The present and future of neurotrophic factors for Parkinson’s

Original article: Trophic factors for Parkinson’s disease: Where are we and where do we go from here?, European Journal of Neuroscience: October, 2018. 

The takeaway

Progress with neurotrophic factors has been hampered by difficulties of non-replication and disappointing trial results. This review outlines the trajectories of four important candidate therapies, and identifies the need to rethink aspects of the science.

Why is it important?

By reviewing progress and pinpointing how and why efforts in regenerative therapies for Parkinson’s have not yet delivered on their promise, it should be possible to adapt future trials to increase chances of success.

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IMPACT

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  • Proximity 50% 50%
  • Deliverability 40% 40%

Impact Opinion

“This article provides an excellent overview of the field of neurotrophic factors with regards to Parkinson’s. It covers both the preclinical and clinical history, as well as discussing the future. Of particular interest is section 4 on trial design and interpreting trial results. While there is tremendous potential for neurotrophic factors – especially for the area of restorative therapy for Parkinson’s – there are a number of challenges that need to be addressed before we will see significant progress. And luckily, researchers are currently addressing them.”

Background

Neurotrophic factors are proteins generated within the brain naturally which are essential for neurons to grow and survive. Several of these substances have been identified and investigated intensively in preclinical, that is, animal models of Parkinson’s. Success in alleviating movement difficulties and demonstrating dopaminergic neuron survival or even regrowth preclinically is an essential first step before taking trophic factors into human trials. There are several ways in which to model Parkinson’s preclinically, with techniques which attempt to replicate the condition in experimental animals. However, they are all limited in that it has proved impossible to date to mimic the condition which develops over decades and affects many brain systems, not just dopaminergic cells. Clinical trials have also failed to meet their main objectives, and it is essential to understand why this could be, by focusing on appropriate participant selection, and ensuring appropriate dosing that reaches the target brain region. So, despite significant efforts, the results have so far been disappointing for the community. What has been the trajectory of each of the key candidate therapies?

The details

The first neurotrophic factor to show therapeutic potential is Glial cell line-derived neurotrophic factor (GDNF). Results from animal studies were mixed, and one of the main issues has been the development of an effective way of delivering it into the target brain region, involved in the coordination of movement and seated deep in the brain. Seven clinical trials in people with Parkinson’s have taken place, two of which are ongoing. Since 2003, disappointing trial results have led to key lessons about how to improve GDNF delivery. With persistence and insistence that clinical benefit had been witnessed in some patients, two further trials are underway using a specialized delivery system into the brain. The trial in Bristol, UK in 41 patients failed to show improvement with GDNF compared to placebo over 9 months, and has been extended for an additional 9 months with all participants receiving GDNF. The second trial in Bethesda, US, using a gene therapy approach in 25 patients is ongoing. The results are eagerly awaited.

Neurturin is another trophic factor closely related to GDNF, although early preclinical results showed it may not be as effective. The main issues related to its availability and how long it remains active, so efforts focused on gene therapy approaches rather then simply infusing it. The double-blind clinical trial in patients targeting two major movement related regions (the putamen and substantia nigra) did not demonstrate efficacy over the whole group of 52 individuals, although patients within less than 5 years of diagnosis did show improvement. This highlighted issues around candidate suitability and the importance of intervening as early as possible.

Research into Platelet derived growth factor (PDGF) is ongoing, as there are still many open questions regarding its mode of action. Rather than acting directly on dopaminergic neurons, a number of studies showed that it mainly affects another type of cell: pericytes. These cells wrap around the smallest blood vessels supplying the whole brain and can be stimulated by this growth factor. The signaling pathways that are triggered may improve dopaminergic neuron survival indirectly through reducing inflammation and improving blood supply. A small trial in 12 patients however was difficult to interpret as similar benefits were seen in the placebo treated group.

Finally, Cerebral dopaminergic neurotrophic factor (CDNF) has shown promising results preclinically, paving the way to clinical trials, as part of a two-pronged approach alongside GDNF delivery as well. CDNF is currently being trialed in a first-in-human double-blind, placebo-controlled clinical study in patients in Finland and Sweden, the results of which will be available in a few years’ time.

Next steps

The authors point out that the next steps should focus on carefully selecting patient populations, testing earlier in the disease course and waiting long enough before assessing whether therapies lead to clinical improvements.

Original article: Trophic factors for Parkinson’s disease: Where are we and where do we go from here?, European Journal of Neuroscience: October, 2018. Paul, G., & Sullivan, A. M. 

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