The c-Abl idea: mouse studies and a 12-person pilot

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

Han Seok Ko, Ted and Valina Dawson and colleagues (US National Institutes of Health-funded, per PubMed) for the mouse work; Charbel Moussa and Fernando Pagan (Georgetown University) for the pilot.

What happened

c-Abl is an enzyme whose activation has been linked to loss of parkin's protective function and a build-up of the parkin substrate PARIS (landmark 12). Nilotinib, a cancer drug that blocks it, protected dopamine neurons in an MPTP mouse model (Karuppagounder et al., Sci Rep 2014; landmark 2). In October 2015 Georgetown announced, at the Society for Neuroscience meeting in Chicago, a pilot in people with Parkinson's dementia or dementia with Lewy bodies. The full paper (Pagan et al., J Parkinsons Dis 2016;6:503–517) randomised 12 people to 150 mg (5) or 300 mg (7) daily for 24 weeks, with no placebo group. Its primary aims were safety and drug levels; motor and memory scores were exploratory and suggested a possible benefit. The authors said the lack of a placebo group and baseline differences limited any conclusions and called for a randomised, placebo-controlled trial. A public dispute over follow-up design followed.

The controlled trials are now separate files: nilotinib in 75 and 76 patients (landmark 322) and vodobatinib in 513 patients, stopped in 2024 (landmark 323). Radotinib, another c-Abl blocker, is in Phase 2 (landmark 219), as is risvodetinib (landmark 174).

Why it moved us toward a cure

Nilotinib was among the drugs the Cure Parkinson's Trust's repurposing committee prioritised (landmark 119). c-Abl had been shown to switch off parkin in Parkinson's brains (landmark 211). The pilot is a case study in why early excitement fails: it had no placebo group and a tiny sample, and the controlled trials that followed were negative.

Outcome

Superseded by the controlled trials, which found nilotinib and vodobatinib ineffective. The c-Abl idea itself is not closed: radotinib and risvodetinib are still in Phase 2.

Sources

• Karuppagounder et al., Sci Rep 2014;4:4874, DOI 10.1038/srep04874
• Pagan et al., "Nilotinib effects in Parkinson's disease and dementia with Lewy bodies," J Parkinsons Dis 2016;6:503–517, DOI 10.3233/JPD-160867
• Georgetown news release, 17 Oct 2015
• Science of Parkinson's, "Nilotinib: the other phase II trial," 31 Jul 2017 (account of the Georgetown pilot and dispute; a blog)
• Not yet verified: the Georgetown news release text (found by search, not opened); the dose-dispute details (blog only). The pilot paper has a published comment (J Parkinsons Dis 2016;6:519-22) that was not read. No correction or retraction was found for either paper in Crossref or Europe PMC.