Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury

Martin Oudega; Owen Y. Chao; Donna L. Avison; Roderick T. Bronson; William J. Buchser; Andres Hurtado; Barbara Grimpe

doi:10.1016/j.expneurol.2012.06.006

Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury

Martin Oudega, Owen Y. Chao, Donna L. Avison, Roderick T. Bronson, William J. Buchser, Andres Hurtado, Barbara Grimpe

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury.

Original language	English
Pages (from-to)	170-179
Number of pages	10
Journal	Experimental Neurology
Volume	237
Issue number	1
DOIs	https://doi.org/10.1016/j.expneurol.2012.06.006
State	Published - Sep 2012

Keywords

Chondroitin sulfate proteoglycans
DNA enzyme
Functional recovery
Glial scar
Neurotherapeutics
Regeneration
Spinal cord injury

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10.1016/j.expneurol.2012.06.006

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title = "Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury",

abstract = "After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury.",

keywords = "Chondroitin sulfate proteoglycans, DNA enzyme, Functional recovery, Glial scar, Neurotherapeutics, Regeneration, Spinal cord injury",

author = "Martin Oudega and Chao, {Owen Y.} and Avison, {Donna L.} and Bronson, {Roderick T.} and Buchser, {William J.} and Andres Hurtado and Barbara Grimpe",

note = "Funding Information: We thank the Animal/Behavioral and Histology Core Facilities, Dr. Alex Marcillo, and Dr. Beata Frydel of the Miami Project to Cure Paralysis, and Heidrun Podini and Julia Domke. This work was supported by the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh (MO) ; the German Research Foundation (DFG , BG); Forschungskommission of the HHU (BG); Ralph Wilson Medical Research Foundation (BG); Buoniconti Fund (BG); and the Florida State Fund (BG). The authors declare no conflict of interest.",

year = "2012",

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doi = "10.1016/j.expneurol.2012.06.006",

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AU - Oudega, Martin

AU - Chao, Owen Y.

AU - Avison, Donna L.

AU - Bronson, Roderick T.

AU - Buchser, William J.

AU - Hurtado, Andres

AU - Grimpe, Barbara

N1 - Funding Information: We thank the Animal/Behavioral and Histology Core Facilities, Dr. Alex Marcillo, and Dr. Beata Frydel of the Miami Project to Cure Paralysis, and Heidrun Podini and Julia Domke. This work was supported by the Department of Physical Medicine and Rehabilitation at the University of Pittsburgh (MO) ; the German Research Foundation (DFG , BG); Forschungskommission of the HHU (BG); Ralph Wilson Medical Research Foundation (BG); Buoniconti Fund (BG); and the Florida State Fund (BG). The authors declare no conflict of interest.

PY - 2012/9

Y1 - 2012/9

N2 - After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury.

AB - After spinal cord injury, proteoglycans with growth-inhibitory glycosaminoglycan (GAG-) side chains in scar tissue limit spontaneous axonal sprouting/regeneration. Interventions that reduce scar-related inhibition facilitate an axonal growth response and possibly plasticity-based spinal cord repair. Xylosyltransferase-1 (XT-1) is the enzyme that initiates GAG-chain formation. We investigated whether intravenous administration of a deoxyribozyme (DNA enzyme) to XT-1 mRNA (DNAXT-1as) would elicit plasticity after a clinically relevant contusion of the spinal cord in adult rats. Our data showed that systemic DNAXT-1as administration resulted in a significant increase in sensorimotor function and serotonergic axon presence caudal to the injury. DNAXT1as treatment did not cause pathological or toxicological side effects. Importantly, intravenous delivery of DNAXT-1as did not exacerbate contusion-induced neuropathic pain. Collectively, our data demonstrate that DNAXT-1as is a safe neurotherapeutic, which holds promise to become an integral component of therapies that aim to improve the quality of life of persons with spinal cord injury.

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KW - DNA enzyme

KW - Functional recovery

KW - Glial scar

KW - Neurotherapeutics

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JO - Experimental Neurology

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ER -

Systemic administration of a deoxyribozyme to xylosyltransferase-1 mRNA promotes recovery after a spinal cord contusion injury

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