Original article: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease, Acta Neuropathologica Communications: June 28, 2017.
PBT434 is a drug which mops up excess iron known to be harmful to neurons. It had beneficial effects on neuronal survival in three animal models of Parkinson’s, reducing markers of oxidative stress and alpha-synuclein accumulation, and improving movement.
Why is it important?
PBT434 is a novel agent with a much lower iron binding capacity than traditional drugs such as deferiprone, leading to better tolerability as well as neuroprotective effects. This new result provides support for a phase I trial which is currently underway.
- Novelty 65% 65%
- Proximity 50% 50%
- Deliverability 60% 60%
“Our bodies have a ‘Goldilock’ relationship with iron – it is essential, but when the levels of iron get too high it can be harmful. In Parkinson’s, there is evidence suggesting that iron is accumulating in areas of the brain that are affected by Parkinson’s, and causing trouble. This new drug from Prana Biotechnology Ltd represents an exciting new generation of iron-targeting therapies that are heading for the clinic. The preclinical results suggest that PBT434 can not only reduce cell loss, but also reduce the build-up of the aggregating protein alpha-synuclein and lower levels of oxidative stress in models of Parkinson’s. It will be very interesting to watch the progress of PBT434 in the clinical trial process.” – Dr Simon Stott
The excessive accumulation of iron in the brain is known to be harmful to neurons. Targeting iron is one of the ongoing strategies under investigation in two Phase III trials in people with Parkinson’s using deferiprone, an iron chelating drug used normally to prevent excessive iron build up in individuals receiving regular blood transfusions. Now, the novel agent PBT434, which mops up excess iron without the potential adverse effects of traditional drugs like deferiprone, is in the spotlight. A phase I trial assessing its safety and tolerability in healthy individuals in the first instance has just been launched by Prana Biotechnology Ltd (story below), on the back of promising preclinical work which is summarized here.
In this preclinical work, these researchers tested the effects of PBT434 in three different animal models of Parkinson’s. They addressed the effects of the drug on neuronal survival and connectivity, the build-up of alpha-synuclein, the protein which misfolds and harms neurons, markers of oxidative stress as well as the animals’ movement.
The iron binding capacity of PBT434 is significantly lower than that of the traditional iron chelators and was well tolerated. In the treated animals, PBT434 did not lower central iron stores, but it did prevent further loss of neurons, a benefit which increased incrementally as higher doses were used, and enhanced their connections with other neurons. Moreover, alpha-synuclein was reduced as were markers of oxidative stress. Compared to animals who did not receive the active drug, those on the active treatment arm showed improved performance on tests of movement.
The Phase I trial of PBT434 will be the critical first step in establishing its safety and tolerability in humans, before any clinical benefits can be further investigated.
Where can I learn more?
Original article: Finkelstein, D. I., Billings, J. L., Adlard, P. A., Ayton, S., Sedjahtera, A., Masters, C. L., . . . Cherny, R. A. June 28, 2017: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease, Acta Neuropathologica Communications