scholarly journals Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Stuart I. Hodgetts ◽  
Jun Han Yoon ◽  
Alysia Fogliani ◽  
Emmanuel A. Akinpelu ◽  
Danii Baron-Heeris ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Cortical Neurons ◽  
Viral Vector ◽  
Long Distance ◽  
Adult Rats ◽  
F344 Rat ◽  
Mesenchymal Precursor Cells ◽  
Cord Injury ◽  
Mesenchymal Precursor

Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations.

scholarly journals Functional role of exercise-induced cortical organization of sensorimotor cortex after spinal transection

2011 ◽  
Vol 106 (5) ◽  
pp. 2662-2674 ◽  
Author(s):  
T. Kao ◽  
J. S. Shumsky ◽  
E. B. Knudsen ◽  
M. Murray ◽  
K. A. Moxon
Keyword(s):  
Spinal Cord ◽  
Neuronal Activity ◽  
Functional Recovery ◽  
Cortical Neurons ◽  
The Body ◽  
Cortical Reorganization ◽  
Neuron Activity ◽  
Adult Rats ◽  
Cortical Organization ◽  
Cord Injury

Spinal cord transection silences neuronal activity in the deafferented cortex to cutaneous stimulation of the body and untreated animals show no improvement in functional outcome (weight-supported stepping) with time after lesion. However, adult rats spinalized since neonates that receive exercise therapy exhibit greater functional recovery and exhibit more cortical reorganization. This suggests that the change in the somatotopic organization of the cortex may be functionally relevant. To address this issue, we chronically implanted arrays of microwire electrodes into the infragranular layers of the hindlimb somatosensory cortex of adult rats neonatally transected at T8/T9 that received exercise training (spinalized rats) and of normal adult rats. Multiple, single neuron activity was recorded during passive sensory stimulation, when the animals were anesthetized, and during active sensorimotor stimulation during treadmill-induced locomotion when the animal was awake and free to move. Our results demonstrate that cortical neurons recorded from the spinalized rats that received exercise 1) had higher spontaneous firing rates, 2) were more likely to respond to both sensory and sensorimotor stimulations of the forelimbs, and also 3) responded with more spikes per stimulus than those recorded from normal rats, suggesting expansion of the forelimb map into the hindlimb map. During treadmill locomotion the activity of neurons recorded from neonatally spinalized rats was greater during weight-supported steps on the treadmill compared with the neuronal activity during nonweight supported steps. We hypothesize that this increased activity is related to the ability of the animal to take weight supported steps and that, therefore, these changes in cortical organization after spinal cord injury are relevant for functional recovery.

scholarly journals Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

2015 ◽  
Vol 112 (19) ◽  
pp. 6170-6175 ◽  
Author(s):  
Laura Elisabeth Wong ◽  
Molly E. Gibson ◽  
H. Moore Arnold ◽  
Blake Pepinsky ◽  
Eric Frank
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Sensory Function ◽  
Long Distance ◽  
Adult Rats ◽  
Sensory Axons ◽  
Sorting Technique ◽  
Cord Injury

Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRα3). Previous studies reported limited GFRα3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRα3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRα3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury.

scholarly journals Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury

2001 ◽  
Vol 533 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Leonard L. Jones ◽  
Martin Oudega ◽  
Mary Bartlett Bunge ◽  
Mark H. Tuszynski
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Spinal Cord Injury ◽  
Neurotrophic Factors ◽  
Cord Injury

scholarly journals Planet of the AAVs: The Spinal Cord Injury Episode

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 613
Author(s):  
Katerina Stepankova ◽  
Pavla Jendelova ◽  
Lucia Machova Urdzikova
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Spinal Cord Injury ◽  
Cell Types ◽  
Specific Cell ◽  
Adeno Associated Virus ◽  
Adequate Treatment ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Transgene Delivery

The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising approach for the treatment of neurological and neurodegenerative disorders by delivering remedial genes to the central nervous system (CNS), of which the spinal cord is a part. For gene therapy, multiple vectors have been introduced, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors. AAV vectors are a promising system for transgene delivery into the CNS due to their safety profile as well as long-term gene expression. Gene therapy mediated by AAV vectors shows potential for treating SCI by delivering certain genetic information to specific cell types. This review has focused on a potential treatment of SCI by gene therapy using AAV vectors.

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