Targeted Transduction of CNS Neurons with Adenoviral Vectors Carrying Neurotrophic Factor Genes Confers Neuroprotection That Exceeds the Transduced Population

Baumgartner, Brian J.; Shine, H. David

doi:10.1523/jneurosci.17-17-06504.1997

Cited by 113 publications

(79 citation statements)

References 30 publications

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“…Whole series of coronal sections (14-m-thick cryosections) were taken through the full extent of bilateral facial nuclei. The number of survived motor neurons was determined and counted by a blinded observer as described previously (Baumgartner and Shine, 1997). Five independent experiments were performed, and the total number of survived motor neurons was statistically analyzed (Student's t test).…”

Section: Methodsmentioning

confidence: 99%

The Upregulated Expression of Sonic Hedgehog in Motor Neurons after Rat Facial Nerve Axotomy

Akazawa¹,

Tsuzuki²,

Nakamura³

et al. 2004

J. Neurosci.

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Nerve injury leads to the induction of a large number of genes to repair the damage and to restore synaptic transmission. We have attempted to identify molecules whose mRNA expression is altered in response to facial nerve axotomy. Here we report that facial nerve axotomy upregulates Sonic hedgehog (Shh) and its receptor Smoothened (Smo) in facial motor neurons of adult rats, whereas facial nerve axotomy does not upregulate mRNA of Shh or Smo in neonatal rats. We tested whether overexpression of Shh in facial motor neurons of axotomized neonatal rats may promote neuronal survival. Adenovirus-mediated overexpression of Shh, but not that of ␤-galactosidase, transiently rescues axotomy-induced neuronal cell death for 3-5 d after axotomy. Finally, the pharmacological inhibitor of Shh signaling, cyclopamine, induces motor neuron death in adult rats after axotomy. These results suggest that Shh plays a regulatory role in nerve injury.

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Section: Methodsmentioning

confidence: 99%

The Upregulated Expression of Sonic Hedgehog in Motor Neurons after Rat Facial Nerve Axotomy

Akazawa¹,

Tsuzuki²,

Nakamura³

et al. 2004

J. Neurosci.

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“…For example, adenovirus induces high levels of neurotrophin expression in many systems, but unfortunately induces a fairly robust immune response if not administered carefully [105]. Injection of adenovirus into lesioned sciatic nerve supports retrograde transport to the spinal cord and subsequent transgene expression in motoneurons without induction of an immune response [106]. This technique has been used to rescue degenerating motoneurons, as well as supporting sprouting of corticospinal tract axons.…”

Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 99%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

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Summary: Motor, sensory, and autonomic functions can spontaneously return or recover to varying extents in both humans and animals, regardless of the traumatic spinal cord injury (SCI) level and whether it was complete or incomplete. In parallel, adverse and painful functions can appear. The underlying mechanisms for all of these diverse functional changes are summarized under the term plasticity. Our review will describe what is known regarding this phenomenon after traumatic SCI and focus on its relevance to motor and sensory recovery. Although it is still somewhat speculative, plasticity can be found throughout the neuraxis and includes various changes ranging from alterations in the properties of spared neuronal circuitries, intact or lesioned axon collateral sprouting, and synaptic rearrangements. Furthermore, we will discuss a selection of potential approaches for facilitating plasticity as possible SCI treatments. Because a mechanism underlying spontaneous plasticity and recovery might be motor activity and the related neuronal activity, activity-based therapies are being used and investigated both clinically and experimentally. Additional pharmacological and gene-delivery approaches, based on plasticity being dependent on the delicate balance between growth inhibition and promotion as well as the basic intrinsic growth ability of the neurons themselves, have been found to be effective alone and in combination with activitybased therapies. The positive results have to be tempered with the reality that not all plasticity is beneficial. Therefore, a tremendous number of questions still need to be addressed. Ultimately, answers to these questions will enhance plasticity's potential for improving the quality of life for persons with SCI.

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“…IRES-dependent GFP expression might be expected to be lower in eyes injected with bi-cistronic AAV vectors, 39 nonetheless the data suggest that neurotrophic factors released by transduced RGCs facilitate the survival of neighbouring nontransduced RGCs via some form of bystander effect. 56 There is evidence that some of the trophic effects of viral vector-mediated release of CNTF on non-transduced RGCs may be via the stimulation of other neuronal and glial populations in the retina. …”

Section: Rgc Survival and Regeneration Following On Crushmentioning

confidence: 99%

AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells

et al. 2006

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We compared the effects of intravitreal injection of bicistronic adeno-associated viral (AAV-2) vectors encoding enhanced green fluorescent protein (GFP) and either ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43) on adult retinal ganglion cell (RGC) survival and regeneration following (i) optic nerve (ON) crush or (ii) after ON cut and attachment of a peripheral nerve (PN). At 7 weeks after ON crush, quantification of bIII-tubulin immunostaining revealed that, compared to AAV-GFP controls, RGC survival was not enhanced by AAV-GAP43-GFP but was increased in AAV-CNTF-GFP (mean RGCs/retina: 17 4507358 s.e.m.) and AAV-BDNF-GFP injected eyes (10 20074064 RGCs/ retina). Consistent with increased RGC viability in AAV-CNTF-GFP and AAV-BDNF-GFP injected eyes, these animals possessed many bIII-tubulin-and GFP-positive fibres proximal to the ON crush. However, only in the AAV-CNTF-GFP group were regenerating RGC axons seen in distal ON (11357367 axons/nerve, 0.5 mm post-crush), some reaching the optic chiasm. RGCs were immunoreactive for CNTF and quantitative RT-PCR revealed a substantial increase in CNTF mRNA expression in retinas transduced with AAV-CNTF-GFP. The combination of AAV-CNTF-GFP transduction of RGCs with autologous PN-ON transplantation resulted in even greater RGC survival and regeneration. At 7 weeks after PN transplantation there were 27 954 (72833) surviving RGCs/retina, about 25% of the adult RGC population. Of these, 13 352 (71868) RGCs/retina were retrogradely labelled after fluorogold injections into PN grafts. In summary, AAV-mediated expression of CNTF promotes long-term survival and regeneration of injured adult RGCs, effects that are substantially enhanced by combining gene and cell-based therapies/interventions.

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Targeted Transduction of CNS Neurons with Adenoviral Vectors Carrying Neurotrophic Factor Genes Confers Neuroprotection That Exceeds the Transduced Population

Cited by 113 publications

References 30 publications

The Upregulated Expression of Sonic Hedgehog in Motor Neurons after Rat Facial Nerve Axotomy

The Upregulated Expression of Sonic Hedgehog in Motor Neurons after Rat Facial Nerve Axotomy

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells

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