reports employment, stock ownership, and travel for Prothena

reports employment, stock ownership, and travel for Prothena. demonstrates that serum synuclein can be safely modulated in a dosedependent manner after single intravenous infusions of an antisynuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson’s disease. 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. Keywords: Parkinson’s disease, clinical trial, protein aggregation, protein misfolding, synucleinopathy Parkinson’s disease is a neurodegenerative disorder that manifests a spectrum of motor, psychiatric, cognitive, sleep, and autonomic signs and symptoms. The key underlying motor manifestation is caused by a slow and progressive degeneration of dopamineproducing neurons in the substantia nigra. 1, 2Parkinson’s disease affects 7 to 10 million persons worldwide, 3making it the second most prevalent neurodegenerative disorder after Alzheimer’s disease. 4Parkinson’s disease is also associated with significant economic burden; in 2010, in the United States, medical expenses related to Parkinson’s disease were approximately 2fold higher than they were for an agematched population without Parkinson’s disease. 5 Currently available treatments for Parkinson’s disease target the dopaminergic features of the disease but do little to address its nondopaminergic symptoms and fail to treat the underlying neurodegeneration and progressive decline in neurologic function. In addition , nonmotor symptoms of the disease (such as psychosis, sleep behavior disorder, gastrointestinal dysfunction, and cognitive impairment), which can be direct or indirect outcomes of dopaminergic and other neuronal loss, are often resistant to dopamine replacement strategies and may be exacerbated by treatment under some conditions. 6, 7Furthermore, with prolonged use, currently available treatments are often associated with eventual disabling fluctuations, dyskinesias, and doselimiting side effects that decrease their benefits. 8, 9There is a significant unmet need for diseasemodifying therapeutic approaches that potentially slow or halt the progression of Parkinson’s disease, thereby reducing the substantial personal and economic burdens it creates. The aggregationprone synuclein protein is the major component of Lewy bodies and Lewy neurites, which are neuropathologic hallmarks of Parkinson’s disease and other neurodegenerative diseases. 10, 11, 12Missense mutations in the synuclein gene and the overexpression of the nonmutated protein because of gene duplication or triplication are Chlorobutanol associated with early onset Parkinson’s disease. 13Furthermore, strong correlations between clinical manifestations in Parkinson’s disease and the presence and severity of synuclein pathology in the brain and peripheral nerves have been reported. 14In preclinical studies, transgenic mice that overexpress synuclein with missense mutations demonstrate a number of key features of the disease. 15, 16, 17 Although the etiology of Parkinson’s disease is Chlorobutanol yet to be determined, substantial clinical and nonclinical data suggest that soluble aggregated forms of synuclein (eg, oligomers, soluble protofibrils) selfpropagate and may spread between interconnected nervous system regions and contribute to disease progression. For instance, the pattern of Lewy pathology in patients with Parkinson’s disease is generally consistent with disease propagation over interconnected neuronal networks14; embryonic mesencephalic neurons transplanted into Parkinson’s disease patients develop synuclein pathology a decade after initial grafting, 18, 19and intracerebral injection of aggregated synuclein accelerates the onset of neurologic symptoms and death in transgenic mice expressing human synuclein. 20In addition to the established Chlorobutanol role of Lewy bodies, soluble aggregated synuclein species have also been proposed as a major neurotoxic form of the protein in the pathophysiology of Parkinson’s disease. 21Altogether, these genetic, neuropathologic, and nonclinical data support the therapeutic potential of agents that target aggregated forms of synuclein and block the celltocell transmission of synuclein in patients with Parkinson’s disease. We have developed a monoclonal immunoglobulin G1 antibody, PRX002, designed to preferentially target soluble and insoluble aggregated forms of synuclein. PRX002 is derived from the murine monoclonal antibody 9E4, which was developed based on results of immunization Chlorobutanol Nrp2 experiments that showed that antibodies Chlorobutanol directed against carboxyl terminus epitopes of synuclein were the most effective at reducing both the neuronal accumulation of synuclein and the behavioral deterioration in animal models. 15, 16For.