AI-driven therapeutic antisense oligonucleotide for processing-deficient progeroid laminopathies

Area of Science:

• Biochemistry
• Genetics
• Cardiovascular Biology

Background:

• Progeroid laminopathies (PLs), including Hutchinson-Gilford progeria syndrome (HGPS), are rare genetic disorders characterized by premature aging and early mortality, primarily due to cardiovascular complications.
• Antisense oligonucleotides (ASOs) show therapeutic potential for PLs, but optimal design and cardiovascular effects require further investigation.

Purpose of the Study:

• To develop an AI-driven pipeline for designing therapeutic antisense oligonucleotides (ASOs) targeting LMNA transcripts.
• To evaluate the efficacy and safety of ASO-mediated suppression of pathogenic lamin A isoforms in cellular and animal models of progeroid laminopathies.

Main Methods:

• An AI pipeline was used to design ASOs targeting the 3'UTR of LMNA transcripts.
• Candidate ASOs were tested in patient-derived induced pluripotent stem cell-derived cardiomyocytes (PL-iCMs), cardiac organoids, and LMNA transgenic mice.
• Efficacy, toxicity, and transcriptional responses were assessed via molecular, histological, and biochemical analyses.

Main Results:

• The optimized ASO, LM2556, selectively reduced pathogenic lamin A isoforms (progerin and farnesylated pre-lamin A) while preserving lamin C.
• LM2556 treatment mitigated cellular senescence and improved cardiac structure and function in vitro and in organoids.
• In vivo, LM2556 demonstrated safety (no hepatotoxicity or nephrotoxicity), ameliorated progeroid features, improved cardiovascular pathology, and extended median lifespan by 82.86% in LMNA transgenic mice.

Conclusions:

• An AI-based framework for therapeutic ASO design was established.
• Targeting the 3'UTR of LMNA transcripts with ASOs effectively suppresses pathogenic lamin A isoforms.
• This approach offers a proof-of-concept for treating systemic progeroid phenotypes and associated cardiovascular complications.