BRF110

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 (PD) is, after Alzheimer’s disease, the second most-common neurodegenerative disorder affecting 1–2% of the global population over the age of 65 (1, 2). Aging being a primary risk factor for PD (3), its economic burden on our society in terms of medical care will escalate with our aging population. The major pathophysiological features of PD include selective and progressive degeneration of A9 midbrain dopaminergic (mDA) neurons in the substantia nigra and widespread accumulation of intraneuronal proteinaceous inclusions, called Lewy bodies, whose major component is misfolded α-synuclein. A9 DA neurons project to the dorsal striatum and form the nigrostriatal pathway, which controls voluntary movements. Degeneration of this pathway in PD patients results in decreased dopamine levels in the striatum, leading to clinical manifestations, such as resting tremor, rigidity, bradykinesia, and gait dysfunctions (1, 2). Since its introduction in the 1960s, dopamine replacement therapy through levodopa (l-dopa) and DA agonist administration remain the standard treatment for PD (4). Although this pharmacological treatment dramatically improves the quality of life of numerous PD patients, its efficacy wanes over time and the need for increased dosage eventually induces severe side effects, such as dyskinesia. Although there are alternative surgical treatments, such as deep brain stimulation (5), both forms of treatment are symptomatic and cannot stop or modify the disease progression. Therefore, there is a significant unmet need for the development of novel neuroprotective and disease-modifying therapeutics for PD. In PNAS, Spathis et al. (6) introduce a novel compound, BRF110, which is a unique Nurr1: retinoid X receptor-α (RXRα)-selective “agonist” that can prevent DA neurons’ demise and striatal DA denervation in vivo in several preclinical models of PD. Remarkably, this study shows that BRF110 is not only neuroprotective in sparing mDA neurons, but also upon a single administration led to significant … [↵][1]1Email: kskim{at}mclean.harvard.edu. [1]: #xref-corresp-1-1