Gene editing of SNCA

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Boris Kantor, Ornit Chiba-Falek and colleagues at Duke (2018; US National Institute of Neurological Disorders and Stroke grant R01 NS085011, plus a Kahn Neurotechnology Development Award); H.H. Yoon, Sang Ryong Jeon (senior author) and colleagues in Korea (2022); C.A.M. Torres, B. Schüle (senior author) and colleagues at Stanford, with L.S. Qi and D. Kirik (2023 preprint).

What happened

Extra copies of SNCA cause Parkinson's (landmark 14), so lowering it is a direct target. Three steps stand out.

2018, turn the gene down. Kantor et al. used a deactivated Cas9 ("dCas9", which finds a DNA address without cutting) fused to DNMT3A, an enzyme that adds methyl "off" tags, aimed at SNCA intron 1. Delivered by lentivirus into dopamine neurons derived from a patient with SNCA triplication, it lowered SNCA mRNA and protein by about 30% (figure from a 2019 methods paper) and reversed some cell-stress signs (Molecular Therapy 26:2638-2649).

2022, cut the mutant gene. Yoon et al. used an AAV carrying SaCas9-KKH and a guide aimed at A53T-SNCA, in cells and in rats given a virus that overexpresses that mutant. It reduced alpha-synuclein, microglial activation and dopamine-neuron loss, and rescued movement (CRISPR Journal 5(1):95-108). The authors present it as a prevention strategy for A53T-specific disease, so it would protect only carriers of that mutation.

2023, silence in the brain. A Stanford preprint (Torres et al., bioRxiv, 5 Sep 2023) put an AAV9 dSaCas9-KRAB repressor aimed at the human SNCA promoter into the substantia nigra of mice carrying a human SNCA gene: SNCA mRNA fell 73% at one month and 63% at six months, and protein 37% and 32%. An early immune reaction to the vector faded by six months. No movement tests were reported. No peer-reviewed version was found by 20 Oct 2026.

Why it moved us toward a cure

It is a one-time, source-level way to lower synuclein, unlike antibodies that need repeated infusions. Together with landmark 49, which found the regulatory switch for SNCA, it points to where to aim. Delivery needs improving (landmark 111).

Outcome

Open, preclinical. No clinical editing trial for SNCA was found; the Stanford preprint speaks only of future pre-clinical work toward clinical translation. No correction or retraction was found for the two published papers. Open problems: how much synuclein can be lowered safely (the protein has normal roles; landmark 34), off-target edits, immune reactions to Cas9 and AAV, and lasting effect.

Sources

• Kantor et al., Mol Ther 2018;26(11):2638-2649, DOI 10.1016/j.ymthe.2018.08.019, PMID 30266652 (abstract via Europe PMC) · Inside Precision Medicine · Tagliafierro et al., JoVE 2019 (30%)
• Yoon et al., CRISPR J 2022;5(1):95-108, DOI 10.1089/crispr.2021.0025, PMID 35191750 (abstract via Europe PMC)
• Torres et al., "Robust nuclease-dead S. aureus dCas9-mediated alpha-synuclein knockdown in substantia nigra in a humanized mouse model of Parkinson's disease," bioRxiv 2023, DOI 10.1101/2023.09.05.556425 (full text read; preprint, not peer reviewed)
• Not yet verified: the 2018 paper's own percentage (the 30% comes from the 2019 methods paper and the Stanford preprint's discussion); funders of the 2022 paper and the preprint; other SNCA-editing studies after 2022 (one search found none).