NM_170707.4(LMNA):c.475G>T (p.Glu159Ter)

Adenine base editing (ABE) has demonstrated transformative preclinical results in Hutchinson-Gilford progeria syndrome by correcting the canonical LMNA c.1824C>T mutation in mouse models. This proof-of-concept raises the question of whether ABE or other base editors could be adapted for additional pathogenic LMNA variants, including nonsense mutations like c.475G>T (p.Glu159Ter). While the canonical progeria ABE strategy targeted a specific C-to-T transition amenable to ABE correction, nonsense mutations present different editing requirements that may necessitate alternative base editing or prime editing strategies.

Koblan et al. (Nature 2021; PMID: 33408413) demonstrated that a single intravenous injection of AAV9-delivered ABE in a mouse model of HGPS corrected the pathogenic c.1824C>T variant in multiple organs, dramatically extending lifespan and improving vascular pathology. Whisenant et al. (Nat Commun 2022; PMID: 35654881) showed that transient ABE expression was sufficient to correct the mutation and improve skin phenotype, suggesting that permanent genomic integration of the editor may not be necessary. An editorial in NEJM (Kim & Eriksson 2021; PMID: 33826825) highlighted the broader implications of base editing for progeroid syndromes. The p.Glu159Ter variant (ClinVar: 694069) introduces a premature stop codon in exon 3 of LMNA via a G>T transversion. Unlike the classic progeria C>T transition correctable by ABE (A·T to G·C), reversing a G>T transversion would require either a cytosine base editor (CBE) to convert the complementary C·A back to C·G on the antisense strand, or prime editing to directly install the correct sequence. Both approaches have shown improving precision and delivery efficiency in recent years.

No preclinical or clinical data exist for base editing of the specific p.Glu159Ter variant. The proven ABE strategy for canonical HGPS cannot be directly applied to this nonsense mutation due to the different base change required. CBE and prime editing, while theoretically applicable, have different off-target profiles and editing efficiencies compared to ABE. Systemic AAV9 delivery raises concerns about immunogenicity and dose-dependent hepatotoxicity observed in other AAV gene therapy programs. LMNA is expressed in virtually all differentiated somatic cells, creating a challenge for achieving sufficient editing efficiency across all relevant tissues. The extreme rarity of individual LMNA variants makes clinical trial design for variant-specific therapies highly challenging.