Broad brain biodistribution conferred by an AAV to restore TDP-43 function mitigates Frontotemporal Demenia-like deficits.

ABSTRACT: TDP-43 dysfunction is an early pathogenic determinant of frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), a devastating disorder currently without effective therapy. Here, we exploit a blood-brain-barrier (BBB)-permeable AAV (AAV-PHP.eB) that confers broad brain biodistribution to restore TDP-43 function in a TDP-43 deficient model (CamKIIa-CreER;Tardbp mice) that mimics the early stage of TDP-43 dysfunction occurring in FTLD-TDP. Intracerebroventricular delivery by AAV-PHP.eB of CTR, our previously characterized splicing repressor, revealed its accumulation in ~40% of adult hippocampal neurons. Remarkably, treatment of adult CamKIIa-CreER;Tardbp ^f/f mice with AAV-PHP.eB-CTR restored TDP-43 function, attenuated neuronal aberrant activity a

SUBMITTER: Cao T 

PROVIDER: S-EPMC12424654 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature