Objective/Rationale:
A role for the synaptic protein alpha-synuclein in Parkinson’s disease is suggested by human genetic studies, the histopathology in patients with Parkinson’s disease and studies using pre-clinical models. Recent work further suggests that compounds that bind to specific regions of alpha-synuclein can prevent its toxic effects in the brain. We will test whether a compound (NPT200-11) that prevents alpha-synuclein toxicity in vitro can do such in pre-clinical models. If NPT200-11 does prevent this toxicity, we will further evaluate safety and pharmacokinetic properties to see if it might be a drug candidate for the treatment of Parkinson’s disease.
Project Description:
We will test whether NPT200-11 prevents the adverse effects of alpha-synuclein in models genetically modified to produce human alpha-synuclein in the brain. Following preliminary positive findings, we will determine what dose is required to produce beneficial effects in these models. This will allow us to estimate what dose might be required to produce beneficial effects in humans. In parallel, we will test whether NPT200-11 has undesired toxicities or other safety issues. This will be determined using in vitro and in vivo experiments that help predict whether a compound will be safe in humans.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If NPT200-11 is found to have robust benefits in a pre-clinical model of Parkinson’s disease, and if it is also shown to be a compound that can be safely given to humans, then NPT200-11 could be further evaluated as a potential treatment for Parkinson’s disease. Since the mechanism of NPT200-11 is to prevent the progressive neuronal damage caused by alpha-synuclein, the goal is to prevent the further progression of the disorder.
Anticipated Outcome:
The first anticipated outcome of these studies will be to resolve whether or not this compound, that prevents alpha-synuclein from taking on toxic conformations in vitro, also prevents alpha-synuclein toxicity in pre-clinical models.The second anticipated outcome of these studies will be to resolve whether the compound is safe enough to continue to move forward toward eventual trials in human subjects.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.
Final Outcome
The studies demonstrated beneficial actions of NPT200-11 in several alpha-synuclein based animal models of Parkinson's disease. The compound decreased the accumulation of alpha-synuclein in the brain and other tissues including the heart and retina. It decreased alpha-synuclein mediated dysregulation of neurochemistry. And, it improved motor function in these animals. These studies not only demonstrated the beneficial effects of NPT200-11 in animal models, they identified the lowest dose and plasma level required for activity, thus providing a target dose for future studies in humans. The finding that NPT200-11 had beneficial effects in the retina and peripheral tissues lays the foundation for potentially identifying measured clinical endpoints for this compound in patients.
The researchers also demonstrated that NPT200-11 normalizes an alpha-synuclein caused dysregulation of calcium dynamics in the brain pointing to one possible explanation for how clearing misfolded alpha-synuclein from cell membranes may result in improved neuronal function.
The initial pharmacokinetic, safety and toxicological studies needed to more fully characterize NPT200-11 before proposing its entry into clinical trials have also been completed.
Presentations & Publications
2014 Society for Neuroscience Meeting:
Biophysical characterization of the interaction of NPT200-11 with alpha-SYNUCLEIN BALAZS SZOKE, WOLF WRASIDLO, EMILY STOCKING, IGOR TSIGELNY, ROBERT KONRAT, AMY D. PAULINO, DIANA L. PRICE, STEFAN WINTER, ELIEZER MASLIAH, DOUGLAS BONHAUS, DIETER MEIER
The novel alpha-synuclein stabilizer NPT200-11 reduces retinal deposits of ASYN-eGFP in a transgenic mouse
model of Parkinson's disease/Lewy body disease: D. L. PRICE, E. M. ROCKENSTEIN, M. MANTE, W. WRASIDLO, E. MASLIAH, D. W.BONHAUS, D. H. MEIER
The novel alpha-synuclein stabilizer NPT200-11 improves behavior, neuropathology, and Biochemistry in the
murine thy1-ASYN transgenic model of Parkinson's disease M. A. KOIKE, D. L. PRICE, B. M. WHITE, E. ROCKENSTEIN, W. WRASIDLO, I. TSIGELNY, D. MEIER, E. MASLIAH, D. W. BONHAUS