Previously funded research What happens with the results of projects we fund? The Cure Parkinson’s Trust has a targeted research strategy. We want results. As our research portfolio has matured, much of our pre-clinical work now is focused on a three stage process: 1. Identifying potential drugs that work on a specific target 2. Understanding what effect these drugs have on these targets 3. If positive, identify a pathway for the drug to move towards clinical trial through our Linked Clinical Trials (LCT) programme. We have funded work with Professors Kambiz Alavian, Maria Spillantini, Anders Bjorklund and Ted Dawson as well as Dr Katherine Roper, all of whom have identified possible drug candidates that eventually might be relevant for the LCT trials programme. We believe in funding work has a high likelihood of leading us on to the next step. For example we funded Professor Steve Gill to solve the mechanical problem of finding a new way to deliver the large sticky GDNF molecule directly into the part of the brain where it was needed. The resulting convection enhanced delivery mechanism is now being used in a clinical trial in Bristol and we will have results later this year. Study - 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. Read about the exciting next phase of trials in this drug class. 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 persist 12 months after exenatide exposure in Parkinson's disease' - (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. Stopping dopamine neuron degeneration by preventing Alpha-synuclein redistribution at the synapses - Professor Maria Spillantini, Cambrige University - Professor Spillantini and the team at Cambridge believe that reducing the clumps and restoring normal distribution of alpha-synuclein in nerve endings will restore normal release of dopamine and therefore normal communication between the neurons, thereby reducing the clinical symptoms of Parkinson’s. This project followed on from an earlier study funded by CPT and tested whether neuronal dysfunction in Parkinson’s initiates at the synapse where alpha-synuclein forms toxic aggregates. Two compounds were introduced to determine whether they we able to restore communication between nerve cells and in doing so possibly indicate a new therapeutic target for a cure. Study - a-Synuclein–Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons - Professor Anders Bjorklund - NURR1 plays a key role in the maintenance of the dopaminergic system of the brain and mutations in this gene have been associated with dopaminergic dysfunction in Parkinson's. CPT's previously funded work in NURR1 has now moved on to the next pre-clinical phase. Study - 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 - The Cure Parkinson’s Trust had the opportunity to fund some extremely original research involving a mass laboratory screening of around 100,000 already approved drugs to determine which of them would act on a newly discovered natural compound (known as PARIS) that had recently been shown to compromise dopaminergic neurones and cellular energy processes. We reasoned that if compounds that could disarm it were identified then we might be able to use this knowledge to slow the progression of PD. The drugs identified from this screening process could then be fed directly into our Linked Clinical Trials (LCT) programme which could move (one or more of) them quickly into clinical trials with people with Parkinson’s to prove their benefit. 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. Identification of new drugs to improve neuronal energy production for treatment of PD - Dr Kambiz Alavian, Imperial College, London - Nerve cells (neurons) have a high-energy demand for transferring information as electrical signals to other cells and for storing information in the brain. Most of the energy for neurons comes from mitochondria. Mitochondrial dysfunction, leading to reduced energy production, is a known contributing factor in the development of PD. Dr Alavian’s lab focused on modifying the molecular mechanisms underlying mitochondrial energy production. The therapeutic focus of his research set to identify new ways for enhancing the efficiency of mitochondrial energy production for treatment of PD. CPT funded Dr Alavian to conduct a drug screen using a library of 12,000 small molecules identifying a number of possible agents to enhance mitochondrial energy production. By enhancing mitochondrial metabolic efficiency, these drugs may be able to protect against neurodegeneration caused by several stress factors, including mutations in the PD genes. The next step is to test these agents in pre-clinical models of PD, in order to assess the safety and efficacy of each drug to see if any could be progressed to trial, via CPT’s LCT programme. Study - 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. Study - 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. Study - Investigating the potential of using the Rabies (RVG9R-p137) virus in treating models of Parkinson’s expressing alpha-synuclein: Professor Roger Barker, Cambridge University - The Rabies virus is a neurotrophic virus which means it can cross the highly impermeable blood brain barrier. By stripping out the rabies virus within, the remaining vessel can be used as a targeted carrier for potential Parkinson’s therapies. Professor Barker is using this vessel to explore treatments delivered into the brain which could counteract the overproduction of alpha-synuclein in Parkinson’s. This project has been generously supported by the Masonic Samaritan Fund.More information can be found in the following paper:'A novel neuroprotective therapy for Parkinson’s disease using a viral noncoding RNA that protects mitochondrial Complex I activity' - (Kuan et al., 2012). Click here to read more. Study - Convection Enhanced Delivery System - Professor Steven Gill - 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. Study - 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. Study - 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). Study - 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 modification - Brotchie 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. Autophagy Inducers (FU-288) - Enhancing autophagy (tyhe natural degradation of dysfunctional or unnecessary 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 human use. Studies in a model of alpha-synuclein over expression have shown that FU-288 can provide behavioural recovery by reducing PD symptoms as well as reducing alpha-synuclein accumulation and protect dopaminergic neurones from premature death.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.