LRRK2 Inhibition for PD-related Neurodegeneration

A recent study conducted by researchers at the University of Alabama at Birmingham, in collaboration with Pfizer, has shown that inhibiting leucine-rich repeat kinase 2 (LRRK2) blocks α-synuclein-induced neurodegeneration in an animal model of Parkinson disease (PD). The compound may ultimately be used for the treatment of PD in humans.

PD is associated with the death of dopaminergic substantia nigra neurons. The causes of PD are not clear. The observation that α-synuclein accumulates in the protein deposits found within the brains of people with PD has led many researchers to believe that α-synuclein is the culprit behind PD-associated neurodegeneration and cell loss. α-synuclein and LRRK2 are specifically implicated as possible causes of late-onset PD.

PD is currently treated with medications that increase dopamine or its availability and activity. Current medications help with PD symptoms, but do not halt neurodegeneration. They are also associated with side effects including tardive dyskinesia, adding more motor problems to the ones people with PD already have. PD has no cure and treatments that prevent PD progression are greatly needed.

Led by João P.L. Daher, of the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, the researchers sought to test whether inhibiting LRRK2 kinase using a compound called PF-06447475 reduced neurodegeneration in rodent models of PD.  

The scientists injected rats with a viral vector expressing α-synuclein into the substantia nigra. They used this approach in wild-type rats and transgenic rats that were altered to express a gene that has been associated with familial PD, the G2019S-LRRK2 mutation. They treated the rats either with the inhibitor PF-06447475 or a control compound.

The rats expressing G2019S-LRRK2 had “exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein” according to the study authors. PF-06447475 blocked neurodegeneration in these animals that had extreme deterioration of substantia nigra neurons, and also blocked neurodegeneration in the wild-type animals that had been injected with the viral vector overexpressing α-synuclein.

PF-06447475 did not appear to causes side effects in the rats, and specifically did not induce deterioration of the lung, kidney, or liver.

Daher and colleagues noted in their report that “These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a four-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein over-expression.”

A strategy that prevents neurodegeneration caused by α-synuclein would be a novel treatment for PD – one that not only addressed the symptoms of PD but potentially halted the progression of the disease. People with LRRK2-associated mutations could be identified through genotyping, and PF-06447475 might be used as an early preventative approach. Hopefully the compound will advance to human clinical trials and will eventually benefit people living with PD.

Key Points

• PF-06447475, a compound that inhibits leucine-rich repeat kinase 2 (LRRK2), is being explored as a treatment for PD.

• Researchers found that PF-06447475 blocked α-synuclein-induced neurodegeneration in animal models of PD.

• PF-06447475 could ultimately prevent neurodegeneration and disease progression of PD.