Abstract
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.
Highlights
Most spinal cord injury (SCI) results from contusion rather than transection injuries, and cervical injuries (~60–70% of all SCI) produce greater deficits and threaten more critical survival systems than thoracic/lumbar SCI
It is widely acknowledged that combinations of therapies are required for effective treatment of SCI, in some animals AAVCNTFmCherry was applied in combination with viable or nonviable rat mesenchymal precursor cells grafted into the spinal lesion site two weeks after SCI to modulate the local inhibitory environment
As discussed more fully below, different types of associated viral vector (AAV) vectors have previously been injected into the cortex in SCI studies, and mesenchymal precursor cells (MPCs) grafts have been tested after SCI, but to our knowledge no trials have—until now—combined these therapeutic approaches
Summary
Most spinal cord injury (SCI) results from contusion rather than transection injuries, and cervical injuries (~60–70% of all SCI) produce greater deficits and threaten more critical survival systems than thoracic/lumbar SCI. Most studies in rodents have attempted this by the delivery of purified neurotrophic growth factors and/or by cell transplantation using donor cells engineered to overexpress the growth factors, the Neural Plasticity factors usually applied to the injury site itself (see [2]). In such studies, functional improvements usually reflect sprouting and some plasticity in collateral and/or intraspinal pathways Our gene therapy approach targets corticospinal neurons (CSN) and is aimed at enhancing axonal plasticity and inducing regeneration of CST axons, leading to behavioural improvements after SCI. Injection of AAV-CNTFmCherry into the cortical regions of the brain that project onto the output pathways of the CST allows expression of CNTF in neurons, including CSN, at the time of SCI
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