NIH Research Festival
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder that affects tissues of mesenchymal origin. Most HGPS individuals harbor a de novo c.1824C>T (p.G608G) mutation in the lamin A (LMNA) gene, which activates a cryptic splice donor site resulting in production of a toxic protein termed ‚Äúprogerin‚Äù. Clinical manifestations include growth deficiency, lipodystrophy, cardiovascular defects, and bone dysplasia. Currently lonafarnib, a farnesyltransferase inhibitor, is the only FDA-approved treatment. For development of new therapeutics, a reliable biomarker is needed to demonstrate qualitative or quantitative efficacy of disease progression or treatment response. We have developed a novel liquid biopsy approach to characterize phenotypic progression in two HGPS mouse models, as assessed by plasma concentration of cell-free DNA (cfDNA). With a High Sensitivity DNA chip, we observed elevations of cfDNA in heterozygous and homozygous HGPS mice compared to their age-matched counterparts. Digital droplet PCR (ddPCR) amplification targeting short and long interspersed retrotransposable elements (LINEs/SINEs) within cfDNA extracted from small plasma volumes greatly improved assay sensitivity and provided independent validation of cfDNA trends. Validation of cfDNA levels as a clinical biomarker for therapeutic response was achieved by demonstrating quantitative reductions in plasma LINE and SINE copy number up to 56% in 8-week mice treated in vivo with a locus-specific DNA base editor that corrects the mutation and partially rescues the HGPS phenotype. Thus, plasma cfDNA has the right properties to serve as a reliable biomarker for disease progression and treatment response in HGPS mouse models and can now be tested in human trial samples.
Scientific Focus Area: Cell Biology
This page was last updated on Monday, September 25, 2023