Neurology Central

Preclinical efficacy could see fast-tracking of liver drug to Parkinson’s disease clinical trials

Ursodeoxycholic acid (UDCA), an agent already approved for use in the treatment of liver disease, has demonstrated potential efficacy in slowing the progression of Parkinson’s disease (PD) in a preclinical study published recently in Neurology. The results of the investigation, which was carried out by investigators at the University of Sheffield and the University of York (both UK), support the potential fast-tracking of UDCA into human PD clinical trials.

The genetic mechanisms responsible for the development of PD and its associated neurodegeneration are currently unclear, with the most common inherited genetic defect known to be mutation of the LRRK2 gene. Defects in the mitochondria are also associated with PD as nerve cells have particularly high energy demands, fluctuations in which crucially affect their survival.

Discussing the study, investigator Heather Mortiboys (University of Sheffield) explained: “We demonstrated the beneficial effects of UDCA in the tissue of LRRK2 carriers with PD as well as currently asymptomatic LRRK2 carriers. In both cases, UDCA improved mitochondrial function as demonstrated by the increase in oxygen consumption and cellular energy levels.”

The results also demonstrate the beneficial effects of UDCA on dopaminergic neurons, the nerve cells affected in PD in vivo. Specifically, the team harnessed an in vivo fruit fly model of PD to investigate the efficacy of UDCA. LRRK2-mediated mitochondrial defects of dopaminergic neurons can be tracked by progressive loss of visual function. It was demonstrated that visual responses were sustained in flies who received UDCA.

Chris Elliott, collaborator from the University of York, elucidated: “The treatment of fruit flies carrying the faulty LRRK2 gene with UDCA showed a profound rescue of dopaminergic signaling. Feeding the flies with UDCA partway through their life slows the rate at which the fly brain then degenerates. Thus, mitochondrial rescue agents may be a promising novel strategy for disease-modifying therapy in LRRK2-related Parkinson’s.”

Commenting on the potential scope of these findings, investigator Oliver Bandmann of the University of Sheffield suggested: “Whilst we have been looking at Parkinson’s patients who carry the LRRK2 mutation, mitochondrial defects are also present in other inherited and sporadic forms of Parkinson’s, where we do not know the causes yet. Our hope is therefore, that UDCA might be beneficial for other types of PD and might also show benefits in other neurodegenerative diseases.”

As UDCA has been approved for use in the treatment of liver disease for many decades, its investigation in clinical trials could have a substantial cost-saving impact and save years of research.

Source: The University of Sheffield press release: