Researchers at the University of Alabama at Birmingham (UAB) and Pfizer Inc. recently reported encouraging findings on a new inhibitor drug that can reduce neurodegeneration in animal models of Parkinson’s disease. The study was published in The Journal of Biological Chemistry and is entitled “LRRK2 Pharmacological Inhibition Abates α-Synuclein Induced Neurodegeneration”.
Parkinson’s disease is a progressive neurodegenerative disorder that develops gradually, with patients usually experiencing the first symptoms around the age of 60 or older. As the disease progresses, the symptoms worsen from a barely noticeable tremor in the hands to serious difficulties in speaking, locomotion, coordination and balance. The disease is caused by the loss of the neurotransmitter dopamine due to premature death of dopaminergic neurons in the brain, which play an important role in voluntary movement and behavioral processes (mood, stress, reward, addiction). Abnormal aggregates or deposits of a protein called alpha-synuclein within neurons are also a typical characteristic of Parkinson’s. It is estimated that up to 10 million people worldwide suffer from the disease. There is currently no cure for Parkinson’s or therapies able to halt or slow disease progression.
Previous studies have indicated a link between mutations in certain genes and Parkinson’s pathogenesis, including alpha-synuclein and also leucine-rich repeat kinase 2 (LRRK2). The mutation G2019S in LRRK2, in particular, has been reported to increase the protein’s activity and is present in around 2% of all Parkinson’s patients. Interestingly, the deletion of LRRK2 gene in rats was found to protect them from neurodegeneration, suggesting that LRRK2 inhibition might induce neuroprotection, becoming a potential viable therapeutic approach. However, a recent study using several animal models showed that long-term use (e.g. 4 weeks) of LRRK2 kinase inhibitors can induce serious adverse effects.
In the present study, researchers tested the ability of a Pfizer LRRK2 kinase inhibitor (PF-06447475) to prevent alpha-synuclein induced neurodegeneration in rat models. The team used wild-type rats and transgenic rats expressing the G2019S-LRRK2 mutation from humans. Both animal groups were intracranially injected with a viral delivery system expressing the human alpha-synuclein to properly mimic Parkinson’s features in humans, namely the degeneration of dopaminergic neurons in the brain and the accumulation of alpha-synuclein in surviving neurons. Subsequent treatment with either PF-06447475 or a control was performed for a period of four weeks.
Researchers found that the LRRK2 inhibitor PF-06447475 strongly mitigated both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression. In addition, PF-06447475 offered a potent neuroprotective effect in wild-type rats, suggesting that the inhibitor is also effective in animals with normal LRRK2 expression.
“That is important because only 2 percent of Parkinson’s disease patients have the G2019S mutation,” explained the study’s senior author Dr. Andrew West in a news release. “These wild-type rats really excited us because it suggests the therapeutic action of the drug may extend to the majority of Parkinson’s disease patients. This has invigorated our collaborative efforts with Pfizer Inc. and the Michael J. Fox Foundation for Parkinson’s Research to invest more effort in LRRK2 inhibitors.”
Importantly, researchers found no adverse effects upon a 4-week treatment with the PF-06447475 inhibitor. The team concluded that pharmacological inhibition of LRRK2 is well-tolerated in rats and provides neuroprotection from alpha-synuclein over-expression, counteracting dopaminergic neurodegeneration.
“Because our observations were limited to a four-week period, we are not sure whether neurodegeneration associated with alpha-synuclein is truly prevented or just delayed,” explained the research team. “Either way, any interruption of neurodegeneration associated with Parkinson’s disease might represent a significant therapeutic advance.”
“For a patient with disease onset in the mid-60s, Parkinson’s disease runs its course over 10 to 15 years. So, if we can slow down the disease by even 50 percent, that may be effectively as good as a cure, given the available symptomatic treatments.” added Dr. West.
However, Dr. West advises caution when extrapolating the results obtained in rat models into humans. “We have to be very careful with what our models can tell us. We need to think critically about what type of benefit we can expect to see in humans because there are recent examples where improper clinical trial design have hindered the development of a new class of drugs for years and sometimes decades.”