The disease is caused by a de novo heterozygous dominant mutation in the LMNA gene (encoding nuclear A-type lamins), most frequently the single base substitution c.1824C>T (p.Gly608Gly) (“classic HGPS”, in ~90% of patients). This synonymous mutation activates an alternative splice donor site in LMNA exon 11, which produces an aberrant mRNA lacking 150 nucleotides (LMNAΔ150) that translates into a truncated version of prelamin A called progerin. The C-terminal end of progerin lacks the cleavage site for the endoprotease ZMPSTE24; therefore, progerin remains irreversibly farnesylated and methylated and exerts a dominant-negative damaging effect. Progerin accumulation causes multiple alterations in cells, including aberrant nuclear morphology, severe heterochromatin loss, mislocalization and loss of chromatin-associated proteins and DNA damage repair proteins, and telomere and mitochondrial dysfunction, among other alterations, which ultimately cause cell senescence and eventually cell death.
Lonafarnib has been estimated to extend the lifespan of HGPS patients by 2.5 years (17% increase), and has been approved by the US Food and Drug Administration and the European Medicines Agency (commercialized as Zokinvy) for the treatment of HGPS and other progeroid laminopathies. Other therapeutic approaches such as gene-editing to correct the HGPS-causing mutation and antisense oligonucleotide delivery to block pathogenic splicing of mutant LMNA transcripts, are still subject to many limitations that must be addressed to ensure safe and efficient clinical translation.
For reasons that remain unknown and unpredictable, HGPS progression shows high inter-individual variability (eg, lifespan in HGPS patients ranges from 6 to 20 years). HGPS stage and progression and patient responses to treatment are currently gauged from evaluating clinical manifestations, but there is a lack of clinically meaningful shorter-term biomarkers that permit monitoring of disease progression after diagnosis or assessment of therapeutic success in treated patients. ProgerOmics seeks to fill this gap by identifying robust “circulating” biomarkers of HGPS prognosis that can give clinicians the information they need to
While previous studies have applied several high-throughput omics modalities in progerin-expressing animal models and human cells for the unbiased identification of disease biomarkers, these studies have not led to the incorporation of disease-progression biomarkers into clinical practice, largely due to the multifaceted cellular and molecular basis of HGPS and its complex clinical phenotype, which requires a holistic strategy that has not been implemented to date. Omics-based HGPS studies have generally been limited by the use of a single omics strategy and the analysis of a single tissue/cell type without considering distinct disease stages.
Multi-omics data along with cardiovascular phenotyping data will be integrated to identify robust biomarkers of HGPS presence and progression. The possible clinical use of these biomarkers will be assessed in a pilot study with plasma and PBMCs from HPGS patients. In case of validation, HGPS patients will be direct beneficiaries of the ProgerOmics results. Our studies are expected to lay the ground for improved monitoring of HGPS progression and therapeutic efficacy in clinical trials using circulating biomarkers, which will improve personalized medicine for patients.
