Neutralization of Pathogenic PC-OxPL by AAV-Delivered scFv as a Therapeutic Strategy for Amyotrophic Lateral Sclerosis

We identify a distinct signature of oxidized phosphatidylcholines (PC‑OxPL) in the cerebrospinal fluid (CSF) of sporadic ALS (sALS) patients and show that APOE-containing particles are their main carriers. In human iPSC‑derived motor neurons, PC‑OxPL induces disease‑related transcriptional changes and TDP‑43 pathology, establishing it as a driver of ALS‑like neurodegeneration in vitro.

To counteract this toxicity, we engineered PC‑OxPL‑VecTab®, an AAV‑delivered single‑chain antibody fragment that targets PC‑OxPL neoepitopes. PC‑OxPL‑VecTab® neutralizes PC‑OxPL–induced neurotoxicity, reduces TDP‑43 aggregation, and prevents motor neuron loss and behavioral deficits in an sALS CSF transfer mouse model. Intrathecal delivery in minipigs achieved broad motor neuron transduction at therapeutic levels, supporting translational potential.