CRISPR-Mediated Transcriptional and Splicing Regulation of Alpha-Synuclein for the Treatment of Neurodegenerative Disorders

Brief Description

Parkinson’s disease and related synucleinopathies currently lack disease-modifying cures, as existing treatments only manage symptoms associated with alpha-synuclein (aSyn) aggregation. To address this, UC Berkeley researchers have developed a suite of non-viral, CRISPR-mediated strategies designed for the permanent downregulation of the endogenous SNCA gene and the LRRK2 risk allele. By utilizing precise base editing of regulatory regions, genomic excision of non-coding sequences, and splicing modulation, this platform provides a durable, single-administration alternative to transient RNA-targeting therapies. The invention further enables allele-selective knockout of the LRRK2 G2019S mutation, employing a specialized CRISPR-Cas9 variant to discriminate between mutant and wild-type genes, thereby offering a highly specific and permanent therapeutic intervention for neurodegenerative disorders.

Suggested uses

• Therapeutic treatment for Parkinson’s Disease (idiopathic and familial)
• Intervention for other alpha-synucleinopathies, including Multiple System Atrophy (MSA) and Dementia with Lewy Bodies
• Prophylactic treatment for individuals with genetic biomarkers indicating high risk for Parkinson's

Advantages

• Induces a durable genetic change that eliminates the need for repeated dosing associated with RNA-targeting therapies
• Base editing avoids double-stranded breaks and unpredictable insertions/deletions (indels)
• Capable of targeting specific risk mutations without impacting healthy wild-type alleles
• Compatible with diverse delivery mechanisms including ribonucleoproteins (RNPs), lipid nanoparticles (LNPs), and peptide-mediated delivery