Parkinson’s disease (PD) is a common, chronic, fast-progressing, non-communicable disease. As the second most frequent neurodegenerative disorder worldwide, PD affects millions of people - about 1% of the over-60s. It is estimated that the prevalence will at least double by 2030.
None of the currently available drugs can slow down the dramatic progression of the motor handicap (e.g. falls) and non-motor handicap (dementia), which generally lead to institutionalization and death.
Today, most patients with PD irremediably progress to a severe state of dependence. In Europe, the cost of PD was estimated to be at least €13.9 billion in 2010. The huge and increasing socio-economic impact of PD and the immense emotional burden placed on patients and their caregivers represent a great challenge to society.
There is an urgent need for a “game-changer” strategy, with the development of disease-modifier treatments with neuroprotective effects that can help to avoid this dramatic situation in PD and, more generally, in other neurodegenerative diseases with common physiopathological mechanisms.
Iron and Oxidative Stress in PD
For many years, the excess oxidative stress related to mitochondriopathy has been considered as one of the main mechanisms involved in cell death (Schapira and Patel, 2014). Oxidative stress is exacerbated by free iron. Chelation of this free iron has powerful antioxidant properties known to dramatically increase cell survival.
However, we reasoned that to develop this therapeutic approach in humans, chelation strategies that target local and regional iron overload in the brain will necessarily need to avoid systemic iron depletion via the redistribution of iron to endogenous acceptors (i.e. in order to prevent harmful systemic metal loss).
This is the new concept of “conservative iron chelation” (Cabantchik et al. 2013).
We recently demonstrated for the first time the feasibility, efficacy and acceptability of the conservative iron chelation approach in pilot translational studies in PD with a prototype drug: deferiprone (DFP) (in the FAIR-PARK-I project that was led by FAIR-PARK-II's coordinator, David Devos and funded by French Ministry of Health).
In this pilot translational study, conservative iron chelation was assessed in cell-based models, corroborated in an animal model and then translated into a clinical setting (Devos et al., 2014).
Repositioning of an approved drug
DFP is approved for treating systemic iron overload in transfused patients with thalassemia. DFP has been on the EU market since 1999, with a favourable risk/benefit balance at 100 mg/kg/day.
We shall adopt a repositioning strategy by using DFP at a lower dose of 30 mg/kg/day in this new indication for local iron overload in PD. DFP will be the first-in-class drug for this novel therapeutic strategy.
At present, no neuroprotective drugs are available.
If DFP treatment were associated with significant slower disease progression, it would be the first non-dopaminergic drug to have a proven disease-modifying effect in PD.
Indeed, if our academic proof-of-concept study is successful, this new approach could be offered to the population of patients with PD as a whole. This would represent a considerable advance for patients and would have a huge socio-econoomic impact.