The LRRK2 gene: the first gene-based drug target

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

Two groups, published back to back in the same issue of Neuron (44:595–600 and 44:601–607, November 2004): Coro Paisán-Ruíz, Andrew Singleton, Nicholas Wood and colleagues (Valencia, the US National Institute on Aging and University College London); and Alexander Zimprich, Thomas Gasser (Tübingen), Zbigniew Wszolek, Matthew Farrer and Mayo Clinic colleagues. The locus (PARK8) had been mapped in 2002 by Funayama and colleagues in a Japanese family; Funayama's team later found the LRRK2 mutation in that family (2005). Funders of the discovery papers were not checked.

What happened

Paisán-Ruíz found missense mutations in five families from England and Spain; Zimprich found six disease-linked mutations in 46 families and a wide range of brain pathology, including Lewy-body Parkinson's. LRRK2 became the most common known genetic cause: its G2019S mutation is found in about 1% of sporadic and 4% of hereditary cases worldwide (Healy et al., Lancet Neurol 2008). G2019S raises the enzyme's activity two- to threefold, and other pathogenic variants increase its phosphorylation of Rab proteins (Steger et al., eLife 2016), so drug makers built inhibitors to switch it down. The trials have their own files: the first human studies (landmark 200, landmark 229); LUMA, in which BIIB122 hit its target but did not slow progression in 648 people with early Parkinson's in 2026 (landmark 145); and BEACON in mutation carriers (landmark 159).

Why it moved us toward a cure

This was the first gene-based "druggable" target, and it set the template for precision trials in genetically defined patients.

Outcome

Open. The target is real, but the first inhibitor failed in broad early Parkinson's; the genetic subgroup is still being tested (BEACON data expected in the first half of 2027).

On 17 October 2024 the Michael J. Fox Foundation launched the LRRK2 Investigative Therapeutics Exchange (LITE), a three-year programme led by Dario Alessi and Esther Sammler at the University of Dundee, with "tens of millions of dollars of grant support" (no exact figure is given in the MJFF announcement or the Dundee release). The earlier figure of "over $40 million" could not be confirmed and was removed. The Foundation's 2024 Year in Review says it "secured over $40 million in funding to launch" LITE.

Sources

• MJFF LITE announcement, 17 Oct 2024 (funding facts only) · University of Dundee release
• Paisán-Ruíz et al., Neuron 2004;44:595–600, DOI 10.1016/j.neuron.2004.10.023 (PMID 15541308)
• Zimprich et al., Neuron 2004;44:601–607, DOI 10.1016/j.neuron.2004.11.005 (PubMed 15541309)
• Funayama et al., Ann Neurol 2005;57:918–921, DOI 10.1002/ana.20484, PMID 15880653 · Healy et al., Lancet Neurol 2008;7:583–590, DOI 10.1016/S1474-4422(08)70117-0, PMID 18539534 · Steger et al., eLife 2016;5:e12813, DOI 10.7554/eLife.12813, PMID 26824392
• Alzforum commentary
• LUMA topline, May 2026
• Full data, NeurologyLive Oct 2026