Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson–Gilford progeria syndrome

“…To understand the molecular mechanism and cellular pathophysiology of HGPS and the effects of drug treatment, mainly cell culture and animal model studies are conducted (Piekarowicz et al 2019;Vidak and Foisner 2016). For cell culture studies, mostly the tissues from HGPS patients (primary culture/cell lines) and mouse embryonic fibroblasts (MEFs) from progeroid mice are used (Piekarowicz et al 2019), and a number of markers based on the phenotype of HGPS cells are observed.…”

“…To understand the molecular mechanism and cellular pathophysiology of HGPS and the effects of drug treatment, mainly cell culture and animal model studies are conducted (Piekarowicz et al 2019;Vidak and Foisner 2016). For cell culture studies, mostly the tissues from HGPS patients (primary culture/cell lines) and mouse embryonic fibroblasts (MEFs) from progeroid mice are used (Piekarowicz et al 2019), and a number of markers based on the phenotype of HGPS cells are observed. The biomarkers include nuclear blebbing, cellular senescence (measured by the status of βgalactosidase), progerin level, ratio of progerin to lamin A/C/B, mitochondrial function, nuclear trafficking, cellular proliferation, ROS (reactive oxygen species) generation and antioxidant status, epigenetic markers (viz.…”

“…H3K9me3), LAP2 (lamina-associated polypeptide) levels, DNA double strand breaks (γ-H2AX foci), intracellular signaling pathways (e.g., mTOR, ERK1-3, Akt, NF-κB pathways), etc. (Piekarowicz et al 2019). More than 200 cell lines are available now for the study of HGPS and progeroid laminopathies (Gordon 2019d).…”

Nucleus–cytoplasm cross‐talk in the aging brain

“…Additional typical features include cardiovascular disease and stroke, atherosclerosis, hip dislocations, and other abnormalities. Individuals with HGPS die of heart disease at an average age of 13 years, with a range of about 8 to 21 years (Piekarowicz, Machowska, Dzianisava, & Rzepecki, ; Ullrich & Gordon, ). Mutant lamins trigger nuclear lamina abnormalities, make the nuclear envelope unstable, and progressively damages the nucleus, in turn making cells more likely to die prematurely (Prokocimer, Barkan, & Gruenbaum, ).…”

Potential Benefits of Allogeneic Haploidentical Adipose Tissue-Derived Stromal Vascular Fraction in a Hutchinson–Gilford Progeria Syndrome Patient

“…In HGPS cells, however, the wild-type LMNA gene is also expressed. Thus, a combination of lamin A/C and progerin is detectable at the nuclear level, although the molecular reason for such a phenomenon is not well understood (Yang et al, 2008;Piekarowicz et al, 2019). Because of the laminopathy created by progerin, HGPS patients show growth retardation early in their childhood, along with other symptoms of physiological aging: loss of hair, skin thinning, joint rigidity, osteoporosis, and so on.…”