<i>SNCA</i>-targeted epigenome therapy for Parkinson's disease alleviates pathological and behavioral perturbations in a mouse model.

ABSTRACT: Alpha-synuclein (SNCA) overexpression is implicated in Parkinson's disease (PD) pathogenesis, making SNCA downregulation a promising therapeutic strategy. We developed a SNCA-targeted epigenome therapy using an all-in-one lentiviral vector (LV) carrying deactivated CRISPR/(d)Cas9, gRNA targeted at SNCA-intron1, and either the catalytic domain of DNA-methyltransferase3A (DNMT3A), or a synthetic repressor molecule of Krüppel-associated box (KRAB)/ methyl CpG binding protein 2 transcription repression domain (MeCp2-TRD). Therapeutic efficacy was evaluated in a new PD mouse model, generated with an adeno-associated viral vector carrying an engineered minigene comprised of the human (h)A53T-SNCA expressed via the human native regulatory region. Both therapeutic vecto

SUBMITTER: O'Donovan B 

PROVIDER: S-EPMC12262707 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature