STAR Compounds Show Potential to Treat GBA1-linked Parkinson’s
Gain Therapeutics announced that preclinical studies with two of its compounds, GT-02287 and GT-02329, showed they could reduce the alpha-synuclein aggregates that characterize Parkinson’s and increase glucocerebrosidase protein levels in cell models of Parkinson’s and Gaucher disease.
GT-02287 and GT-02329 are known as STARs, which stands for structurally targeted allosteric regulators. These regulators are designed to help mutated proteins fold correctly and recover their function.
The preclinical studies, conducted at the University of Maryland School of Medicine (UMSOM), evaluated GT-02287 and GT-02329 in Gaucher’s disease and in Parkinson’s that is associated with a mutated GBA1 gene. This gene encodes beta-glucocerebrosidase (GCase), an enzyme active in lysosomes (the recycling centers of the cell) that is know to be involved in these and other neurodegenerative diseases.
“This breakthrough in the ability to restore enzyme function for Parkinson’s Disease and Gaucher’s Disease is unprecedented for a small molecule and will contribute to a major shift in how we think about treating various neurodegenerative and lysosomal storage diseases with a genetic predisposition,” Eric I. Richman, Gain CEO, said in a press release.
“This brings tremendous hope to the population of individuals who are diagnosed with various forms of alpha synucleinopathies, including those with Parkinson’s Disease, Alzheimer’s, Lewy Body Dementia, and all forms of Gaucher’s Disease,” Richman added.
Researchers used induced pluripotent stem cells (iPSC) — cells that can be differentiated into numerous cell types — from patients with either GBA1-associated Parkinson’s or Gaucher to test the two candidates’ effectiveness. This “disease-in-a-dish” iPSC model allows for efficient testing of numerous candidates.
Results showed that both STARs, GT-02287 and GT-02329, can increase the levels of GCase and restore its activity in dopaminergic cells, the nerve cells that secrete dopamine and are affected in Parkinson’s. They also increased the localization of GCase to its place in the lysosome.
In general, data showed that GT-02287 and GT-02329 can bind to, stabilize, and restore the function of misfolded GCase proteins, leading to the restoration of GCase function and, subsequently, to the depletion of toxic aggregates of alpha-synuclein.
“Our studies in iPSC-derived cortical and dopaminergic neurons from neuronopathic Gaucher Disease patients show that these compounds significantly increase the levels of GCase protein, its transport to the lysosome, and its enzymatic activity,” said Ricardo Feldman, PhD, associate professor of microbiology and immunology at UMSOM.
“In dopaminergic neurons, the two lead STAR chaperones also decrease the levels of the hallmark of Parkinson’s Disease – [alpha-synuclein aggregates], demonstrating their potential to treat GBA1-associated Parkinson’s Disease,” said Ricardo Feldman, PhD, associate professor of microbiology and immunology at UMSOM.
The results obtained in cells were confirmed by data on a rat model of Parkinson’s disease, in which these STARS were found to reduce aggregation of alpha-synuclein proteins and reverse the neurodegenerative process, ultimately easing the animal’s locomotor activity.
“This data demonstrates that our STARs are able to guide misfolded forms of the GCase enzyme to their proper shape and restore enzymatic activity, establishing an important novel approach for direct treatment of GBA1 Parkinson’s Disease and other alpha-synucleinopathies,” said Manolo Bellotto, PhD, general manager at Gain Therapeutics.
These results were presented at The Michael J. Fox Foundation for Parkinson’s Research’s “Innovating from Drug Discover to the Clinic: Novel Approaches to PD Therapeutic Development” webinar.
The company believes that due to their small size, STARs might be administered as an oral medication and reach organs and tissues that may not be accessible through current therapeutic options.
It is also planning to start “IND [investigational new drug]-enabling studies for Gaucher and Parkinson’s Disease shortly,” Richman said. These studies support an IND application, a necessary step in getting U.S. Food and Drug Administration approval to open clinical trials of an investigational compound in people.