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Sildenafil as a candidate drug for Alzheimer’s disease: Real-world patient data observation and mechanistic observations from patient-induced pluripotent stem cell-derived neurons.

ABSTRACT: Sildenafil as a candidate drug for Alzheimer’s disease: Real-world patient data observation and mechanistic observations from patient-induced pluripotent stem cell-derived neurons.

PROVIDER: PRJNA1071604 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27819515_1.fastq.gz	Fastqsanger.gz
	SRR27819515_2.fastq.gz	Fastqsanger.gz
	SRR27819516_1.fastq.gz	Fastqsanger.gz
	SRR27819516_2.fastq.gz	Fastqsanger.gz
	SRR27819517_1.fastq.gz	Fastqsanger.gz

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Sildenafil as a candidate drug for Alzheimer’s disease: Real-world patient data observation and mechanistic observations from patient-induced pluripotent stem cell-derived neurons.

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.

2024-02-05 | GSE254742 | GEO

Pluripotent stem cell-based screening uncovers sildenafil as a mitochondrial disease therapy

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.

2026-02-09 | PXD059519 | Pride

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Project description: Not available

| S-EPMC10977448 | biostudies-literature

Reprogramming-driven drug discovery uncovers sildenafil as a candidate drug for mitochondrial disease

Project description:Mitochondrial disease is a group of rare inherited conditions affecting mitochondrial function. A severe untreatable form of mitochondrial disease is Leigh syndrome (LS) characterized by psychomotor regression and acute metabolic crises. To accelerate drug discovery for mitochondrial disease, we focused on drug repurposing and made use of 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 LS NPCs. Among PDE5i, we prioritized Sildenafil due to its established safety profile in children. 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. In a mouse model of LS, Sildenafil led to lifespan extension and amelioration of metabolic and encephalopathy phenotypes. Lastly, chronic off-label treatment with Sildenafil in six LS patients demonstrated good tolerability and clinical improvements. Our findings highlight the potential of iPSC-driven drug discovery for rare diseases and position Sildenafil as a promising candidate drug for patients with mitochondrial disease.

2026-05-31 | GSE293169 | GEO

Reprogramming-driven drug discovery uncovers sildenafil as a candidate drug 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.

2026-02-10 | GSE292178 | GEO

GNPS - sildenafil sildenafil sildenafil sildenafil sildenafil sildenafil sildenafil

Project description:sil sildenafil sildenafil sildenafil sildenafil sildenafil sildenafil

2024-07-26 | MSV000095448 | GNPS

Murine Marfan Syndrome Sildenafil Treatment

Project description:Murine Marfan Syndrome Sildenafil Treatment

| PRJNA527824 | ENA

Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: a real-world study

Project description:Using patient derived lung cancer organoids to predict clinical response and find theraputic mechanisms

| PXD037076 |

Comparison of gene expression profiles in hearts exposed to pressure overload (PO) with or without sildenafil treatment in PERK wild type (flx) or PERK cardiac-specific knockout 8cko) mice.

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.

2020-07-10 | GSE154081 | GEO

Sildenafil Combined with Controlled Hypothermia Mitigates Microglial Activation After Neonatal Hypoxia-Ischemia in Rat.

Project description:The only validated treatment to prevent brain damage associated with hypoxia-ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation. HI was induced in P10 Sprague–Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI), and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size, glial activation were analyzed by immunohistochemistry, qRT-PCR and proteomic analyses performed at P13. Exposure to any treatment was not associated with significant reduction in lesions size both in cerebral cortex and hippocampus, 72h after HI. Significant reductions in either Iba1+ (within the ipsilateral hemisphere) or GFAP+ cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia sorted cells, pro-inflammatory markers, ie. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex-dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including notably genes related to neutrophilic functions. Our findings demonstrate that Sildenafil combined with controlled hypothermia confers maximum effect to mitigate microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

2024-04-30 | PXD045168 | Pride

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