Delivery of Hypoxia-Inducible Heme Oxygenase-1 Gene for Site-Specific Gene Therapy in the Ischemic Stroke Animal Model

Choi, Manbok; Oh, Jungju; Rhim, Taiyoun; Lee, Minhyung

doi:10.1007/s11095-016-1962-9

Cited by 7 publications

(5 citation statements)

References 33 publications

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“…In a rat MCAO model using stereotaxic instrumentation, treatment with an adenoviral vector overexpressing HO-1 resulted in decreased infarct volume and attenuation of neurologic deficits [27]. Because of the deleterious side effects of viral vectors, such as immunogenicity and oncogenicity [28], non-viral gene carriers have been investigated and were shown to induce site-specific HO-1 gene expression and therapeutic effect when applied as stereotaxic injection into the rat ischemic brain [29]. HO-1 gene transfer into injured carotid arteries of ApoE-null mice led to earlier thrombolysis with decreased plasminogen activator-1 expression [30].…”

Section: The Ho-1 Pathway and Ischemic Stroke: Preclinical Resultsmentioning

confidence: 99%

Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke

Bereczki

Balla

2018

CPD

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Stroke is the second-leading cause of death and a leading cause of serious long-term disability worldwide, with an increasing global burden due to the growing and aging population. However, strict eligibility criteria for current treatment opportunities make novel therapeutic approaches desirable. Oxidative stress plays a pivotal role during cerebral ischemia, eventually leading to neuronal injury and cell death. The significant correlation between redox imbalance and ischemic stroke has led to various treatment strategies targeting the endogenous antioxidant system in order to ameliorate the adverse prognosis in patients with cerebral infarction. One of the most extensively investigated cellular defense pathway in this regard is the Nrf2-heme oxygenase-1 (HO-1) axis. In this review, our aim is to focus on the potential clinical relevance of targeting the HO-1 pathway in ischemic stroke.

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Section: The Ho-1 Pathway and Ischemic Stroke: Preclinical Resultsmentioning

confidence: 99%

Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke

Bereczki

Balla

2018

CPD

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“… 8 Experimental models simulating brain ischemia demonstrated that augmenting HO‐1 expression through gene therapy led to reduced infarct volume and alleviation of neurological impairments. 16 , 34 Additionally, HO‐1's downstream metabolites may also exert a protective effect in ischemic stroke. CO exerts a potent anti‐inflammatory effect in diverse diseases, and biliverdin is subsequently transformed into bilirubin, 35 which can function as an antioxidant.…”

Section: Discussionmentioning

confidence: 99%

“…Previous literature suggests that HO‐1 may protect ischemic stroke through its anti‐inflammatory, antioxidant, antiapoptotic, and vasorelaxant effects by degrading the oxidant heme 8 . Experimental models simulating brain ischemia demonstrated that augmenting HO‐1 expression through gene therapy led to reduced infarct volume and alleviation of neurological impairments 16,34 . Additionally, HO‐1's downstream metabolites may also exert a protective effect in ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Serum heme oxygenase‐1 level predicts clinical outcome after acute ischemic stroke

Wang,

Cui,

Chen

et al. 2024

CNS Neurosci Ther

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AimsThe relationship between heme oxygenase‐1 (HO‐1) and human ischemic stroke outcome remains unclear, which was investigated in this study.MethodsAcute ischemic stroke patients admitted within 24 h were enrolled. Serum HO‐1 levels at baseline were measured via ELISA. Poor 3‐month functional outcome was defined as modified Rankin Scale (mRS) score 3–6. Multivariable‐adjusted binary logistic regression and restricted cubic spline models were employed to examine association between serum HO‐1 and functional outcome. HO‐1's additive prognostic utility was assessed by net reclassification index (NRI) and integrated discrimination improvement (IDI).ResultsOf 194 eligible patients, 79 (40.7%) developed poor functional outcomes at 3‐month follow‐up. The highest quartile of serum HO‐1 was independently associated with a lower risk of poor functional outcome (adjusted OR 0.13, 95% CI 0.04–0.45; p = 0.001) compared with the lowest HO‐1 category. The relationship between higher HO‐1 levels and reduced risk of poor functional outcome was linear and dose responsive (p = 0.002 for linearity). Incorporating HO‐1 into the analysis with conventional factors significantly improved reclassification for poor functional outcomes (NRI = 41.2%, p = 0.004; IDI = 5.0%, p = 0.004).ConclusionsElevated serum HO‐1 levels at baseline were independently associated with improved 3‐month functional outcomes post‐ischemic stroke. Serum HO‐1 measurement may enhance outcome prediction beyond conventional clinical factors.

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“…Various treatments are being tried to improve outcomes in ischemic stroke, but most of these treatments are based on drugs such as tPA. Recently, attempts have been made to treat ischemic brains by using gene therapies to regulate HO‐1 gene expression (Choi et al, 2016), inhibit the NLRP3 inflammasome (Zhu et al, 2021), deliver OPA1‐ΔS1 to affected tissues (Lai et al, 2020), or utilize glial cell line‐derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) to reduce tissue damage (Shang et al, 2010; Yamashita & Abe, 2016; Yamashita et al, 2009). However, no previous studies have targeted early ischemic damage in glia using a therapeutic nanoparticle approach.…”

Section: Discussionmentioning

confidence: 99%

PINK1 siRNA‐loaded poly(lactic‐co‐glycolic acid) nanoparticles provide neuroprotection in a mouse model of photothrombosis‐induced ischemic stroke

Choi

Shin

Lee

et al. 2023

Glia

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PTEN‐induced kinase 1 (PINK1) is a well‐known critical marker in the pathway for mitophagy regulation as well as mitochondrial dysfunction. Evidence suggests that mitochondrial dynamics and mitophagy flux play an important role in the development of brain damage from stroke pathogenesis. In this study, we propose a treatment strategy using nanoparticles that can control PINK1. We used a murine photothrombotic ischemic stroke (PTS) model in which clogging of blood vessels is induced with Rose Bengal (RB) to cause brain damage. We targeted PINK1 with poly(lactic‐co‐glycolic acid) (PLGA)‐based nanoparticles loaded with PINK1 siRNA (PINK1 NPs). After characterizing siRNA loading in the nanoparticles, we assessed the efficacy of PINK1 NPs in mice with PTS using immunohistochemistry, 1% 2,3,5‐triphenyltetrazolium chloride staining, measurement of motor dysfunction, and Western blot. PINK1 was highly expressed in microglia 24 h after PTS induction. PINK1 siRNA treatment increased phagocytic activity, migration, and expression of an anti‐inflammatory state in microglia. In addition, the PLGA nanoparticles were selectively taken up by microglia and specifically regulated PINK1 expression in those cells. Treatment with PINK1 NPs prior to stroke induction reduced expression of mitophagy‐inducing factors, infarct volume, and motor dysfunction in mice with photothrombotic ischemia. Experiments with PINK1‐knockout mice and microglia depletion with PLX3397 confirmed a decrease in stroke‐induced infarct volume and behavioral dysfunction. Application of nanoparticles for PINK1 inhibition attenuates RB‐induced photothrombotic ischemic injury by inhibiting microglia responses, suggesting that a nanomedical approach targeting the PINK1 pathway may provide a therapeutic avenue for stroke treatment.

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Delivery of Hypoxia-Inducible Heme Oxygenase-1 Gene for Site-Specific Gene Therapy in the Ischemic Stroke Animal Model

Abstract: pEpo-SV-HO-1 induced HO-1 gene expression and therapeutic effect in the ischemic brain. Therefore, pEpo-SV-HO-1 may be useful for site-specific gene therapy of ischemic stroke.

Cited by 7 publications

References 33 publications

Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke

Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke

Serum heme oxygenase‐1 level predicts clinical outcome after acute ischemic stroke

PINK1 siRNA‐loaded poly(lactic‐co‐glycolic acid) nanoparticles provide neuroprotection in a mouse model of photothrombosis‐induced ischemic stroke

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