Researchers based at Otto von Guericke University of Magdeburg and the Center of Behavioral Brain Sciences (CBBS), Germany, have reported results on siRNA treatment to block apoptotic cell death using a neuroprotective process following optic nerve damage. The novel interfering RNA or siRNA treatment against caspase-3 protein expression injected intraocularly in vivo rodent models, has shown that just under 60% activity was lowered for the levels cell death. The neuroprotective approach blocking apoptosis in retinal neurons “may be promising for neuroprotection or restoration of central visual system damage and other neurological disorders”.
Apoptosis is a genetically controlled mechanism of cell death in which the cell activates a specific set of instructions leading to the deconstruction of the cell from within. Such cell death contrasts markedly with the more familiar mechanism known as necrosis. Necrosis occurs when a cell is injured mechanically, such as through nerve damage, or receives some shock whereby it is unable to continue carrying out the activities of life. Though the end result of both apoptosis and necrosis are the same, that is the death of the cell, the mechanisms leading to such death are crucially different. Whereas necrosis is characterized by swelling, rupture, leakage and inflammation, apoptosis appears as a more deliberate and choreographed affair. Cells dying by apoptosis replace swelling with shrinkage and rupture with an elegant packaging of cellular contents into a convenient size for disposal. There is no leakage of cellular material and no inflammation. The remaining fragments of an “apoptosed” cell are neatly and quietly disposed of by either neighbouring healthy cells or by the body’s household staff – the macrophages. Diseases associated with too much apoptosis include neurodegenerative disorders such as retinitis pigmentosa, Parkinson’s disease and Alzheimer’s, while diseases associated with too little apoptosis include a broad range of cancers in which the natural checks to inhibit uncontrolled cell proliferation have been lost. The actual mechanics of apoptosis are mediated by a specific set of proteins – the “caspases” – which are responsible for the deconstruction of the cell from within. Once the caspases are activated, the process of orderly shut-down begins and so researchers have naturally sought to find ways to block caspase activation in order to halt cell death. This is precisely what German researchers aimed to do at the University of Magdeburg to block caspase activity and inhibit cell death.
The visual system used as a model of CNS degeneration to evaluate the neuroprotection of blocking the caspase-3 synthesis using nanoparticle delivery with small interfering RNA (siRNA) in the retina. The researchers used the novel and non-viral gene therapy strategy to block the key apoptotic effectors (caspase-3 gene expression) used the siRNAs significantly blocked caspase-3 protein expression in neuronal cells lowering retinal capsase-3 immunofluorescence by 57.9% in models with optic nerve crush model. Commenting on the their study, researchers stated that, ”we demonstrated for the first time that siRNA can be delivered to the CNS with non-viral, polymeric nanoparticles, comprising a novel gene therapy approach to down-regulatecaspase-3 expression and protect post-mitotic neurons from apoptosis”.