Therapy for Parkinson's Disease: What is in the Pipeline?

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement. We designed BRF110, a unique in vivo active Nurr1:RXRα-selective lead molecule, which prevents DAergic neuron demise and striatal DAergic denervation in vivo against PD-causing toxins in a Nurr1-dependent manner. BRF110 also protects against PD-related genetic mutations in patient induced pluripotent stem cell (iPSC)-derived DAergic neurons and a genetic mouse PD model. Remarkably, besides neuroprotection, BRF110 up-regulates tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH1) transcription; increases striatal DA in vivo; and has symptomatic efficacy in two postneurodegeneration PD models, without inducing dyskinesias on chronic daily treatment. The combined neuroprotective and symptomatic effects of BRF110 identify Nurr1:RXRα activation as a potential monotherapeutic approach for PD.Parkinson's disease | target validation | neuroprotection

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“…Neuroprotective approaches, although aimed at the core of PD pathology, so far have not delivered the expected results (26).…”

Section: Discussionmentioning

confidence: 99%

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Spathis

Asvos

Ziavra

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, as might be expected, there has been a time lag in drug development with few novel therapies coming to market in recent years [98,99]. For PD research to move forward, we need to consider the impact of the numerous recent insights on the development of new drugs and tailored strategies.…”

Section: Discussionmentioning

confidence: 99%

Unmet needs in Parkinson's disease: New horizons in a changing landscape

Bhidayasiri

Laar

2016

Parkinsonism & Related Disorders

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a b s t r a c tThe success of levodopa and other classes of drugs have meant that most people with Parkinson's disease enjoy a good quality of life for many years. However, despite the availability of several drugs and formulations that can be used as monotherapy and in combination, there are a number of disease features that the current therapies are unable to address. The disease continues to progress despite treatment, patients suffer from a myriad of motor and non-motor symptoms, and a neuroprotective therapy is urgently required. To move forward with medical and surgical management, it is important to consider new insights that recent research offers and in this review we examine how a better understanding of the disease pathology and progression might improve and enrich our daily clinical practice. It is also timely to consider the service provision changes that will increasingly be needed to effectively manage the needs of the aging population.

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“…Unfortunately, clinical trials often failed in translating the encouraging results obtained from in vitro and in vivo experimental findings. To some extent, the suboptimal selection of enrolled patients and the lack of measurable biomarkers or reliable outcomes account for such failures [ 1 – 3 ]. Genetically defined populations (LRRK2 or GBA mutations) seem to be suitable candidates for neuroprotection [ 2 ], but it is well known that less than 10% of PD cases can be ascribed to a monogenic mutation [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Outlining a Population “at Risk” of Parkinson’s Disease: Evidence from a Case-Control Study

Schirinzi

Martella

D'Elia

et al. 2016

Parkinson's Disease

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The multifactorial pathogenesis of Parkinson's Disease (PD) requires a careful identification of populations “at risk” of developing the disease. In this case-control study we analyzed a large Italian population, in an attempt to outline general criteria to define a population “at risk” of PD. We enrolled 300 PD patients and 300 controls, gender and age matched, from the same urban geographical area. All subjects were interviewed on demographics, family history of PD, occupational and environmental toxicants exposure, smoking status, and alcohol consumption. A sample of 65 patients and 65 controls also underwent serum dosing of iron, copper, mercury, and manganese by means of Inductively Coupled-Plasma-Mass-Spectrometry (ICP-MS). Positive family history, toxicants exposure, non-current-smoker, and alcohol nonconsumer status occurred as significant risk factors in our population. The number of concurring risk factors overlapping in the same subject impressively increased the overall risk. No significant differences were measured in the metal serum levels. Our findings indicate that combination of three to four concurrent PD-risk factors defines a condition “at risk” of PD. A simple stratification, based on these questionnaires, might be of help in identifying subjects suitable for neuroprotective strategies.

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Therapy for Parkinson's Disease: What is in the Pipeline?

Cited by 23 publications

References 68 publications

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson’s disease

Unmet needs in Parkinson's disease: New horizons in a changing landscape

Outlining a Population “at Risk” of Parkinson’s Disease: Evidence from a Case-Control Study

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