Evaluating the Efficacy of Miglustat and Ambroxol Combination Therapy in a Phase 1b/2 Virtual Drug Trial for Type 1 Tay-Sachs Disease Using aiHumanoid Simulations

Abstract

Abstract (Draft1)Type 1 Tay-Sachs Disease (TSD) is a rare and severe neurodegenerative disorder caused by HEXA Loss of Function (LOF) gene mutations, leading to the accumulation of lysosomal GM2 gangliosides and progressive neurological decline, with high lethality before age 10. Current treatments are primarily palliative, focusing on symptom management. This study investigates the therapeutic potential of Miglustat and Ambroxol, individually and combined, in slowing neurodegeneration and cognitive decline in Type 1 TSD, leveraging aiHumanoid virtual simulations. Miglustat, a substrate reduction therapy, and Ambroxol, a pharmacological chaperone, offer complementary mechanisms that may enhance lysosomal function and reduce ganglioside accumulation. In a virtual Phase 1b/2 trial, simulated cohorts of children received these treatments across four dose levels (10%, 20%, 33.3%, and 50% of maximum tolerated dose [MTD]), with outcomes assessed at intervals from birth to 10 years. Key metrics included cognitive and motor function, quality of life, and lysosomal enzyme activity. Results indicated that combination therapy significantly reduced neurodegenerative symptoms and improved cognitive and motor outcomes, particularly at intermediate dose levels. Findings suggest that Miglustat and Ambroxol may provide a beneficial intervention strategy, warranting further clinical evaluation. These results also provide important potential insights into dose optimization and therapeutic synergies, offering a basis for real-world trials in Type 1 Tay-Sachs Disease. The use of aiHumanoid simulations demonstrates a novel approach for drug testing in rare diseases, enabling detailed assessment of efficacy and safety profiles across developmental stages. The trials findings are based on virtual simulations rather than traditional clinical trials.