A Non-Viral Vector for Targeting Gene Therapy to Motoneurons in the CNS

Miana-Mena, Francisco Javier; Muñoz, Marı́a Jesús; Roux, Sylvie; Ciriza, Jesús; Zaragoza, Pilar; Brûlet, Philippe; Osta, Rosario

doi:10.1159/000080050

Cited by 16 publications

(11 citation statements)

References 70 publications

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“…One of the most well-known hybrid proteins that has been used for this purpose is the hybrid protein encoded by lacZ -fragment C. This protein has been tested in vitro and in vivo to determine its activity in the hypoglossal system, and the detection of the labeled motor neurons was dependent on time post-injection [60–62]. Since neuronal integrity is crucial for fragment C internalization, the transneuronal molecular pathway at neuromuscular junctions was intensively studied using this hybrid protein [63].…”

Section: Molecular Structure and Properties Of Fragment C: Toward mentioning

confidence: 99%

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

Calvo

Oliván

Manzano

et al. 2012

IJMS

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When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C) can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP-2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport.

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Section: Molecular Structure and Properties Of Fragment C: Toward mentioning

confidence: 99%

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

Calvo

Oliván

Manzano

et al. 2012

IJMS

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“…Furthermore, TTC-conjugation was shown to radically improve neuronal internalization of even large proteins, such as human IgG [32] or glucose oxidase [33], and to enable neuronal delivery of DNA coupled to the TTC with polylysine bridge [34]. Similar findings were found later using TTC coupled with beta-galactosidase (β-gal-TTC) delivered intramuscularly either as β-gal-TTC fusion protein [35,36,37] or as direct “naked DNA” plasmid injection in Xenopus [38] and in mice [37]. It was also demonstrated that β-gal-TTC is transneuronally transported to second and higher-order interconnected neurons [36] and that the transport to motor neurons was dependent on neuronal activity [39].…”

Section: Ttc As a Neuronal Retrograde Tracer And Carrier Of Therapmentioning

confidence: 85%

Tetanus Toxin C-Fragment: The Courier and the Cure?

Toivonen

Oliván

Osta

2010

Toxins

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In many neurological disorders strategies for a specific delivery of a biological activity from the periphery to the central nervous system (CNS) remains a considerable challenge for successful therapy. Reporter assays have established that the non-toxic C-fragment of tetanus toxin (TTC), provided either as protein or encoded by non-viral naked DNA plasmid, binds pre-synaptic motor neuron terminals and can facilitate the retrograde axonal transport of desired therapeutic molecules to the CNS. Alleviated symptoms in animal models of neurological diseases upon delivery of therapeutic molecules offer a hopeful prospect for TTC therapy. This review focuses on what has been learned on TTC-mediated neuronal targeting, and discusses the recent discovery that, instead of being merely a carrier molecule, TTC itself may well harbor neuroprotective properties.

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“…A similar problem exists with the experiments utilising TeNT heavy chain chemically conjugated to PLL to mediate gene delivery [107]. A separate study expressing fragment of TeNT within muscle cells avoided the use of polycations but concluded that the inclusion of the TeNT fragment encoded by a plasmid injected into muscle mass did not have any influence on the expression of the transfected gene [108].…”

Section: Attenuated Toxins As Nucleic Acid Delivery Systemsmentioning

confidence: 99%

The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery

Shorter¹,

Gollings²,

Gorringe-Pattrick³

et al. 2016

Expert Opinion on Drug Delivery

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Abstract.Introduction: The potential of gene replacement therapy has been underscored by the market authorisation of alipogene tiparvovec (Glybera) and GSK2696273 (Strimvelis) in the EU and recombinant adenovirus-p53 (Gendicine) in China. Common to these systems is the use of attenuated viruses for "drug" delivery. Whilst viral delivery systems are being developed for siRNA, their application to antisense delivery remains problematic. Non-viral delivery remains experimental, with some notable successes. However, stability and the "PEG dilemma", balancing toxicity and limited (often liver-tropic) PK-PD, with the membrane destabilising activity, necessary for nucleocytosolic access and transfection remain a problem. Areas Covered:Here we review the use of attenuated protein toxins as a delivery vehicle for nucleic acids, their relationship to the PEG-dilemma, and their biological properties with specific reference to their intracellular trafficking. Expert opinion:The possibility of using attenuated toxins as antisense and siRNA delivery systems has been demonstrated in vitro. Systems based upon attenuated anthrax toxin have been shown to have high activity (equivalent to nucleofection) and low toxicity whilst not requiring cationic "helpers" or condensing agents, divorcing these systems from the problems associated with the PEG dilemma. It remains to be seen whether these systems can operate safely, efficiently and reproducibly, in vivo or in the clinic. Key words.Antisense, Drug Delivery, Endocytosis, Gene Therapy, siRNA, Toxin. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 This paper covers:1) The deferential between the challenges associated with gene and siRNA / antisense delivery.2) Why this differential is important within the context of existing rate limits to nonviral therapy i.e. the PEG dilemma.3) The use of protein toxins as part of non-viral DNA delivery systems. 4) How toxins navigate the endomembrane system. 5) Recent successes using toxins to deliver siRNA and antisense oligonucleotides.

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A Non-Viral Vector for Targeting Gene Therapy to Motoneurons in the CNS

Cited by 16 publications

References 70 publications

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

Fragment C of Tetanus Toxin: New Insights into Its Neuronal Signaling Pathway

Tetanus Toxin C-Fragment: The Courier and the Cure?

The potential of toxin-based drug delivery systems for enhanced nucleic acid therapeutic delivery

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