Researchers from the Center for Neurogenetics and colleagues from the Northwestern University Feinberg School of Medicine report a novel small-molecule modulator called S-181 shows promise in preclinical research animal studies for the treatment of a familial form of Parkinson’s disease however researchers caution it is not yet ready for Phase I trials in humans.
A mutation in the GBA1 gene represent the most commonly known genetic risk factor for Parkinson’s disease (PD). The BBA1 gene encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In animal models, of PD, preclinical research evidences that a novel molecule modulator of GCase offers both a promising precision medicine pathway for treatment of this subgroup of PD patients and a possible broader treatment option for sporadic “wild-type” Parkinson’s disease reports Catarina Silva of Parkinson’s News Today.
What is S-181?
A novel small molecule modulatory developed by Dmitri Krainc, MD chair of the Department of Neurology and director of the Center for Neurogenetics and colleagues at Northwestern University Feinberg School of Medicine which was recently reported in the October 16 issues of Science Translational Medicine.
S-181 bind to GCase and modulates its activity—treating these patient derived neurons with S-181 partially restored lysosomal function and lowered accumulations of Parkinson’s-related toxic molecules, including oxidized dopamine and glucosylceramide reports Ms. Silva. Additionally S-181 decreased accumulations of alpha-synuclein—one of the main elements of PD’s hallmark protein deposits known as Lewy bodies.
Mice with a mutated GBA1 gene were treated with S-181. The treatment, reported the investigators, improved the activity of non-mutated GCase and reduced the production of barely active GCase-dependent harmful molecules, decreasing alpha synuclein accumulation in the brain. In a MedicalXpress press release, investigator Dimitri Krainc, MD, PhD noted that the study “highlights wild-type GCase activation as a potential therapeutic target for multiple forms of Parkinson’s disease.”
Comments on Risk of GBA1 gene
It is known that the GBA mutation associated with PD indicates potentially more aggressive form of the disease than perhaps with other PD patients. Experts in the field report that this class of patient may decline faster that non-GBA PD patients when it comes to motor and cognitive factors. It appears that GBA-PD patients face a higher risk of dementia and other cognitive issues long term than those who are non-GBA PD patients. Note that GBA mutation is associated with Gaucher disease, a common lysosomal storage disease—in this case GCase deficiency triggers accumulation of glucocerebroside and factors into enlargement of spleen and liver.
About Center for Neurogenetics
The Simpson Querrey Center for Neurogenetics aims to study rare diseases (affecting less than 200,000 people in the US at a given time) as a window to understanding more common conditions and develop new treatments across the lifespan. The initial focus is on neurodegenerative diseases for which conventional drug development has been particularly challenging, primarily due to the lack of accurate molecular targets and biomarkers. Our recent scientific discoveries have established a new direction for the development of targeted treatments for neurodegenerative disorders.
Dimitri Krainc, MD, Chair, Department of Neurology