Oral therapy GT-02287 shows promise in Parkinson’s mice models

Phase 1 trial of treatment candidate expected to start later this year

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by Andrea Lobo |

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A hand holds a mouse alongside a rack with three filled vials.

Gain Therapeutics’ GT-02287, an oral investigational therapy for Parkinson’s disease, was found to reduce blood levels of neurofilament light chain (NfL), a biomarker of nerve cell degeneration, in mouse models of the disorder.

Further, the treatment lessened recognizable features associated with Parkinson’s symptoms — such as alpha-synuclein aggregates, or clumps, inflammation, and neuronal loss — while enhancing the motor function of the animals.

These findings will be presented by Gain in two posters at the International Congress of Parkinson’s Disease and Movement Disorders 2023, to be held Aug. 27-31 in Copenhagen, in Denmark.

The company now is expecting to test GT-02287 in a Phase 1 clinical trial later this year.

“We look forward to initiating our Phase 1 clinical study in healthy volunteers very soon and advancing the development of this potentially best-in-class treatment for GBA1 Parkinson’s disease,” Matthias Alder, CEO of Gain Therapeutics, said in a company press release.

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Gain granted $2.8M to develop lead therapy for GBA1 Parkinson’s

2 studies on GT-02287 being presented at global congress

GT-02287 is designed to increase the activity of beta-glucocerebrosidase, or GCase, an enzyme that plays a critical role in the functioning of lysosomes — the cell compartments responsible for clearing cellular waste.

Low GCase activity is commonly found in Parkinson’s and is believed to contribute to the harmful buildup of the alpha-synuclein protein, a hallmark of the disease, in patients. Mutations in the GBA1 gene, responsible for the GCase enzyme, also are linked to a higher Parkinson’s risk.

GT-02287 was created using Gain’s Site-directed Enzyme Enhancement Therapy (SEE-Tx) system, which studies protein structures to predict interactions with potential therapies. By attaching to GCase, GT-02287 aims to enhance the protein’s stability, ensuring it maintains the necessary shape for proper functionality.

In cell-based models, GT-02287 was shown to correct several abnormalities associated with Parkinson’s disease. In previous preclinical studies, the therapy improved the health of nerve cells and fine motor skills in Parkinson’s mice models.

In one new study, titled “Neuroprotective effect of GT-02287, a brain-penetrant structurally targeted allosteric regulator of glucocerebrosidase, leads to a significant reduction of plasma NfL levels and improvement in behavioural deficits in a mouse model of GBA1 Parkinson’s disease,” researchers created a mouse model that mimics what occurs in people with GBA1-associated Parkinson’s.

The oral administration of GT-02287 over 14 days significantly reduced the levels of agreggated alpha-synuclein, neuroinflammation, and neuronal death.

GT-02287 … markedly decreased plasma NfL, an emerging and important neurodegeneration biomarker that can be measured in blood, which is very exciting as we consider its application in clinical trials.


Treatment with GT-02287 also increased the levels of dopamine and tyrosine hydroxylase, a marker of dopamine-producing neurons — the nerve cells that are progressively lost in Parkinson’s — while improving motor strength and coordination.

“GT-02287 also markedly decreased plasma NfL, an emerging and important neurodegeneration biomarker that can be measured in blood, which is very exciting as we consider its application in clinical trials,” said Joanne Taylor, PhD, senior vice president of research at Gain.

In a second study, titled “GT-02287, a brain-penetrant structurally targeted allosteric regulator for glucocerebrosidase shows evidence of pharmacological efficacy in an animal model of Parkinson’s disease,” the therapy restored GCase levels in the brain of another Parkinson’s mouse model. It also reduced the levels of aggregated alpha-synuclein.

Similarly, the treatment was found to reduce inflammation, improve lysosomal health, and increase tyrosine hydroxylase levels in the substantia nigra, a brain region where dopamine-producing neurons are mainly found.

Together, the studies support the planned clinical trial, Adler said.

“The robust data from both posters demonstrate that our lead drug candidate GT-02287 can restore GCase protein function, protect against the neuropathological features of Parkinson’s disease, and reduce neurodegeneration measured by the emerging biomarker NfL,” Alder said.

Taylor will present the two posters at the conference.

“The compelling data from two preclinical Parkinson’s disease models with our lead drug candidate GT-02287 show that this orally administered allosteric regulator of GCase restored enzymatic function and significantly reduced the pathological hallmarks and motor dysfunction associated with Parkinson’s disease,” Taylor said.