Neuroprotection of Spinal Motoneurons Following Targeted Transduction with an Adenoviral Vector Carrying the Gene for Glial Cell Line-Derived Neurotrophic Factor

Baumgartner, Brian J.; Shine, H. David

doi:10.1006/exnr.1998.6878

Cited by 90 publications

(51 citation statements)

References 52 publications

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“…After intramuscular gene transfer of an adenoviral vector encoding CT-1 into neonate pmn mice, we measured high amounts of recombinant CT-1 mRNA and protein in the injected muscles and elevated CT-1 bioactivities in serum. Adenoviral CT-1 expression was also detected by RT-PCR in the spinal cord, in line with the previously reported retrograde transport of adenovirus in α-motoneurons (27,43,44). The levels of adenoviral CT-1 mRNAs in the lumbar spinal cords, however, were low, probably owing to the perturbation of axonal transport in pmn mice (45).…”

Section: Discussionsupporting

confidence: 88%

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

Bordet¹,

Schmalbruch²,

Pettmann³

et al. 1999

J. Clin. Invest.

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Cardiotrophin-1 (CT-1), an IL-6-related cytokine, causes hypertrophy of cardiac myocytes and has pleiotropic effects on various other cell types, including motoneurons. Here, we analyzed systemic CT-1 effects in progressive motor neuronopathy (pmn) mice that suffer from progressive motoneuronal degeneration, muscle paralysis, and premature death. Administration of an adenoviral CT-1 vector to newborn pmn mice leads to sustained CT-1 expression in the injected muscles and bloodstream, prolonged survival of animals, and improved motor functions. CT-1-treated pmn mice showed a significantly reduced degeneration of facial motoneuron cytons and phrenic nerve myelinated axons. The terminal innervation of skeletal muscle, grossly disturbed in untreated pmn mice, was almost completely preserved in CT-1-treated pmn mice. The remarkable neuroprotection conferred by CT-1 might become clinically relevant if CT-1 side effects, including cardiotoxicity, could be circumvented by a more targeted delivery of this cytokine to the nervous system.

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Section: Discussionsupporting

confidence: 88%

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

Bordet¹,

Schmalbruch²,

Pettmann³

et al. 1999

J. Clin. Invest.

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“…The use of recombinant replication-defective adenovirus to mediate the gene transfer of NT-3 or CNTF resulted in increased neuronal survival and enhanced axonal growth (Smith et al, 1996;Djikhuizen et al, 1997;Zhang et al, 1998). In addition, adenovirusmediated gene transfer of neurotrophins increased motor neuron survival after facial nerve injury (Gravel et al, 1997;Baumgartner and Shine, 1998), rescued dopaminergic neurons in a mouse model of Parkinson's disease (Choi-Lundberg et al, 1997), and induced sprouting of motor terminals in the pmn (progressive motor neuropathy) mutant mouse (Haase et al, 1997).…”

Section: Abstract: Gene Therapy; Regeneration; Neurotrophins; Chronimentioning

confidence: 99%

“…Because adenoviruses injected into the dorsal horn do not appear to diffuse into the ventral horn, the virus may become accessible to motor neurons by endocytosis into dendrites that extend dorsally. Of all the neurons within the spinal cord, motor neurons have been shown to efficiently uptake and express recombinant adenoviruses (Gravel et al, 1997;Baumgartner and Shine, 1998).…”

Section: Expression Of Cams and Ntfs In The Adult Spinal Cordmentioning

confidence: 99%

Extensive Sprouting of Sensory Afferents and Hyperalgesia Induced by Conditional Expression of Nerve Growth Factor in the Adult Spinal Cord

et al. 2000

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Genetic transfer of growth-promoting molecules was proposed as a potential strategy to modify the nonpermissive nature of the adult CNS to induce axonal regeneration. To evaluate whether overexpression of neurotrophins or cellular adhesion molecules would effect axonal plasticity, adenoviruses encoding fibroblast growth factor-2 (FGF-2/Adts), nerve growth factor (NGF/Adts), neurotrophin-3, and the cell adhesion molecules N-cadherin and L1 were injected into the dorsal horn of the adult spinal cord. Transgene expression was primarily localized to astrocytes in the dorsal horn and motor neurons within the ventral horn. Overexpression of these factors, with the exception of NGF/Adts, failed to increase axonal sprouting. Eight days after NGF/Adts injections, axonal sprouting within the dorsal horn was apparent, and after 4 weeks, extensive spouting was observed throughout the entire dorsal horn, extending into the ventral horn and the white matter of the lateral funiculus. These axons were identified primarily as a subpopulation of nociceptive fibers expressing calcitonin gene-related peptide and substance-P. Behavioral analysis revealed thermal hyperalgesia and perturbation of accurate paw placement on gridwalking tasks for both FGF-2-and NGF-treated animals. These results indicate that the administration of growth-promoting molecules can induce robust axonal plasticity of normal adult primary sensory neurons into areas of transgene expression, causing significant alterations in behavioral responses. This observation also indicates that gene transfer protocols that aim to reconstruct diseased or injured pathways should also be designed to prevent the sprouting of the normal circuitry from adjacent unaffected neurons.

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“…Neonatal motoneurons are also protected from axotomy-induced death if they are transduced with adenoviral vectors carrying NF genes (Advnf; Gravel et al, 1997;Shine, 1997, 1998;Giménz y Ribotta et al, 1997). However, neuroprotection from axotomy-induced neuronal death by directly applied NFs in neonates is transient, lasting only 2-3 weeks (Zurn et al, 1994;Eriksson et al, 1994;Vejsada et al, 1995;Schmalbruch and Rosenthal, 1995), and by Adv-nf-mediated expression only 3-5 weeks (Gravel et al, 1997;Baumgartner and Shine, 1998). These observa-tions suggest that NFs alone are not sufficient to permanently rescue motoneurons from nerve injury (Vejsada et al, 1995;Schmalbruch and Rosenthal, 1995).…”

Section: Introductionmentioning

confidence: 89%

Permanent rescue of lesioned neonatal motoneurons and enhanced axonal regeneration by adenovirus-mediated expression of glial cell-line-derived neurotrophic factor

Baumgartner

Shine

1998

J. Neurosci. Res.

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Axotomy of peripheral nerves in neonatal rats induces motoneuron death that can be delayed but not arrested by the application of several neurotrophic factors (NFs) or adenoviral vectors carrying genes for NFs. We tested whether an adenoviral vector carrying the gene for glial cell-line-derived neurotrophic factor (Adv.RSV-GDNF) would prevent neonatal motoneuron death after facial nerve transection or crush. Nerve transection eliminates the pathway for axonal regeneration, while nerve crush preserves the pathway necessary for target reinnervation that may be required for the permanent rescue of motoneurons. Both types of injury cause substantial motoneuron death in neonatal animals. Adv.RSV-GDNF or a control vector carrying the beta-galactosidase gene (Adv.RSV-betagal) was injected into facial muscles 2 days before the nerve was transected, or Adv.RSV-GDNF, Adv.RSV-betagal, Adv.d1312 (a vector lacking a transgene), or vehicle was injected into facial muscles immediately after nerve crush. Four weeks after nerve transection, few motoneurons survived after Adv.RSV-GDNF and Adv.RSV-betagal treatment (6.1% and 2.4%, respectively). Four weeks after nerve crush, 40% of the motoneurons survived after Adv.RSV-GDNF treatment but only 17% survived in control groups. By 20 weeks, 39% of the motoneurons of the Adv.RSV-GDNF treatment groups survived but only 15-19% survived in controls. The numbers of myelinated axons of the buccal nerve branch of Adv.RSV-GDNF treatment groups were also higher than controls at 4 and 20 weeks (24% and 100% compared to 4.4-6.2% and 25-33% for Adv.RSV-GDNF and controls, respectively). By 20 weeks, Adv.RSV-GDNF-treated animals recovered 50% of the contralateral vibrissal function, while in controls only 5-11% of function was restored.

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Neuroprotection of Spinal Motoneurons Following Targeted Transduction with an Adenoviral Vector Carrying the Gene for Glial Cell Line-Derived Neurotrophic Factor

Cited by 90 publications

References 52 publications

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

Extensive Sprouting of Sensory Afferents and Hyperalgesia Induced by Conditional Expression of Nerve Growth Factor in the Adult Spinal Cord

Permanent rescue of lesioned neonatal motoneurons and enhanced axonal regeneration by adenovirus-mediated expression of glial cell-line-derived neurotrophic factor

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