Published project results, on going progress to a cure 1) Exenatide (Exendin-4) study: Dr Tom Foltynie, UCL London The Cure Parkinson’s Trust provided support for the setup and conduct of this ground-breaking trial evaluating the safety and efficacy of Exenatide as a treatment for Parkinson’s disease. Patients were randomised into 2 groups, one group injecting Exenatide twice daily for a 12 month period, the other group acting as a comparison “control” group. All patients were seen for a further assessment at 14 month and 24 month stages which gave positive insight into the neuroprotective and restorative effects of Exenatide beyond cessation of administration of the drug. The results of this study can be viewed in the following papers:'Exenatide and the treatment of patients with Parkinson's disease' - (Aviles-Olmos et al., 2013). Click here here to read more.'Motor and cognitive advantages persit 12 months after exenatide exposure in Parkinson's diseae' - (Aviles-Olmos et al., 2014). Click here to read more.'Exenatide as a potential treatment for patients with Parkinson’s disease: first steps into the clinic' - (Foltynie & Aviles-Olmos, 2014). Click here to read more. Read further information about the next phase of trials in this drug class. 2) Calcium channels – why are they important? Exploring the role of calcium in Parkinson’s. Professor David Dexter & Dr Mike Hurley, Imperial College, London Calcium helps play an important role in neuronal pathways where it assists in neurotransmitter release from neurones - calcium enters dopamine neurones through particular calcium channels (the Cav1.3 subtype) and Dr Hurley has been exploring how these channels are affected by 'oxidative stress', which in turn impacts mitochondrial function. This study will help us identify what drugs might be effective in managing calcium in dopamine cells and help prevent oxidative stress, thereby reducing inflammation and slowing down the progression of Parkinson’s.More information can be found in the following papers:'Calcium dysregulation in Parkinson's disease' - (Schapira, 2013). Click here to read more. 'Parkinson's disease is associated with altered expression of Cav1 channels and calcium binding proteins' - (Hurley et al., 2013). Click here to read more. 'Altered expression of brain proteinase-activated receptor-2, trypsin-2 and serpin proteinase inhibitors in Parkinson's disease' - (Hurley et al., 2015). Click here to read more. 3) Monitoring alpha-synuclein oligomers and LRRK2 dimers to screen for novel disease modifying Parkinson’s drug therapies: Dr Javier Alegre-Abarrátegui, University of Oxford The LRRK2 protein contains two enzymes which are catalysts that accelerate chemical reactions inside a cell. Enzyme activity can often be relatively easily modified by small drugs, making enzymes attractive targets for drug therapies. Reducing the activity of LRRK2 delays the progression of cell death by preventing alpha-synuclein aggregation, suggesting that there is an interaction between the proteins in Parkinson’s. This project investigated how alpha-synuclein and LRRK2 molecules interact with themselves and with each other. Dr Alegre-Abarrategui developed novel tests to measure the interactions between LRRK2 and alpha-synuclein molecules. These tests could prove critical for future screening for drugs which prevent such interactions occurring. The results of this project can be viewed in the following paper:'Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain' - (Roberts, Wade-Martins & Alegre-Abarrategui, 2015). Click here to read more.4) Blocking Paris to preserve PGC-1α: Investigating the role of Paris in models of PGC-1α, Dr Ted Dawson, John Hopkins University School of Medicine, Boston, USA A rare Parkinson’s gene PARK 2 affects the Parkin protein, Parkin has the specific job of labelling proteins for destruction. It was recently discovered that Parkin regulates the cellular expression of an enzyme called PARIS, targeting it for degradation. In Parkinson’s Parkin is inactive, allowing the accumulation of PARIS to toxic levels. PARIS represses the expression PGC-1α, a protein which controls the function of individual mitochondria. Therefore, too much PARIS leads to mitochondrial dysfunction and a loss of dopaminergic neurones. Professor Dawson and colleagues have been screening drugs to block the way PARIS acts on PGC-1α, to protect mitochondria.More information can be found in the following paper:'PARIS (ZNF746) Repression of PGC-1α Contributes to Neurodegeneration in Parkinson’s disease' - (Shin et al., 2011). Click here to read more.5) Convection Enhanced Delivery System In 2006 we funded Professor Steven Gill to create a novel delivery mechanism which would allow delivery of large proteins with pin-point accuracy to the substantia nigra area of the midbrain in Parkinson’s. This new system called the Convection Enhanced Delivery System is being trialled now in the GDNF Study in Bristol. For more details of this work, see the section on Regenerative medicine.6) Differentiation of GMP-grade human embryonic stem cells to midbrain dopaminergic neurones for transplantation, Dr Tilo Kunath, MRC Centre for Regenerative Medicine Dr Kunath continues to investigate and screen the best cell lines to use for the Transeuro project. The Cure Parkinson's Trust is funding this work for one year to maximize the number of cell lines that can be considered.Click here to download more information. 7) Screen of FDA-approved drugs for repositioning as modulators of PARK2 function Dr Katherine Roper, Leeds University Over the last ten years, the majority of the proteins associated with inherited forms of Parkinson’s have been identified. Restoring these proteins activity would potentially not only be useful for treating inherited forms of Parkinson's but also in the sporadic disease. Parkin is a protein whose biological activity is lost in a large percentage of inherited Parkinson's. Dr Roper has developed a simple test to measure Parkin activity which was used to screen FDA-approved drugs for restorative properties of Parkin activity. A number of such compounds were identified. These compounds can be developed as Parkinson's treatments far more swiftly, with a greater chance of success than the development of entirely new drugs which have to undergo a series of expensive and time-consuming clinical trials with a low FDA approval rate (1 in 10 between 2004 and 2010). 8) Drug Discovery Programme: Dr Jon Brotchie Dr Brotchie and colleagues’ research aims were to increase understanding of brain mechanisms underlying Parkinson’s disease, and to translate that understanding into novel treatments and cures that will impact positively on quality of life. Disease modificationBrotchie and colleagues took two approaches to disease modification, the first to identify small molecule inducers of neurotrophic factors, the second to target alpha-synuclein as a key mechanism of the pathology. While several molecules of each type showed no or limited promise, two approaches were identified as having significant potential. Steroidal sapogenin inducers of GDNF and BDNF (PYM50028, Cogane): This small, orally active molecule induces neurotrophic factor synthesis, restoring dopaminergic and motor function in MPTP models of Parkinson's. PYM50028 has successfully passed safety, toxicology and initial Phase 1 clinical studies in healthy human volunteers and PD patients. PYM50028 entered a large proof of concept, Phase II study, CONFIDENT-PD (400+ patients) to assess whether it was able to provide benefit when administered daily for 6 months, with inconclusive results.More information can be found in the following paper:'PYM50028, a novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced by MPP in mesencephalic neurons and by MPTP in a mouse model of Parkinson’s disease' - (Visanji et al., 2008). Click here to read more. Autophagy inducers (FU-288): Enhancing autophagy (the natural degradation of dysfunctional or unneccessary cellular components) has the potential to be disease modifying as it could provide a means of clearing alpha-synuclein aggregates. FU-288 is based upon a natural molecule that stimulates autophagy. It is generally regarded as safe for human use, and thus could, if appropriate, be readily developed for clinical use. Studies in a model of alpha-synuclein over-expression have shown that FU-288 can provide behavioural recovery by reducing Parkinsonian symptoms as well as reducing the alpha–synuclein accumulation and protect dopaminergic neurones from death.