Project description:Alzheimer’s disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential beneficial effect in AD. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced prevalence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32-0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49-1.00) compared to spironolactone. We found that sildenafil treatment significantly reduced tau hyper-phosphorylation (pTau181, pTau205) in a dose-dependent manner in both familial and sporadic AD patient derived neurons. Further RNA-seq data analysis of sildenafil-treated AD patient iPSC-derived neurons revealed that sildenafil specifically targeting AD related genes and molecular pathways involved in axon guidance, AD-presenilin, neurogenesis, neurodegeneration, synaptic dysregulation, vascular smooth muscle contraction (VSMC) and cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway, mechanistically supporting the potential beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. However, randomized clinical trials are required to validate sildenafil as a potential treatment of AD.
Project description:Differential expression in the presence and absence of sildenafil following romidepsin We performed cDNA microarray analysis using an GeneChip® Human Gene 2.0 ST Array to identify cellular genes that may be differentially expressed in the presence and absence of sildenafil following romidepsin treatment in SNK6
Project description:Recently, it is reported that sildenafil suppresses maturation of PO-induced miRNAs. However, the mechanism of how sildenafil coupled NO-cGMP-PKG signaling affects this maturation was not unraveled. Here, we show that PERK-mediated suppression of miRNAs by sildenafil is vital to keep mitochondrial homeostasis, using cardiac-specific PERK knockout (cko) mice.
Project description:Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS) causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical safety. Sildenafil corrects mitochondrial membrane potential defects, restores neurodevelopmental pathways, and normalizes calcium responses in LS brain organoids. In small and large mammalian models of LS, sildenafil extends the lifespan and ameliorates disease phenotypes. Off-label individual basis treatment with sildenafil in six LS patients improves their motor function and resistance to metabolic crises. Collectively, the findings highlight the potential of iPSC-driven drug discovery and position sildenafil as a promising drug candidate for mitochondrial disease.
Project description:Mitochondrial diseases are a group of rare inherited disorders that affect mitochondrial function. A severe untreatable form of mitochondrial disease is Leigh syndrome (LS), which is characterized by psychomotor regression and acute metabolic crises during which patients quickly deteriorate. To accelerate drug discovery for mitochondrial diseases, we focused on drug repurposing and used induced pluripotent stem cell (iPSC)-derived neuronal precursor cells (NPCs) from LS patients to screen a library of 5,632 repurposable compounds. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads capable of normalizing mitochondrial polarization in NPCs of LS patients. Among the PDE5i, we prioritized Sildenafil due to its established safety profile in children and adults. Sildenafil restored key pathways regulating nervous system development, enhanced neurite outgrowth in LS neurons, and mitigated abnormal calcium responses in LS brain organoids under metabolic stress. Chronic off-label compassionate treatment of six LS patients with Sildenafil showed good tolerability and clear clinical improvements. Our findings highlight the potential of iPSC-driven drug discovery for rare diseases and position Sildenafil as a promising drug candidate for patients with mitochondrial diseases.
Project description:Mitochondrial diseases are a group of rare inherited disorders that affect mitochondrial function. A severe untreatable form of mitochondrial disease is Leigh syndrome (LS), which is characterized by psychomotor regression and acute metabolic crises during which patients quickly deteriorate. To accelerate drug discovery for mitochondrial diseases, we focused on drug repurposing and used induced pluripotent stem cell (iPSC)-derived neuronal precursor cells (NPCs) from LS patients to screen a library of 5,632 repurposable compounds. We identified phosphodiesterase 5 inhibitors (PDE5i) as leads capable of normalizing mitochondrial polarization in NPCs of LS patients. Among the PDE5i, we prioritized Sildenafil due to its established safety profile in children and adults. Sildenafil restored key pathways regulating nervous system development, enhanced neurite outgrowth in LS neurons, and mitigated abnormal calcium responses in LS brain organoids under metabolic stress. Chronic off-label compassionate treatment of six LS patients with Sildenafil showed good tolerability and clear clinical improvements. Our findings highlight the potential of iPSC-driven drug discovery for rare diseases and position Sildenafil as a promising drug candidate for patients with mitochondrial diseases.