suggested that progerin was responsible for the activation
of the NLRP3 inflammasome [95], which is a multiprotein complex having an intracellular
sensor comprising NLRP3 itself, the adapter protein ASC, and the catalytic subunit (Cas-
pase 1), which cleaves pro IL-1β to the mature IL-1β. Furthermore, it was revealed that the
activation was associated with alterations in nuclear morphology, indicating its relation to
the induction of IL-1β by progerin [92,95].
Here, we discuss the pathologies caused by progerin and its possible link to aging
in normal individuals without mutations in the LMNA gene. Considerable evidence
reveals that a reduction in progerin in cells leads to a reduction in pathology. In the
following two sections, we discuss various attempts to directly or indirectly target progerin
to achieve therapeutic benefits for HGPS and address the challenges of translating them
into clinical trials.
Cells 2023, 12, 2299 7 of 17

4. Targeting and Inhibiting Progerin at mRNA and DNA Level

Cellular progerin levels are correlated with the severity of the premature aging pheno-
type. Approximately 20 years ago, the specific knockdown of progerin mRNA by RNA
interference was shown to alleviate cellular aging features [96,97]. Short hairpin RNA
constructs were designed to target progerin mRNA and mutate pre-spliced LMNA mR-
NAs with 1824 C->T mutations. The expression of shRNA using lentiviruses significantly
decreased progerin expression and in turn led to the improvement of the abnormal nu-
clear morphology, the recovery of proliferative potential, and a reduction in senescent
cells [96,97]. These findings justify the potential use of gene therapy for HGPS treatment.
Antisense oligonucleotide (ASO)-based therapies are promising strategies for the
treatment of various diseases by blocking the expression of the target gene at the mRNA
level through binding, followed by inactivation of the specific RNA by steric blockade
or by promoting RNA degradation to specific sites on the mRNA [98,99]. The first ASO
treatment in HGPS was tested in vitro by transfecting fibroblasts from patients with HGPS
with an ASO targeting the progerin mRNA sequence. This approach effectively reduced
progerin expression and ameliorated progerin-induced phenotypes [100]. In subsequent
studies using several types of ASOs, similar results were obtained with fibroblasts from
patients with HGPS [65,101,102] and from HGPS-like patients containing non-classical
LMNA mutations that can induce progerin expression [103]. However, these studies
revealed that progerin-targeting ASOs also decrease endogenous lamin A levels, raising
concerns about the probable risk of lamin A depletion in vivo. However, mice lacking lamin
A but maintaining lamin C expression showed no apparent phenotypes when compared to
wild-type controls [65,104], encouraging researchers to test the potential of ASOs to reduce
progerin levels in vivo. Another study showed that aortic progerin levels were reduced by
approximately 50% in LmnaG609G/G609G mice treated with ASOs selected through an in vitro
approach that targeted a 70-nucleotide region located upstream of the mutation that causes
HGPS. This treatment alleviated the HGPS-associated vascular phenotype by reducing
the loss of SMCs and early fibrosis; however, no longevity data have been reported [101].
Two recent studies demonstrated the promising efficacy of the ASO-dependent inhibition
of progerin expression in homozygous transgenic G608G BAC mice [105,106], an HGPS
mouse model that encodes human progerin and lamins A/C in addition to endogenous
mouse lamins A/C [64]. The main advantage of this model over the LmnaG609G/G609G
mice is that the candidate ASOs have greater translational potential because they target
the human (not mouse) LMNA gene. The top candidates were selected based on their
ability to reduce progerin and lamin A levels without reducing lamin C expression both
in vitro and in vivo. Weekly treatment of asymptomatic two-to-six-day-old to one-week-
old BAC mice with selected ASOs significantly reduced progerin mRNA levels in many
tissues; however, the reduction in progerin protein levels was less pronounced [105,106],
similar to the results obtained in LmnaG609G/G609G mice [65], raising concerns about the
high stability of protein levels and the need for inhibitors that efficiently reduce progerin
expression. In two studies, ASO treatment was shown to increase the lifespan of BAC
mice by 35–60% [105,106]; however, in one study, it was shown to partially prevent SMC
loss and early thickening of the ascending aorta, two key features of the HGPS vascular
phenotype [106]. The use of oligonucleotides to manipulate protein production has become
an important therapeutic strategy in treating genetic diseases and cancer; however, the
development of chemically modified nucleic acids, bio-conjugation to escort the moiety,
and the formulation of nanoparticle carriers are required for the delivery of oligonucleotide
drugs [107]. Although these technological advances have led to the clinical approval of
several ASO drugs, efficient and targeted delivery remains a major challenge for HGPS, in
which the causative protein is expressed throughout the body and progressively affects
tissues and organs.
Although ASOs have proven useful in mouse models (transgenic human G608G BAC
mice) of HGPS, these models require continuous administration and do not eliminate the
cause of the disease. Additionally, the treated animals die prematurely from HGPS. Consid-
Cells 2023, 12, 2299 8 of 17

ering the currently available information, adenine base editors (ABEs) appear to be more
advantageous than CRISPR/Cas9 approaches because they do not induce double-stranded
DNA breaks, inhibit lamin A, or efficiently correct mutations that cause HGPS. Furthermore,
it prevents HGPS-associated vascular features and extends the lifespan more than any other
tested treatment [108]. Recently, the transient expression of an ABE and single-guide RNA
using MS2 bacteriophage-lentivirus chimeric particles corrected the mutation in 20.8–24.1%
of skin cells in an HGPS mouse model (human tetop-LAG608G minigene), indicating
that it could be a good approach for future gene-editing therapies [109]. However, two
major challenges limit their application: moderate editing efficiency and the off-target
mutagenesis of DNA and RNA. Further pre-clinical studies are required to improve the
safety and effectiveness of ABE-based therapies by enhancing their efficiency, optimizing
vectors, fine-tuning doses, and defining the optimal treatment duration to achieve the best
outcomes for patients before moving to clinical trials.

5. Treatments and Clinical Trials for HGPS

Several efforts have been made to efficiently treat HGPS using mouse models and cell
lines from human patients. Treatment with the mTOR inhibitor rapamycin abolishes nu-
clear hemorrhage, delays cellular senescence, and enhances progerin degradation in HGPS
cells via autophagic mechanisms [33,110]. Endogenous neuropeptide Y (NPY) increases
caloric-restriction-induced autophagy in the hypothalamus, suggesting that NPY alleviates
some features of cellular senescence in HGPS cells [111]. To restore impaired proteostasis
in HGPS, the cells were treated with sulforaphane (SFN), an antioxidant derived from cru-
ciferous vegetables, which increases the degradation of progerin by enhancing autophagic
activity and reversing the premature aging features of HGPS cells [112,113]. The balance
between type A lamins has been reported to be regulated by the RNA-binding protein
SRSF1; therefore, one group hypothesized that the inhibition of this protein could have a
therapeutic effect on HGPS and evaluated the antidiabetic drug metformin to propose a
new approach to treat HGPS that could be added to the therapies currently analyzed [114].
The proteasome inhibitor MG132 was found to induce progerin clearance in classic HGPS
by activating autophagy and regulating splicing [115]. Additionally, it was able to induce
aberrant prelamin A clearance and improve cellular phenotypes in HGPS-like patient cells
beyond those previously described in classic HGPS, providing pre-clinical evidence for a
potential treatment for children with HGPS-like or classic HGPS using a promising class of
molecules [116]. Recently, Zhang and colleagues found that BUBR1, a core component of
the spindle assembly checkpoint, was suppressed during HGPS cellular senescence, and
the remaining BUBR1 was engaged in the nuclear membrane by binding to the C-terminus
of progerin, thereby limiting the function of BUBR1. Based on this, they created a unique
progerin C-terminal peptide (UPCP) that efficiently blocked the binding of progerin to
BUBR1 and interfered with the interaction of PTBP1 with progerin to promote the expres-
sion of BUBR1. UPCP significantly inhibited HGPS cell senescence and improved the
progeroid phenotype in an HGPS mouse model (LmnaG609G/G609G ) [117].
Several studies have reported the role of inflammatory molecules in progeria and the
efficacy of therapies aimed at counteracting the pro-inflammatory state of HGPS [92,93,118].
Treatment of HGPS fibroblasts with MnTBAP/baricitinib (bar) combination therapy sustained
the positive effects of bar, enhancing mitochondrial function and decreasing the levels of
progerin and inflammatory factors (superoxide dismutase mimetic, MnTBAP, and JAK1/2
inhibitor, bar). Overall, co-treatment with MnTBAP/bar alleviated the abnormal phenotype
of HGPS fibroblasts, making it a promising therapeutic strategy for patients with HGPS [118].
HGPS cells exhibited enhanced nuclear protein export activity due to the progerin-driven
overexpression of chromosomal region maintenance 1 (CRM1). Pharmacologically inhibiting
CRM1 with Leptomycin B mitigates the senescent phenotype of HGPS cells [119]. High levels
of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with age-related processes,
have been observed in HGPS cells and mouse models (LmnaG609G/G609G ). The blockade of
IL-6 activity by tocilizumab, a specific antibody against the IL-6 receptor, reversed premature
Cells 2023, 12, 2299 9 of 17

aging features in both HGPS fibroblasts and model mice [120]. Pharmacological inhibition
of the NLRP3 inflammasome by the selective inhibitor MCC950 led to an improvement in
the cellular phenotype, a significant extension of lifespan in a mouse model (Zmpste24−/− ),
and a reduction in inflammasome-dependent inflammation [95]. MG132 was able to reduce
the TNF-α-induced inflammatory cytokine secretion of IL-1β, Il-6, TNF-α, IFN-γ, and TGF-β
in HGPS-like patient cells [116]. Several in vitro and in vivo studies have been conducted
to ameliorate bone and adipose tissue conditions in progeria. A mouse model (transgenic
mice, tetop-LAG608G+; Sp7-tTA+) with the osteoblast-and osteocyte-inducible expression
of progerin [121] was used to investigate the recovery from HGPS bone abnormalities by
silencing the mutation and the beneficial effect of treatment with resveratrol. Complete
silencing of the transgenic progerin expression normalized the bone morphology and min-
eralization, including improvements in the frequency of rib fractures and callus formation,
an increased number of osteocytes, and normalized dentinogenesis. However, despite these
positive findings, resveratrol treatment showed no beneficial effects [122]. Using an HGPS
mouse model (transgenic G608G BAC), Cubria et al. (2020) showed that treatment with
pravastatin and zoledronic acid significantly improved bone structure, mechanical properties,
and cartilage structure parameters, thereby improving the musculoskeletal phenotype of
the disease [89]. Progerin accumulation and high paracrine activation in adipocyte tissue
caused chronic inflammation and cellular senescence in a tetop-LAG608G+ mouse model. The
pro-inflammatory cytokines IL-1α, IL-1β, IL-6, IL-17α, interferon gamma (IFNγ), and TNF-α
were significantly higher than in controls [123]. Additionally, the loss of fat and fat deposits
has been observed in LmnaG609G/G609G mice [65,124]. Hartinger et al. [125] tested the effects
of bar (a JAK1/2 inhibitor and an anti-inflammatory agent) and a combination of bar and lon-
afarnib (a farnesyltransferase inhibitor) on adipogenesis using skin-derived precursors (SKPs).
Compared to mock-treated HGPS SKPs, bar and the combination of bar and lonafarnib treat-
ments improved the differentiation of HGPS SKPs into adipocytes and lipid droplet formation,
demonstrating the beneficial effect of combination treatment on adipogenesis in HGPS and
other lipodystrophies [125]. Recently, HGPS-associated vascular pathological features were
recovered by CRISPR/dCas9-activated Oct4 expression, which extended the lifespan of a
mouse model (transgenic G608G BAC) [126]. The miR-59 was markedly upregulated in HGPS
patient cells and multiple tissues in an HGPS mouse model (LmnaG609G/G609G ). Treatment
with AAV9-mediated anti-miR-59 reduced fibrosis in several organisms, alleviated epidermal
thinning and dermal fat loss, and extended the longevity of mouse models [53]. The efforts
discussed in this section for efficient HGPS treatment are summarized in Table 1.

Table 1. The list of the various treatments for HGPS.

Treatments Targets Action Study Design Refs

(Cell or Animal Model)
Rapamycin mTOR Autophagic induction HGPS fibroblasts [33,110]
SFN (antioxidant derived from
cruciferous vegetables) stimulates HGPS fibroblasts,
Sulforaphane (SFN) Free radicals proteasome activity and autophagy Human nucleus pulposus cells, [112,113]
in normal and HGPS LmnaG609G/G609G mice
fibroblast cultures
A-type lamins is controlled by HGPS mesenchymal stem cells,
serine/arginine-rich splicing SRSF1. SRSF1 expression is
Metformin HGPS fibroblasts, [114]
factor 1 (SRSF1) transcriptionally regulated by the
antidiabetic drug metformin. LmnaG609G/G609G fibroblasts

Zoledronic acid prevents

hydroxymethylglutaryl-CoA bone fractures
Pravastatin and Zoledronic Pravastatin is used for treating high Transgenic G608G BAC mice
(HMG-CoA) reductase [89]
acid
/bone resorption cholesterol and preventing heart
attacks and strokes
NPY mediates caloric
Neuropeptide Y Autophagy HGPS fibroblasts [111]
restriction-induced autophagy
Autophagic activation after the loss HGPS fibroblasts,
of proteasomal activity. LmnaG609G/G609G mouse,
MG132 Proteasome 26S [115,116]
Downregulation of SRSF1 and HGPS-like fibroblasts,
reduction of inflammatory cytokines MAD-B syndrome fibroblasts
Unique Progerin C-terminal UPCP blocks the binding between HGPS fibroblasts,
Progerin-BUBR1 [117]
peptide (UPCP) Progerin and BUBR1 LmnaG609G/G609G mouse
Cells 2023, 12, 2299 10 of 17

Table 1. Cont.

Treatments Targets Action Study Design Refs

(Cell or Animal Model)
HGPS fibroblast,
Non-farnesylated prelamin A
Zmpste24−/− fibroblast,
Lonafarnib Farnesyltransferase production by inhibition of Transgenic G608G BAC mice [119,127–129]
farnesyltransferase activity
Zmpste24−/− mice
HGPS fibroblasts,
The small molecule specifically WRN fibroblasts and
Progerinin
Progerin bindsto Progerin and induces cardiomyocytes, [59,96,124]
(SLC-D011)
its degradation
LMNAG609G/G609G mice
Inhibition of peroxynitrite-
Peroxynitrite induced oxidative reactions
MnTBAP and Baricitinib HGPS fibroblasts [118]
/Janus kinase /anti-inflammatory action by
JAK1/2 inhibitor
Immunosuppression by HGPS fibroblasts,
Tocilizumab IL-6 [120]
anti-IL-6 antibody LmnaG609G/G609G mouse
Inhibition of peroxynitrite-induced
HGPS fibroblasts,
Janus kinase oxidative reactions FPLD2 syndrome fibroblasts,
Baricitinib and lonafarnib [125]
/Farnesyltransferase /anti-inflammatory action by
MAD-B syndrome fibroblasts
JAK1/2 inhibitor
AAV9-mediated miR-59 inhibition HGPS fibroblasts,
Anti-miR-59 microRNA-59 [53]
by antisense oligonucleotide LmnaG609G/G609G mouse
HGPS fibroblast,
Inflammasome inactivation by
MCC950 NLRP3 Zmpste24−/− mice, [95]
NLRP3 inhibition
LMNAG609G/G609G mice

In addition to these experimental studies on the treatment of HGPS, several clinical

trials have been conducted (Table 2). Eiger BioPharmaceuticals developed orally active lon-
afarnib (Zokinvy™), a farnesyltransferase inhibitor, under a license from Merck & Co. [130].
The drug was initially discovered by Merck & Co. as an investigational drug for cancer;
however, its development was discontinued owing to its lack of efficacy [130]. In HGPS
cells, the drug inhibits farnesyltransferase activity and blocks the subsequent aggregation
of progerin and progerin-like proteins in the nucleus and cellular cytoskeleton [127,131].
However, in in vitro experiments, lonafarnib showed cytotoxic effects, leading to the for-
mation of donut-shaped nuclei [132] and cell death [133,134]. After 20 years of basic and
clinical research and multiple clinical trials [128,129,135], the FDA recently approved lon-
afarnib (20 November 2020, in the USA) as the first drug to treat HGPS (NCT00425607).
This represents an important milestone because children with progeria can be treated with
medications that improve their vascular phenotypes and extend their life expectancy. How-
ever, much work remains to be done to improve the quality of life, increase life expectancy,
and ultimately cure patients with HGPS.

Table 2. The list of the clinical trials for HGPS and related progeria up to date.

Clinical Trials Drugs Stage Number of First Posted (Year)

Study Type Status or Main Finding
NCT# Individuals /Recruiting Status
2007 Found life span extension
NCT00425607 Lonafarnib Phase II 29 Interventional /complete (about 1.6 years)
Found the reduction of the
Zoledronate and 2008 alternative prenylation induced
NCT00731016 Phase II 15 Interventional
pravastatin /complete
by Lonafarnib
Zoledronate, No additional improvement of
pravastatin, and 2009
NCT00879034 Phase II 5 Interventional the tri-therapy as compared to
/complete
Lonafarnib lonafarnib alone
Zoledronate,
pravastatin, and 2009 Optimizing the efficient
NCT00916747 Phase II 85 Interventional /active tri-therapy combination
Lonafarnib
2015 Defining Maximum-tolerated
NCT02579044 Everolimus and 80 /Enrolling by
Phase I/II Interventional dose (MTD) of everolimus &
Lonafarnib invitation efficacy of combination
No safety concerns with the
2020 Progerinin at all testing doses
NCT04512963 Progerinin Phase I 64 Interventional /complete and food conditions (up to the
maximum dose of 2400 mg)
Cells 2023, 12, 2299 11 of 17

After the identification of the effects of zoledronate and pravastatin, a second clinical
trial was initiated using these two drugs (NCT00731016), followed by a tri-therapy clinical
trial combining lonafarnib, zoledronate, and pravastatin (NCT00879034 and NCT00916747).
Despite the lack of additional improvements in the tri-therapy compared to lonafarnib
alone, as reported in the results of the last clinical trial [136], researchers continued their
efforts to find the optimal conditions for the tri-therapy combination.
Targeting the farnesylation and methylation of progerin with chemical inhibitors
ameliorates some progerin-induced changes, but several questions persist concerning
the underlying mechanisms. All tested strategies aimed at inhibiting isoprenylcysteine
carboxyl-methyltransferase (ICMT) improved progeroid features. However, genetic inac-
tivation and treatment with a target inhibitor (C75) appeared to increase progerin levels
in cells [137]. The main disadvantage of blocking FTase and ICMT to treat HGPS is that
these endogenous enzymes target several other proteins in addition to progerin. Therefore,
changes in homeostatic farnesylation and methylation following FTase and ICMT inhibition
may have deleterious side effects that partially offset the positive outcome of reducing
the progerin-induced disease. The impact of mTOR signaling downstream of AKT should
also be assessed, as mTOR haploinsufficiency extends the lifespan of the HGPS mouse
model (transgenic G608G BAC) [138]. Lonafarnib and everolimus reduced pathology in an
iPSC-derived tissue-engineered blood vessel model [139]. Furthermore, the combination
of ICMT-targeting drugs with mTOR inhibitors such as everolimus, which are currently
being tested in HGPS trials alongside lonafarnib (NCT02579044), has the potential to yield
further positive effects.
Park et al. developed treatment strategies that targeted progerin more specifically us-
ing progerinin (or SLC-D011), an inhibitor drug that directly targets progerin, induces its
degradation, and finally disrupts the interaction between progerin and lamin A. The oral ad-
ministration of progerinin to an HGPS mouse model (LmnaG609G/G609G ) increased its lifespan
by approximately 50% [59,96,124]. Before studies on diseased states, randomized, double-
blind, placebo-controlled, single ascending dose (SAD) studies including food interactions
were conducted. This was followed by multiple ascending dose (MAD) studies to evaluate the
safety, tolerability, pharmacokinetics, and pharmacodynamic profiles of progerinin (SLC-D011)
in healthy volunteers (NCT04512963). To the best of our knowledge, this is the first in-human
study of progerinin. Additionally, progerinin had an excellent safety profile across all tested
doses or food conditions (up to a maximum dose of 2400 mg). The study subjects in the phase
I trial tolerated the drug well and confirmed an increase in exposure to progerinin under
different food conditions, with fasting showing the least exposure, followed by low-fat and
high-fat. The final enrollment included 63 healthy volunteers, with 47 subjects in the SAD
phase and 16 subjects in the MAD phase, at one site in the USA. The drug–drug interaction
potential was not clinically significant; therefore, dose adjustment was not necessary because
a phase I, open-labeled, fixed-sequence study was safely completed to assess the effects of a
CYP3A4 inhibitor (itraconazole) and a CYP3A4 inducer (phenytoin ER) on the single-dose
pharmacokinetics of progerinin in healthy volunteers.

6. Concluding Remarks
In this review, we introduce progerin as a pathogenic factor that induces HGPS
(Figure 1) and provide relevant evidence in support of this. Multiple efforts to understand
the causes of HGPS and develop treatments and clinical studies have been described; how-
ever, not all researchers’ contributions were included in this short review (Tables 1 and 2).
We might suggest that genome editing is the best option for the treatment of monogenic
diseases. However, for systemic diseases such as HGPS, there are at least two requirements:
(i) the delivery of the system to every cell in the body, and (ii) the demonstration of the
absence of off-target effects in all cells. Furthermore, there is an indispensable need to
strengthen the regulation of genotoxicity with regard to gene therapy in pediatric diseases.
Finally, we believe that it is appropriate to expedite efficacy-based approvals for patients
suffering from HGPS, as long as no toxicity risks are raised. We look forward to the upcom-
Cells 2023, 12, 2299 12 of 17

ing clinical trials for HGPS and progeroid laminopathies and hope to learn more about the
relationship between progerin and aging.

Author Contributions: Conceptualization, B.-H.K. and B.-J.P.; investigation, B.-H.K., Y.-H.C., T.-G.W.,
S.-M.K. and S.P.; writing—original draft preparation, B.-H.K.; writing—review and editing, Y.-H.C.,
T.-G.W., S.-M.K. and S.P.; supervision, B.-J.P. All authors have read and agreed to the published
version of the manuscript.
Funding: This work was supported by the Progeria Research Foundation (Grant #PRF 2019-75), a
National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-
2020R1A4A1019322), and the 2023 Regional Industry-Linked University Open-Lab Development
Support Program through the Commercialization Promotion Agency for R&D Outcomes (COMPA)
funded by the Ministry of Science and ICT (2023openlab(RnD)_02) to B.-J.P.
Conflicts of Interest: Bae-Hoon Kim, Yeon-Ho Chung, Tae-Gyun Woo, and Bum-Joon Park are
employees of PRG S&T Co., Ltd.

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