Geriatric Research, Education and Clinical Center, St. Louis Veterans Affairs Medical Center and Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Amyloid beta protein (Abeta) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Abeta, can be reversed with i.c.v. injections of an Abeta antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with (32)P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 +/- 0.39 microl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.
"The BBB separates the circulating blood from the brain tissue and regulates the CNS chemical microenvironment, preventing the spontaneous diffusion of many macro-molecules from the bloodstream into the CNS. For these reasons, systemic ASO delivery is inefficient and necessitates doses that are 100-fold higher than required by direct intra-CNS delivery, in order to approach similar tissue concentrations (Banks et al., 2001; Erickson et al., 2012). Such high doses may further result in increased risk of toxicity, such as hepatotoxicity (Swayze et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, encourage direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity.
Brain research 04/2014; 1584. DOI:10.1016/j.brainres.2014.04.005 · 2.84 Impact Factor
"Even if systemic delivery would represent a less invasive therapeutic protocol, it still has several disadvantages: the majority of AONs end up in the liver and kidney for each of the different AON chemistries (Sazani et al., 2002; Fluiter et al., 2003; Swayze et al., 2007; Aartsma-Rus and van Ommen, 2009). Moreover, although some AONs have been shown to cross the BBB, approximately 100-fold higher doses must be delivered systemically to achieve AONs concentrations similar to those achieved by intra-CNS delivery (Banks et al., 2001; Erickson et al., 2012) increasing the risk of toxicity. Many animal studies have therefore employed alternative routes of administration (intraparenchimal injections in specific brain areas, intracerebroventricular injections, intrathecal injections), sometimes administering the AONs FIG. 9. Pelizaeus-Merzbacher disease. "
[Show abstract][Hide abstract] ABSTRACT: Alternative splicing is an important regulator of the transcriptome. However, mutations may cause alteration of splicing patterns, which in turn leads to disease. During the past 10 years, exon skipping has been looked upon as a powerful tool for correction of missplicing in disease and progress has been made towards clinical trials. In this review, we discuss the use of antisense oligonucleotides to correct splicing defects through exon skipping, with a special focus on diseases affecting the nervous system, and the latest stage achieved in its progress.
"Passage across the BBB is extremely hard for large molecular weight compounds such as ASOs, and to date, no reliably consistent method has been developed that can achieve this. Using currently available ASO chemistries, it is likely that any hope of significant BBB penetration would at the very least require massively increased systemic dosing to a degree that would likely result in toxicity [63, 78, 79]. It has, however, been shown that therapeutic doses of ASOs can be delivered intrathecally in nonhuman primates [80, 81]. "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.
Journal of nucleic acids 11/2013; 2013:208245. DOI:10.1155/2013/208245
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