Ocular neuroprotection by siRNA targeting caspase-2

Ahmed, Zubair; Kalinski, Hagar; Berry, Martin; Almasieh, Mohammadali; Ashush, Hagit; Slager, N; Brafman, Anat; Spivak, Igor; Prasad, Narayan; Mett, Igor; Shalom, Edna; Alpert, Evgenia; Polo, Adriana Di; Feinstein, Elena; Logan, Ann

doi:10.1038/cddis.2011.54

Cited by 131 publications

(170 citation statements)

References 67 publications

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“…Our data show that hypothermic protection can be enhanced if combined with gene deficiency in a neonatal mouse model of HI. Our results agree with previous reports showing that Casp2 antisense oligonucleotides and Casp2-specific small-interfering RNA, as well as Casp2 −/− cortical neurons, increase neuronal resistance in vitro to mitochondrial oxidative stress (10,18) and nerve growth factor deprivation (9) and in vivo after experimental ischemic optic neuropathy in the rat (19). Furthermore, Casp2 deficiency was recently demonstrated to provide protection after HI as well as excitotoxic injury and Casp2-specific small-interfering RNA provided protection after excitotoxic injury (11).…”

Section: Discussionsupporting

confidence: 93%

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

et al. 2012

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Articles Translational Investigation nature publishing group INTODUCTION: hypoxia-ischemia (hI) injury in term infants develops with a delay during the recovery phase, opening up a therapeutic window after the insult. hypothermia is currently an established neuroprotective treatment in newborns with neonatal encephalopathy (Ne), saving one in nine infants from developing neurological deficits. caspase-2 is an initiator caspase, a key enzyme in the route to destruction and, therefore, theoretically a potential target for a pharmaceutical strategy to prevent hI brain damage. METHODS:The aim of this study was to explore the neuroprotective efficacy of hypothermia in combination with caspase-2 gene deficiency using the neonatal Rice-Vannucci model of hI injury in mice. RESULTS: hI brain injury was moderately reduced in caspase-2 −/− mice as compared with wild-type (WT) mice. Five hours of hypothermia (33 °c ) vs. normothermia (36 °c) directly after hI provided additive protection overall (temperature P = 0.0004, caspase-2 genotype P = 0.0029), in the hippocampus and thalamus, but not in other gray matter regions or white matter. Delayed hypothermia initiated 2 h after hI in combination with caspase-2 gene deficiency reduced injury in the hippocampus, but not in other brain areas. DISCUSSION: In conclusion, caspase-2 gene deficiency combined with hypothermia provided enhanced neuroprotection as compared with hypothermia alone.

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Section: Discussionsupporting

confidence: 93%

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

et al. 2012

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“…siRNA transfection and western blot analysis NIH3T3 cells were transfected with siRNA oligonucelotides (Shangai GenePharma) using RNAiMax according to the manufacturer's specifications (Invitrogen). siRNA duplexes targeting mDia1, and caspase-2 and -3 were based on previously published sequences (Ahmed et al, 2011;Eng et al, 2006;Wurzer et al, 2003). APP1 (59-GGGAAGAGGCAGAGCGTCA-39) and APP2 (59-CGGAAGAGATC-TCGGAAGT-39), used to silence APP, were generated through the Dharmacon siRNA design algorithm (http://www.thermoscientificbio.…”

Section: Cell Spreading Assaysmentioning

confidence: 99%

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

Pianu

Lefort

Thuiliere

et al. 2014

Journal of Cell Science

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Interference with microtubule stability by beta-amyloid peptide (Ab) has been shown to disrupt dendritic function and axonal trafficking, both early events in Alzheimer's disease. However, it is unclear whether Ab regulation of microtubule dynamics can occur independently of its action on tau. RhoA has been implicated in neurotoxicity by Ab but the mechanism by which this activation generates cytoskeletal changes is also unclear. We found that oligomeric Ab 1-42 induced the formation of stable detyrosinated microtubules in NIH3T3 cells and this function resulted from the activation of a RhoA-dependent microtubule stabilization pathway regulated by integrin signaling and the formin mDia1. Induction of microtubule stability by Ab was also initiated by dimerization of APP and required caspase activity, two previously characterized regulators of neurotoxicity downstream of Ab. Finally, we found that this function was conserved in primary neurons and abolished by Rho inactivation, reinforcing a link between induction of stable detyrosinated microtubules and neuropathogenesis by Ab. Our study reveals a novel activity of Ab on the microtubule cytoskeleton that is independent of tau and associated with pathways linked to microtubule stabilization and Ab-mediated neurotoxicity.

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“…A recent study demonstrated that caspase-2 is expressed and activated primarily in RGCs following optic nerve injury. 94 Moreover, inhibition of caspase-2 expression using a chemically modified siRNA delivered intravitreally led to robust RGC survival after optic nerve crush or cut. 94 This strategy is currently in phase 1 clinical trials for non-arteritic anterior ischemic optic neuropathy (http://clinicaltrials.gov/ct2/show/NCT01064505?term¼ Quark&rank¼3).…”

Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

“…94 Moreover, inhibition of caspase-2 expression using a chemically modified siRNA delivered intravitreally led to robust RGC survival after optic nerve crush or cut. 94 This strategy is currently in phase 1 clinical trials for non-arteritic anterior ischemic optic neuropathy (http://clinicaltrials.gov/ct2/show/NCT01064505?term¼ Quark&rank¼3). Another effective approach has been to target baculoviral IAP repeat-containing 4 (BIRC4), also known as X-linked inhibitor of apoptosis protein, a member of the inhibitors of apoptosis family and a direct inhibitor of several effectors including caspase-3, -7 and -9.…”

Section: Inhibition Of Apoptotic Pathways and Manipulation Of Mitochomentioning

confidence: 99%

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

Wilson

Polo

2011

Gene Ther

Self Cite

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Glaucoma is the leading cause of irreversible blindness worldwide. The primary cause of glaucoma is not known, but several risk factors have been identified, including elevated intraocular pressure and age. Loss of vision in glaucoma is caused by the death of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. Therapeutic strategies aimed at delaying or halting RGC loss, known as neuroprotection, would be valuable to save vision in glaucoma. In this review, we discuss the significant progress that has been made in the use of gene therapy to understand mechanisms underlying RGC degeneration and to promote the survival of these neurons in experimental models of optic nerve injury. Gene Therapy (2012) 19, 127-136; doi:10.1038/gt.2011; published online 6 October 2011Keywords: retinal ganglion cell; neuroprotection; glaucoma NEUROPROTECTION IN GLAUCOMA: RATIONALE AND CURRENT LIMITATIONS Adult-onset glaucoma is an optic neuropathy that affects more than 50 million people around the world, with 47 million having bilateral (both eyes) blindness due to this disease. As more effective diagnostic tools become available, the number of cases is expected to rise, and a recent study predicts that there will be 70 million people with glaucoma in 2020. 1 Glaucoma is considered to be a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. The cause of glaucoma is unknown, but several risk factors have been identified, including high intraocular pressure, age and genetic predisposition. Open angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs; Figure 1) and, as these are central nervous system neurons, their loss is irreversible. At present, there is no cure for glaucoma, and the standard treatment is to lower intraocular pressure by medication or surgery. However, a significant proportion of patients continue to experience visual loss even when pharmacological treatments effectively reduce eye pressure. Therefore, novel therapeutic approaches are needed for its treatment and management.Early-onset glaucoma, comprising primary congenital glaucoma and juvenile open-angle glaucoma, has a clear genetic basis. Between 10 and 30% of individuals with juvenile open-angle glaucoma have mutations in the gene encoding myocilin, 2,3 and, on average, B40% of people with primary congenital glaucoma have mutations in the gene encoding cytochrome P450 protein. 4 Both genes are expressed in the trabecular meshwork and ciliary body, and defects in these genes may cause ocular hypertension. The elucidation of the genetic basis underlying adult-onset glaucoma is difficult because the late onset of disease limits the number of individuals available for linkage analysis. However, at least 29 genetic loci for various forms of glaucoma and 12...

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Ocular neuroprotection by siRNA targeting caspase-2

Cited by 131 publications

References 67 publications

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

Amyloid beta1-42 peptide regulates microtubule stability independently of tau

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

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