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.

In February 2019, the results of the Phase II Bristol study investigating the use of a neurotrophic factor called Glial cell-derived neurotrophic factor (or GDNF) in people with Parkinson’s were published in the research journals Brain and the Journal of Parkinson’s Disease. 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.

The Cure Parkinson’s Trust (CPT) has been involved in and has championed the GDNF story since 2003 through the commitment and determination of the charity’s late co-founder and president Tom Isaacs. Over the last year, CPT 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

CPT 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.

Helen Matthews, Deputy CEO - CPT, said

In the light of last year’s 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, and CPT 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.

Dr Richard Wyse, Director of Research and Development - CPT, said

I am delighted to work with the outstanding team of co-authors of the PDCORE paper who, using a most original approach, successfully re-analysed a complex collection of patient data to produce a completely new way evaluating the clinical progress of patients with Parkinson's.

CPT Deputy Director of Research, Dr Simon Stott, has written an extensive blog on PDCORE - read more here.

The researchers stress that this type of ‘post-hoc’ analysis is NOT intended to provide evidence that GDNF demonstrated efficacy in the Bristol study. Rather they have very carefully analysed the available data with the goal of identifying a superior way to evaluate Parkinson’s patients which is likely to be useful in evaluating therapies, like GDNF, in future trials. This study has now been published in the journal Brain.

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

The Cure Parkinson’s Trust trustees 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.

Dr Simon Stott, Deputy Director of Research - CPT, said

The delivery of neurotrophic factors to the brain is challenging as they cannot cross the blood-brain barrier. Currently getting GDNF or CDNF into the brain involves invasive methods like brain surgery. We hope that this new study being conducted by Prof Mart Saarma’s lab will allow for the development of a less invasive neurotrophic approach. 

4. A webinar about neurotrophic factors for Parkinson's

In collaboration with our partners Van Andel Institute in Michigan (USA) and the Journal of Parkinson’s Disease, The Cure Parkinson’s Trust held a webinar which discussed neurotrophic factors and Parkinson’s. Chaired by Professor Patrik Brundin of Van Andel Institute, the panel of experts included Prof. Howard Federoff (University of California), Prof. Mart Saarma (University of Helsinki) and Lyndsey Isaacs (Trustee, The Cure Parkinson's Trust). Re-watch this webinar.

In addition to these advances , further efforts are being made to progress neurotrophic factor-based clinical research for Parkinson’s. COVID-19 has delayed activities but a new clinical trial testing a GDNF-based gene therapy approach in individuals with Parkinson’s is getting underway. In addition, the biotech company Herantis Global engineering technologies company Renishaw has announced that its drug delivery device, neuroinfuse™, has continued to safely and effectively deliver infusions as part of an extension to a first-in-human clinical trial of cerebral dopamine neurotrophic factor (CDNF). This device was the same used in the recent, CPT-supported Phase II GDNF trial in Bristol. This phase 1-2 clinical study of CDNF, carried out jointly with Herantis Pharma plc, investigated the safety and performance/tolerability of CDNF and neuroinfuse, as a treatment for Parkinson's disease.

The Cure Parkinson’s Trust continues to explore every opportunity for neurotrophic factors in Parkinson’s and will persevere within this field of research until this condition is cured!