Gain Therapeutics presents preclinical data on GT-02287

Gain Therapeutics announced the presentation of new evidence supporting the disease-modifying activity of GT-02287 in preclinical animal models of both GBA-1 and idiopathic Parkinson’s disease during a late-breaker poster session yesterday at the Society for Neuroscience 2024 conference that is being held October 5-9 in Chicago, IL. In animal models of GBA-1 and idiopathic Parkinson’s disease, rescue of motor and cognitive function associated with administration of GT-02287 was observed to be persistent upon wash out of GT-02287 without significant effect in performance for more than a week following discontinuation when compared to the animals in which treatment was continued. Another presentation for GT-02287 yesterday described its association with improved mitochondrial function and neuroprotection in GBA1-Parkinson’s disease models. Finally, a second late-breaker was presented describing the reduction in Tau accumulation associated with GT-02287 in both GBA-1 mutation and wild type cell lines, suggesting GT-02287 may have broader potential as a treatment for tauopathies such as Alzheimer’s disease. The late-breaking poster titled, “GT-02287, a clinical stage GCase regulator, demonstrates disease modifying capacity in both GBA1 and idiopathic Parkinson’s disease models,” was presented on-site October 6 at 3pm CT. In animal models of both GBA1 and idiopathic Parkinson’s disease, GT-02287 was administered after a clinical phenotype was established and then withdrawn from half the animals for more than one week prior to conclusion of the study. Neuromuscular function, motor coordination, and activities of daily living/cognition were measured in wire hang, beam walk, and nest building tests, respectively, throughout the study. GT-02287 was shown to rescue deficits in neuromuscular function and motor coordination in both models as well as to prevent the development of deficits in cognition and activities of daily living. Notably, withdrawal of GT-02287 for more than one week did not significantly affect performance in any of the tests, suggesting a disease modifying effect. The poster titled, “GT-02287, a clinical stage GCase regulator, improves mitochondrial function and provides a neuroprotective effect in GBA1-Parkinson’s disease models,” was presented on-site October 6 at 10am CT. In an in vitro model – in which cultured rat mesencephalic dopaminergic neurons were treated with conduritol beta epoxide to cause partial knockdown of GCase activity comparable to that seen in PD patients carrying heterozygous GBA1 mutations- treatment with GT-02287 reduced the level of mitochondrial reactive oxygen species as well as ameliorating lysosomal pathology, reducing alpha-synuclein aggregation, and providing a neuroprotective effect. In an in vivo model in which mice were subjected to toxic insult by CBE and injection of alpha-synuclein preformed fibrils into the striatum – delayed administration of GT-02287 reduced levels of mitochondrial protein Miro1, an important maker for mitophagy; aggregated alpha-synuclein and plasma neurofilament light chain, a marker of neurodegeneration; as well as completely restoring motor function to control levels. The late-breaking poster titled, “GT-02287, a GCase modulator and Gain Therapeutics’ PD drug candidate prevents Tau accumulation in a cellular model,” was presented on-site October 6 at 1pm CT. Lysosomal Tau accumulation was quantified in human fibroblasts, carrying either the L444P mutant or wild-type GBA engineered to express labelled Tau protein, at basal conditions as well in the presence of Alzheimer’s brain-derived Tau seeds. Basal and seed-induced Tau accumulation was significantly higher in Tau-GBA L444P cells, which express defective GCase, compared to Tau WT GBA cells. Treatment with GT-02287 reduced Tau accumulation in both cells carrying the L444P GBA mutation and those carrying wild-type GBA, demonstrating GT-02287’s potential as a disease-modifying treatment for Alzheimer’s disease and other tauopathies. This work was carried out in collaboration with scientists in the group of Professor Paolo Paganetti at the Laboratories for Translational Research of the Ente Ospedaliero Cantonale in Bellinzona, Switzerland. This study was conducted under the support of an Innosuisse-Swiss Innovation Agency grant with the LRT-EOC and the Universita della Svizzera italiana-affiliated Institute for Research in Biomedicine in Bellinzona, Switzerland.