Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease

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 trial's findings are based on virtual simulations rather than traditional clinical trials.

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Skin and Induced Pluripotent Stem Cells as Biomarkers for Neurodegenerative Diseases

Rallis,

Grech,

Lotsaris

et al. 2024

Genes

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As the global population ages, the rising prevalence of neurodegenerative diseases, characterized by abnormal protein aggregates, presents significant challenges for early diagnosis and disease monitoring. Identifying accessible tissue biomarkers is crucial for advancing our ability to detect and track the progression of these diseases. Among the most promising biomarkers is the skin, which shares a common embryological origin with the brain and central nervous system (CNS). This biological connection positions the skin as a potential reflection of CNS pathology. Over the past decades, gene expression studies have demonstrated that key genes involved in neurodegenerative diseases are also expressed in skin tissues. Genes such as APP, PSEN1, PPA2, PINK1, LRRK2, PLCB4, MAPT, SPAST, and SPG7 are prominent in this regard. Beyond gene expression, proteins related to neurodegenerative diseases—such as α-synuclein, TAU, PARKIN, and prion protein (PrP)—have been isolated from the skin of affected individuals, underscoring the skin’s capacity to mirror neural degeneration. This non-invasive window into neurodegenerative processes is further enhanced by advances in stem cell technology, which have allowed for the generation of human-induced pluripotent stem cells (iPSCs) from patient-derived fibroblasts. These iPSCs offer a valuable model for studying disease mechanisms and developing therapeutic approaches. This review conducts a comprehensive analysis of the literature from databases such as PubMed, Google Scholar, and ResearchGate, emphasizing the unique potential of the skin as a non-invasive biomarker for neurodegenerative diseases. It explores how the skin serves as a bridge between gene expression and disease pathology in both the skin and the CNS. By leveraging this biological connection, the skin emerges as a promising model for enhancing our understanding of neurodegenerative disorders and developing innovative strategies for early detection and treatment. However, significant limitations remain, requiring further validation to establish the specificity and sensitivity of these biomarkers.

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Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease

Cited by 4 publications

References 278 publications

Exposure factors and clinical characteristics associated with Parkinson's disease in GBA1 variant carriers: A Chinese GBA1-PD intrafamilial survey

Exposure factors and clinical characteristics associated with Parkinson's disease in GBA1 variant carriers: A Chinese GBA1-PD intrafamilial survey

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

Skin and Induced Pluripotent Stem Cells as Biomarkers for Neurodegenerative Diseases

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