Passini, MA, Bu, J, Richards, AM, Kinnecom, C, Sardi, SP, Stanek, LM et al.. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 3: 72ra18

Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA.
Science translational medicine (Impact Factor: 15.84). 03/2011; 3(72):72ra18. DOI: 10.1126/scitranslmed.3001777
Source: PubMed


Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2'-O-2-methoxyethyl-modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system-directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.

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    • "Such mutations create an aberrant 5 splice site and activate a common cryptic 3 splice site at position 579 in intron 2 promoting the production of aberrantly spliced mRNA, aberrant translation and ␤thalassemia . Hybridization of a steric-block ON masks the mutated site, reorients the splicing machinery toward the complete removal of the intron, and leads to the production of a functional, fully spliced mRNA [13] [87]. Stimulation of exon inclusion by antisense oligonucleotides is an alternative mechanism being examined also for the potential treatment of spinal muscular atrophy [40]. "
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    ABSTRACT: Peptides are versatile and attractive biomolecules that can be applied to modulate genetic mechanisms like alternative splicing. In this process, a single transcript yields different mature RNAs leading to the production of protein isoforms with diverse or even antagonistic functions. During splicing events, errors can be caused either by mutations present in the genome or by defects or imbalances in regulatory protein factors. In any case, defects in alternative splicing have been related to several genetic diseases including muscular dystrophy, Alzheimer's disease and cancer from almost every origin. One of the most effective approaches to redirect alternative splicing events has been to attach cell-penetrating peptides to oligonucleotides that can modulate a single splicing event and restore correct gene expression. Here, we summarize how natural existing and bioengineered peptides have been applied over the last few years to regulate alternative splicing and genetic expression. Under different genetic and cellular backgrounds, peptides have been shown to function as potent vehicles for splice correction, and their therapeutic benefits have reached clinical trials and patenting stages, emphasizing the use of regulatory peptides as an exciting therapeutic tool for the treatment of different genetic diseases. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Peptides
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    • "The cerebrospinal fluid (CSF) is a unique biofluid that is produced by the choroid plexus and circulates throughout the CNS. Delivery of the RNA into the cerebrospinal fluid (CSF) via the lateral ventricles results in efficient distribution of the infused RNA throughout the CNS including the spinal cord (Kordasiewicz et al., 2012; Passini et al., 2011; Smith et al., 2006). "
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    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.
    Full-text · Article · Apr 2014 · Brain research
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    • "Distal necrosis observed in patients with SMA has also been identified in the mouse model of late-onset SMA [16,63,64]. Tail and ear necrosis have been shown to correlate with disease severity in mice with late-onset SMA, making them good indicators of the efficacy of therapeutic candidate compounds [27]. The tail length and ear integrity of mice from different treatment groups were measured every other day from PND 7 to PND 39 and from PND 50 to PND 96, respectively. "
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    ABSTRACT: Background Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Methods Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Results Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation in these organs. Conclusions Combined treatment beginning at birth and continuing for 1 month conferred protection against neuromuscular damage in mice with milder types of SMA. Further, these mice exhibited enhanced motor performance in adulthood. Therefore, combined treatment could present a feasible treatment option for patients with late-onset SMA.
    Full-text · Article · Feb 2013 · BMC Medicine
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