Finding a cure – our major research targets to slow, stop or reverse Parkinson’s:
Alpha-synuclein is a protein abundant in dopamine producing nerve cells (or neurons). In Parkinson’s however, it mis-folds and aggregates into clumps called Lewy Bodies. It’s thought these may be toxic and the aggregates of alpha-synuclein may also get passed from one neuron to another, causing the spread of the disease through the brain. Cure Parkinson’s is supporting research and clinical trials to tackle alpha-synuclein aggregation; the nortriptyline clinical trial is one such example.Nortriptyline and Parkinson’s
Mitochondria are like ‘battery packs’ inside our cells. Dopamine producing nerve cells (or neurons) in the brain need a lot of energy to do their job – but mitochondria don’t seem to function well in Parkinson’s which may starve the neurons of energy, leading to their death. Mitochondria are also involved in triggering cell self-destruction, which may be another cause of neuron loss in Parkinson’s. Through our International Linked Clinical Trials programme (iLCT), Cure Parkinson’s has prioritised compounds that have the potential to restore vital mitochondrial function, enhancing energy production in dopamine neurons. One such clinical trial is looking to repurpose UDCA, a treatment for liver disease, targeting mitochondrial dysfunction in Parkinson’s.UDCA and Parkinson’s
In Parkinson’s, the neurons’ normal processes for discarding waste may be faulty, allowing toxic substances to build up including the toxic build-up of the protein alpha-synuclein. Methods of restoring the proper biological waste disposal pathways in cells are of great current research interest. GCase is an enzyme that helps to break down proteins ready for proper cellular disposal. GCase is encoded by a region of DNA called the GBA-1 gene, however, around 10% of people with Parkinson’s carry a fault in this GBA-1 gene, and it is thought that this causes their Parkinson’s. Cure Parkinson’s has funded a successful phase 2 clinical trial of a drug called ambroxol, which is thought to increase levels of GCase in cells, thereby improving proper cellular waste disposal. We are now looking to drive this research towards the next phase of clinical development.Ambroxol and Parkinson’s
In Parkinson’s, as with many long-term illnesses, we find chronic inflammation in tissues. Inflammation is an important part of our bodies’ immune defences, but when it is sustained it can cause many damaging effects. In Parkinson’s, inflammation in the brain may contribute to over-production of a toxic form of the protein alpha-synuclein. Chronic low-level inflammation in Parkinson’s is aided by a complex of proteins known as the inflammasome. Researchers have proposed reducing inflammation in Parkinson’s as a means of potentially slowing the progression of the condition. Cure Parkinson’s is currently supporting a phase 2 clinical study in Cambridge evaluating the anti-inflammatory drug azathioprine.Azathioprine and Parkinson’s
Mitochondrial dysfunction also contributes to high levels of very volatile molecules (known as reactive oxygen species) found within dopamine neurons in Parkinson’s. These react with, and damage, their surroundings. They may also contribute to the aggregation of alpha-synuclein. High levels of free and reactive iron molecules are believed to be a source of oxidative stress in dopamine neurons. Iron chelating (removal) medicines which are used to treat people with certain blood disorders, are also being studied in Parkinson’s.Iron chelation and Parkinson’s
Other important research areas
As previously discussed, no two cases of Parkinson’s are the same and as a result, the treatment needs of each individual will be different. This is termed a multi-modal approach.
Looking ahead, once a drug or a treatment has been determined to stop or slow the progression of Parkinson’s, neurons will require ‘neuroprotection’ and this is another important area of Parkinson’s research. Other strategies aim to nourish and protect dopamine neurons by introducing neurotrophic factors.
Of further research interest is dopamine cell replacement therapy, which seeks to introduce healthy functioning dopamine neurons deep into the brain to replace those neurons lost to the disease.
Exenatide is a Glucagon like peptide-1 receptor (or GLP-1R) agonist. This is a class of drug that has traditionally been used for treating diabetes, but has recently been repurposed for Parkinson’s after multiple studies suggested neuroprotective properties in models of Parkinson’s. A number of research studies have been developed to test GLP-1R agonists in Parkinson’s.Exenatide and Parkinson’s
Another area of neuroprotection is that of neurotrophic factors. These are supportive nurturing proteins that the brain produces naturally and they play important roles in both the development of neurons and neuron survival. There are many types of neurotrophic factors which affect different neurons in a variety of ways.Nerve growth factors for Parkinson’s
Neuron replacement – cell replacement therapy
Another avenue of great interest is cell replacement therapy; introducing functional healthy dopamine neurons deep into the brain. Cure Parkinson’s is supporting TRANSEURO, a Europe-wide trial testing dopamine cell-replacement therapies with foetal-derived dopamine neurons in people with Parkinson’s. Other trials are underway around the world using dopamine neurons grown from stem cells.Cell replacement therapy for Parkinson’s
Elsewhere, several research groups are testing immunotherapies (or vaccines) against the Parkinson’s hallmark protein alpha-synuclein. Immunotherapy is a method of directing our immune system to mount defences against specific pathogens or rogue proteins such as the mis-folded alpha-synuclein protein which is a common biological feature of Parkinson’s. Clinical trials of potential vaccines against alpha-synuclein are underway.
Anle138b is a small molecule that has been developed, by the German biotech company MODAG with the support of Cure Parkinson’s, to inhibit alpha-synuclein aggregation; it is hoped that this treatment will slow-down or halt the progression of Parkinson’s.
Also, a biotech company is running a gene therapy trial to introduce a functional version of the GBA-1 gene into the brains of people with Parkinson’s who carry the GBA-1 mutation.