STAR Candidates Boost GCase in Cell, Animal Models

Gain Therapeutics‘ investigational compounds were able to lessen motor symptoms in a rat model of GBA1-associated Parkinson’s disease and also decrease the levels of alpha-synuclein accumulation in nerve cells — two hallmarks of the neurodegenerative disease.

The two candidates — GT-02287 and GT-02329 — are special compounds called STARs (small-molecule structurally targeted allosteric regulators) that were identified using Gain’s proprietary drug discovery platform.

“These data demonstrate that our [STARs] compounds open a new potential approach for direct treatment of GBA1 Parkinson’s disease,” Manolo Bellotto, PhD, general manager and president at Gain, said in a press release. 

The study, “Preclinical Development of Brain-Penetrant Structurally Targeted Allosteric Regulators (STARs) for the Treatment of GBA1 Parkinson’s Disease and Related α-Synucleopathies,” was presented at the XXVI International Association of Parkinsonism and Related Disorders (IAPRD) World Congress held online on May 1–4.

People with GBA1 mutations have up to a five-times greater risk of developing Parkinson’s disease. The GBA1 gene contains the information necessary to produce the enzyme beta-glucocerebrosidase (GCase) — an important component of cells’ recycling factories, called lysosomes. Lack of this enzyme, or its faulty activity, will make cells accumulate toxic substances inside them, such as the protein alpha-synuclein, which may contribute to the neurodegeneration seen in Parkinson’s disease.

Gain’s Site-directed Enzyme Enhancement Therapy (SEE-Tx) system uses the 3-D structure of proteins to identify and predict the affinity of potential drug-binding sites. The newly-discovered STARs are designed to bind to and restore the activity of mutant GCase, which often is misfolded and dysfunctional. The stabilized GCase then is able to reduce the toxic accumulation of alpha-synuclein in Parkinson’s.

“We identified two STAR lead candidates that have the potential to help Parkinson’s patients with GBA1 gene mutations as well as patients whose GCase protein is misfolded due to aging cellular processes,” said Eric I. Richman, CEO at Gain.

Both GT-02287 and GT-02329 stabilized and boosted the activity of GCase in fibroblast cells harvested from patients with Gaucher disease, a condition that has a similar genetic profile to GBA1-associated Parkinson’s and that may increase the risk of developing Parkinson’s.

The compounds also promoted cell survival and reduced alpha-synuclein accumulation in cultured rat dopamine neurons — those that are gradually lost during the course of Parkinson’s.

Orally delivered GT-02329 was found to penetrate the blood-brain barrier — a semipermeable membrane that protects the brain from the outside environment and also is a barrier for adequate drug delivery to the brain — enhancing GCase activity in the brains of healthy mice.

GT-02287 also reduced toxic alpha-synuclein accumulation and improved motor activity in a rat model of Parkinson’s disease.

“Our preclinical data demonstrates that our STAR compounds successfully target protein misfolding rather than treating symptoms of the disease,” Richman said.