An overview of treatment strategies for Hutchinson-Gilford Progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS.

Keywords: AON; FTI; HGPS; MG132; Metformin; Progerin; Rapamycin; ZOPRA.

Figure 1.

Specificity of a wide spectrum of treatment strategies for progeria. Several therapeutic strategies for progeria are shown. In decreasing order for their target specificity, treatment strategies can be mentioned as follows: the mutation-causing disease repair by genome editing (CRISPR as a future possibility to be evaluated), the inhibition of pre-mRNA aberrant splicing (Antisense OligoNucleotides: AONs, Metformin, MG132), the reduction of isoprenylated and methylated progerin levels (Farnesyl transferase inhibitors: FTIs, ZOledronate-PRAvastatin: ZOPRA, Monoaminopyrimidines: Mono-APs, Isoprenylcysteine CarboxyMethyl Transferase (ICMT) inhibitor, GeranylGeranylTransferase Inhibitor: GGTI-2147), the induction of progerin clearance (Rapamycin, Sulforaphane, Retinoids, MG132) and the reduction of the noxious downstream effects due to progerin accumulation (Rock inhibitor: Y-27632, Nuclear factor erythroid-2-Related Factor 2: NRF2 reactivation, Methylene blue, sodium salicylate, DOT1L inhibitor: epz-4777, Remodelin, Vitamin D, Resveratrol, N-Acetyl-Cysteine: NAC, inorganic pyrophosphate: PPi and JH4).

Figure 2.

Treatment strategies for progeria and their targets. Envisaged treatments for progeria target several mechanisms triggering the disease. By acting on the genetic cause, recent advances in genome editing using the CRISPR technique could be beneficial to repair the mutation causing the disease. Other molecules target the aberrant splicing process leading to the production of a truncated protein, by blocking the splice site with AONs or by inhibiting the splicing factor SRSF-1 (Metformin, MG132). During prelamin A maturation, treatments inhibiting isoprenylation (farnesylation or geranylation) or the methylation have shown their effectiveness in reducing progerin toxicity (Statins, aminobisphonates, FTIs, GGTI-2147, monoaminopyrimidines, shICMT). To counter the accumulation of progerin, several molecules have been described as activators of autophagy leading to progerin degradation (Rapamycin, Sulphoraphane, Retinoids and MG132). Finally, by acting on the reduction of the noxious downstream effects of progerin, some approaches have shown their effectiveness against inflammation (sodium salicylate, DOT1L inhibition by epz-4777), oxidative stress (NAC, NRF2 reactivation), nuclear shape abnormalities (Remodelin), mitochondrial abnormalities (Rock inhibitor: Y-27632, Methylene blue), impaired pyrophosphate metabolism (inorganic pyrophosphate: PPi), vitamin D receptor signaling (vitamin D), decreased deacetylase activity (Resveratrol), Progerin/Lamin AC interaction (JH4) or aging hallmarks by reprogramming HGPS cells to pluripotency in vitro and in vivo.