Parkinson's disease affects between 7 and 10 million people worldwide and the number of people diagnosed is soaring due to the ageing population.
It affects dopamine-producing nerve cells in the brain, causing them to gradually deteriorate and die. As a result, people with Parkinson's often experience tremors, rigidity of muscles and problems with speech. In the later stages of the disease, anxiety, depression and dementia are common. Treatments focus on increasing dopamine levels or controlling the symptoms, but currently nothing can slow its progression and, as yet, no cure exists.
However, laboratory studies have found that a protein called cerebral dopamine neurotrophic factor (CDNF) – a type of growth-inducing protein, present in human blood and cerebrospinal fluid – may be able to alleviate Parkinson's symptoms and even stop its progression.
The discovery of CDNF was announced in 2007 by a team that included the coordinator of the EU-funded TREATER project, Mart Saarma of the University of Helsinki in Finland.
'Usually, other neurotrophic factors are not expressed in dopamine neurons. But CDNF was, which made it particularly exciting,' says Saarma. 'CDNF can protect dopamine neurons, but it can also restore some of the degenerated neurons. In later experiments, we noticed that CDNF not only improves motor functions and protects neurons from degeneration, but we also found that it affects some of the non-motor symptoms, such as depression and motivation.'
Now, Saarma's team, under the TREATER project, is carrying out the world's first clinical study in humans.
Clinical trial under way
After regulatory and ethical approvals were met, a primary study was initiated to monitor two patients with Parkinson's disease as they received the first CDNF infusions. This was completed in June 2018, in the absence of any safety concerns being raised.
The proof-of-concept phase 1-2 clinical study currently under way is building on the extensive preclinical research into CDNF, including toxicology studies that show the drug is likely to be safe for patients. The TREATER team is looking at whether the drug is safe and effective at treating the symptoms of Parkinson's disease. Treatment is being carried out at three European university hospitals: Karolinska University Hospital and Skåne University Hospital in Sweden, and Helsinki University Hospital in Finland.
One-third of the patients are receiving monthly infusions of placebo and two-thirds are subjected to monthly infusions of either medium or high doses of CDNF for six months. At the time of writing, most of the 18 patients have been treated at least once either with the drug or with the placebo, and the study's independent safety monitoring committee has approved proceeding to the highest planned CDNF dose.
'So far, we've accumulated data on the clinical safety of CDNF in patients with advanced Parkinson's disease and we're very happy with our progress,' says Pekka Simula, CEO of project partner Herantis Pharma in Finland. 'Later in the project, the clinical study will be "unblinded", which means we will see which of the patients received CDNF and who received the placebo, enabling us to compare the results. Then we hope to also see the first signals of efficacy with CDNF in the treatment of Parkinson's disease.'
'Patients will then be followed by doctors using advanced PET imaging, actigraphy devices to assess their motor symptoms, the Unified Parkinson's Disease Rating Scale and several other means to gather information about how dopamine neurons are doing in the living brains of the patients,' adds Saarma.
Innovative drug delivery
As well as testing the safety of CDNF and its ability to prevent dopamine neuron degeneration and to stimulate neuron regeneration, the TREATER project is exploring the use of a patented drug-delivery system.
'Because the blood-brain barrier keeps unwanted particles and medications separate from the brain, one of the challenges in the treatment of any brain disease is to ensure the drug substance actually reaches the brain,' explains Simula. 'In the primary study, we used the drug-delivery device to administer CDNF directly into the brain and have shown that the device works.'
The device is implanted into the brain by a neurosurgeon. Catheters for delivering the drug are connected to a port fixed to the head, just behind the ear. Filters prevent bacteria and air from entering the brain.
Both elements of the current trial – the drug candidate and the drug-delivery device – have far-reaching potential. CDNF may prove useful in the fight against Parkinson's, while the drug-delivery device could be used for treating other diseases and administering a variety of other drugs directly into the brain.
'If the results of the TREATER clinical study are as good as expected, then both the drug-delivery device and CDNF would be commercialised independently,' says Simula. 'This is great … for a project like this: even if CDNF failed in clinical development, the drug-delivery device could still provide a great commercial opportunity for a European company.'
As the clinical study runs, Saarma and his colleagues are trying to identify easier and cheaper ways to get CDNF to the places in the body where it can best fight the symptoms of Parkinson's.
'Surgery to the brain is always a very demanding procedure, so we're already researching other ways to get CDNF past the blood-brain barrier, delivering it instead under the skin or into the bloodstream,' he says. 'Delivering to the bloodstream would also allow the protein to reach other types of neurons that are damaged in Parkinson's, such as olfactory neurons which affect patients' sense of smell, degenerating enteric dopamine neurons that cause constipation, and neurons which affect motivation and trigger depression.'
Although the TREATER team is awaiting the full results of the study, the project has already reached a milestone by delivering the drug candidate CDNF to patients for the first time. And, as the project continues, the scope for further significant outcomes looks promising.