Glial cell line-derived neurotrophic factor (GDNF) is a protein that has been shown to be neuroprotective for dopamine neurons, the cells in the brain that are badly affected by Parkinson’s. 

Cure Parkinson’s has been involved in and has championed the neurotrophic factor called Glial cell-derived neurotrophic factor (or GDNF) since 2003 through the commitment and determination of the charity’s late co-founder and president Tom Isaacs. In February 2019, the results of the Phase II Bristol study, supported by Cure Parkinson’s, investigating the use of GDNF in people with Parkinson’s were published in the research journals Brain and the Journal of Parkinson’s Disease (JoPD)

Nerve growth or neurotrophic factors are small proteins that support neurons and encourage their growth and survival during development. They have also been shown to rescue neurons in laboratory models of neurodegenerative conditions, exhibiting powerful neuroprotective properties. There has been considerable preclinical research exploring their potential use in Parkinson’s. Unfortunately, the translation of that research into humans has not been easy.

This ground-breaking trial involved the mechanical delivery of this experimental treatment directly into the brains of people with Parkinson’s in an attempt to rescue and restore damaged neurons.

While this clinical trial of GDNF did not meet its primary endpoint (this is a pre-determined measure of efficacy), there were some very interesting findings. The brain imaging data, for example, suggested that GDNF was having a biological effect in the brain. But importantly the clinical findings of the study did not mirror the participant’s experience in terms of benefit. Examples of this were demonstrated in the award winning BBC2 documentary: The Parkinson’s Drug Trial: A Miracle Cure?

As a result, the interpretation of all the results of this trial has been challenging.

Following publication of the trial results, Cure Parkinson’s has been working with research partners and the Parkinson’s community to address some of the uncertainties and issues raised in this trial and to explore the appropriate pathway forward for GDNF.

What progress has been made since the Bristol trial?

1. Research community consensus

Cure Parkinson’s asked Professor Roger Barker of the University of Cambridge to chair a ‘closed’ meeting of international key opinion leaders with direct knowledge and practical experience in the field of GDNF and associated neurotrophic factors. The goal of the meeting was to bring together the wide range of views to identify and agree on what is known pre-clinically and clinically about GDNF, and what still needs further investigation in the field. It is from consensus and a strong scientific foundation that we will be able to find a pathway forward.

In the light of the GDNF trial results, it was important to bring together all the teams internationally that have worked with GDNF over the last 25 years to better understand how to take this therapy and related compounds forward for the benefit of people with Parkinson’s.

The meeting took place last August 2019 kindly hosted by Van Andel Institute (VAI), and Cure Parkinson’s was joined by other key Parkinson’s funding agencies: Michael J Fox Foundation, Parkinson’s UK and the NIH. The meeting also included GDNF trial participant Eros Bresolin and Lyndsey Isaacs, who supported her late husband and trial participant Tom Isaacs. Tom championed GDNF, leading to the recent Bristol trial. A summary of the discussions at that August meeting have now been published in the Journal of Parkinson’s:

2. Clinical outcomes

The clinical outcomes, that are used to evaluate the progression of Parkinson’s, remain an important focus. Many of the participants in the Phase II Bristol trial of GDNF felt their clinical scores did not reflect some of their experiences. CPT and researchers involved in the GDNF study then conducted a more in-depth analysis of the entire study dataset to determine whether there might be combinations of clinical measures that could be brought together to offer a more insightful way to demonstrate any therapeutic effect. The result of this effort is a new composite measurement scale, called PDCORE insert link.

3. Testing novel approaches to target neurotrophic factors for Parkinson’s

The trustees of Cure Parkinson’s have recently approved the funding of a new study focused on another interesting neurotrophic factor called cerebral dopamine neurotrophic factor or CDNF. Prof Mart Saarma and colleagues at the University of Helsinki have discovered a tiny fragment of the CDNF protein, which they have called C-CDNF, that can pass through the blood brain barrier (the protective membrane surrounding the brain and central nervous system) and still exhibit the positive properties of normal CDNF. They will now test this protein in laboratory models of Parkinson’s to assess its potential as a neuroprotective therapy. It is hoped that C-CDNF will allow for a more straightforward oral or peripheral administration of a future neurotrophic factor-based therapy for Parkinson’s.

Neurotrophic Factors and Parkinson’s Webinar

Webinar – Neurotrophic Factors and Parkinson’s

Neurotrophic Factors and Parkinson’s Webinar in association with Journal of Parkinson’s Disease (JoPD)

The panel of experts include: Chair – Professor Patrik Brundin;  Dr. Howard Federoff, Professor of Neurology and Neuroscience, University of California; Professor Mart Saarma – Research Director, University of Helsinki and Lyndsey Isaacs, Trustee, Cure Parkinson’s