Genetics
A single dose of lipid-nanoparticle-delivered TALEN mRNA cuts Lp(a) by over 80% for at least five weeks in transgenic mice (Mol Ther 2025)
Original title: Lipid nanoparticle delivery of TALEN mRNA targeting LPA causes gene disruption and plasma lipoprotein(a) reduction in transgenic mice
Researchers designed transcription activator-like effector nuclease (TALEN) mRNAs to disrupt the human LPA gene as a permanent, single-dose alternative to repeat-dosed Lp(a)-lowering drugs. After screening TALEN mRNAs in vitro for on-target editing and minimal off-target effects, the lead candidates were encapsulated in the LUNAR lipid nanoparticle and given as a single dose to transgenic mice expressing a human LPA transgene. Plasma Lp(a) fell by more than 80%, an effect sustained for at least five weeks, and both standard and long-read next-generation sequencing confirmed gene-inactivating deletions at the LPA transgene loci. This proof-of-concept establishes TALEN-mediated gene editing as a feasible route to permanent Lp(a) reduction, distinct from the antisense and siRNA approaches now in clinical trials, though it remains at the preclinical mouse stage.
Original abstract
Lipoprotein(a), or Lp(a), is encoded by the LPA gene and is a causal genetic risk factor for cardiovascular disease. Individuals with high Lp(a) are at risk for cardiovascular morbidity and are refractory to standard lipid-lowering agents. Lp(a)-lowering therapies currently in clinical development require repetitive dosing, while a gene editing approach presents an opportunity for a single-dose treatment. In this study, mRNAs encoding transcription activator-like effector nucleases (TALENs) were designed to target human LPA for gene disruption and permanent Lp(a) reduction. TALEN mRNAs were screened in vitro and found to cause on-target gene editing and target protein reduction with minimal off-target editing. TALEN mRNAs were then encapsulated with LUNAR, a proprietary lipid nanoparticle (LNP), and administered to transgenic mice that expressed a human LPA transgene. A single dose of TALEN mRNA-LNPs reduced plasma Lp(a) levels in mice by over 80%, which was sustained for at least 5 weeks. Moreover, both standard and long-read next-generation sequencing confirmed the presence of gene-inactivating deletions at LPA transgene loci. Overall, this study serves as a proof-of-concept for using TALEN-mediated gene editing to disrupt LPA in vivo, paving the way for the development of a feasible gene editing therapy for patients with high Lp(a).
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.