A recent two-part documentary by the BBC followed a Phase 2 clinical trial for the drug GDNF. Lead researchers on the trial were testing the ability of GDNF in relieving symptoms of Parkinson’s. A total of 41 diagnosed patients took part in the trial, during which the success of GDNF was tested alongside a placebo.

Glial Cell Derived Neurotrophic Factor [GDNF] is a gene encoding an important protein ligand in the human brain, related to a superfamily of proteins known as TGF-beta proteins. TGF proteins are important in regulation of the cellular system, controlling processes such as cell growth, cell differentiation, and cell death. In the laboratory, a sample of GDNF was shown to promote the survival of dopamine nerve cells. It was also able to prevent the cell death of motor nerve cells, which are highly critical for the movement of the human body. It’s ability to regulate the survival of dopamine neurons in the central nervous system has made GDNF an exciting possibility in the future therapeutics of Parkinson’s Disease.

It is estimated that one in 350 UK adults are currently diagnosed and living with the disease; the prevalence only set to rise over coming decades. Caused by the unexplained degeneration of dopaminergic neurones in an area of the brain called the substantia nigra, Parkinson’s is a complex neurological movement disorder. Dopamine is a vital neurotransmitter involved in the regulation of movement. Decreased concentrations of dopamine leads to decreased regulation of movement; leading to the abnormal and slow movements seen in patients living with the disease.

Like many other neurodegenerative diseases, there is currently no cure.

You don’t have to be a leading neuroscientist to suggest that injection of a drug known to restore neuron function, such as GDNF, into regions of the brain affected in the disease may lead to increased regulation of movement, by preventing the death of dopaminergic nerve cells, thereby potentially reversing the symptoms of Parkinson’s.

The GDNF clinical trial involved the administration of the drug into remote region of the brain via a process known as Convection Enhanced Delivery (CED). This method of delivery meant volunteers were required to undergo advanced brain surgery in which tubes were placed into a region of the brain known as the putamen, in order to infuse areas of the brain known to be affected in Parkinson’s Disease with the drug. Although the approach may sound unpleasant, conclusions of the study found a 99.1% compliance rate amongst volunteers, suggesting the technology used has very little uncomfortable side-effects, and that many volunteers found the benefits of drug infusion outweighed a need for microscopic brain surgery.

Following the first nine month period, in which half of the volunteers received GDNF and the other received a placebo, scans showed that the group receiving the drug had 100% improvement in the regions of their brain affected by their Parkinson’s – hope that the treatment had begun to restore neurons previously damaged.

Due to the extensive surgery required to take part in the study, it was later ruled unethical to not offer GDNF to all volunteers. Therefore, by the 18-month stage of the trial, all patients were receiving regular GDNF infusions. Moderate to large improvements in Parkinson symptoms were recorded.

Whilst initial findings supported the long-term success of GDNF infusions in relieving the debilitating symptoms of Parkinson’s, final statistical data failed to find a statistically significant difference between the group who had been given GDNF for the full 18-months, versus those who had been on the placebo then switched to the drug following the initial 9 month period. In order for a drug to advance along the development timeline, it is critical that an beneficial outcome achieves statistical significance [a different of 20%] in order to rule out the possibility of a ‘placebo effect’ – the psychological process in which the mere thought of being given an active drug in fact improves symptoms of a disease or condition. Final results from this expensive and promising study are therefore disappointing, as scientists were unable to rule out the possibility that improvements seen were due to chance.

Despite falling short of the significance threshold by 14%, pharmaceutical giant Pfizer still showed interest in pursuing the technology and drug further, with the possibility of funding a larger Phase 3 clinical trial. However, in January 2018, the company announced it was no longer providing funding to neurodegenerative research; over decades, many of its other multi-million dollar funded trials had ended in failure and the company had drawn the line.

Despite physical evidence in the form of brain imaging showing the success of GDNF in restoration of damaged dopaminergic neurones in the brains of Parkinson’s patients, and clear clinical improvement in symptoms, the withdrawal of Pfizer’s support for GDNF development is the latest setback in the search for an effective cure for Parkinson’s Disease.