Synuclein-lowering drugs (overview)

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

Ionis (with Biogen, which ended its role in early 2025; see landmark 289), Prevail Therapeutics (a Lilly company) and Regeneron (a secondary source names Alnylam as originator); others are preclinical.

What happened

The three programmes are described in separate files:

• ION464 / BIIB101, an antisense drug into the spinal fluid, Phase 1 (HORIZON, NCT04165486), about 40 people planned, with multiple system atrophy, not Parkinson's; recruiting, estimated completion September 2027 per the registry: landmark 289.
• LY3962681, Lilly's spinal-fluid siRNA, randomised Phase 1 in healthy people and Parkinson's patients (NCT06565195), started 27 Aug 2024, up to 124 planned, recruiting, estimated primary completion July 2030: landmark 288.
• ALN-SNCA, Regeneron's siRNA, randomised Phase 1 in 46 planned people with early Parkinson's (NCT07216066), started 5 Dec 2025, recruiting, estimated primary completion June 2029: landmark 287.

Immune approaches that clear the protein rather than stop its production are covered elsewhere (prasinezumab in dead ends).

Why it moved us toward a cure

Mice lacking synuclein live normally, which supports the safety of lowering it (landmark 201). Lowering the protein at its source tests the central idea behind landmark 14 (less alpha-synuclein, less disease) and could work whatever the strain. A common non-coding variant that raises SNCA output (landmark 49) points the same way.

The spinal-fluid antisense route was proven in people by nusinersen (landmark 256).

Outcome

Open. No alpha-synuclein-lowering therapy has reported efficacy in humans. The MSA trial is proof of concept for the approach, not for Parkinson's.

Earlier-stage work includes a Florey Institute project (Fazel Shabanpoor, funded by the Michael J. Fox Foundation and Shake It Up Australia from 2020–21) to carry a synuclein-lowering antisense drug across the blood-brain barrier with a peptide; no results are public.

Sources

• Shake It Up Australia project page (funding and status facts only)
• Alzforum ION464 page
• JCI Insight 2020, alpha-synuclein antisense drugs as disease-modifying therapy
• NCT06565195 · NCT07216066 · NCT04165486 (read from the registry API, 19 Oct 2026). Other sources are in landmarks 287, 288 and 289.
• Not yet verified: the Alnylam–Regeneron origin of ALN-SNCA (secondary source only); the date Biogen ended its role in ION464; other preclinical programmes (CRISPR, gene-delivered silencing).