Parkinson's Disease and DLB
Build-up of α-synuclein Disrupts Cellular Processes
Synucleinopathies are a group of neurodegenerative disorders in which the protein α-synuclein accumulates abnormally into fibrils, the major constituent of the Lewy bodies that occur inside brain neurons.
Two primary synucleinopathies are Parkinson’s disease and dementia with Lewy bodies (DLB), which each involve a neurodegenerative, progressive decline in motor and cognitive dysfunction.
Synucleinopathies are second only to Alzheimer’s disease in terms of neurodegenerative disease prevalence. In the United States, as many as one million people suffer from Parkinson’s disease and an estimated 1.4 million from DLB. According to the Parkinson’s Foundation and the Lewy Body Dementia Association, the direct healthcare costs for patients with Parkinson’s disease and DLB are estimated to be approximately $25 billion and $31.5 billion per year, respectively.
Only a few symptomatic treatments (largely aimed at controlling agitation) are approved today for these patients, and at present, no disease-modifying therapeutics exist for either patients with Parkinson’s disease or dementia with Lewy bodies.
Increasing evidence suggests that α-synuclein oligomers disrupt key cellular processes including autophagy and elicit neuronal dysfunction and loss of synapses. This, in turn, contributes to the cognitive and motor symptoms of Parkinson’s disease, DLB and other synucleinopathies.
Our decision to advance a σ-2 receptor modulator for the treatment of synucleinopathies is based on several factors. Data indicate that the σ-2 receptor is involved in regulating autophagy and other key cellular pathways that are impaired in synucleinopathies. In addition, it has been reported that a large percentage of DLB patients have both oligomers of Aβ and α-synuclein in the brain. Together, the evidence that σ-2 receptor modulators may block the toxic effects of α-synuclein oligomers and the Aβ oligomer-induced toxicity to neurons, thereby restoring normal neuronal functioning, provided the rationale needed to advance a σ-2 receptor modulator to the clinic in patients with DLB.
The company has been awarded a grant from the National Institute of Aging (part of the National Institutes of Health) to conduct a clinical trial that would assess whether CT1812 has a beneficial effect on patients with DLB.
- It has been demonstrated in in vitro studies in neurons that σ-2 receptor modulators, such as CT1812, block the toxic effects of α-synuclein oligomers.
- It has further been demonstrated in in vitro studies in neurons that σ-2 receptor modulators such as CT1812, block the toxic effects of Aβ oligomers.
- Please visit clinicatrials.gov and reference NCT05225415
- Safety and tolerability of CT1812 has been characterized through completed and ongoing clinical trials in the company’s Alzheimer’s disease program.
- Subject to discussion with the FDA, we plan to initiate a Phase 2 study in adults who have a diagnosis of DLB.
Limegrover CS, Yurko R, Izzo NJ, LaBarbera KM, Rehak C, Look G, Rishton G, Safferstein H, Catalano SM. Sigma‐2 receptor antagonists rescue neuronal dysfunction induced by Parkinson’s patient brain‐derived α‐synuclein. J Neurosci Res. 2021; 00: 1– 16.