Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

One strategy for the use of neural stem cells (NSCs) in treating neurological disorders is as transplantable "biological minipumps", in which genetically engineered neural stem cells serve as sources of secreted therapeutic (neuroprotective or tumoricidal) agents. Neural stem cells are highly mobile within the brain and demonstrate a tropism for various types of central nervous system (CNS) pathology, making them promising candidates for targeted gene delivery vehicles. Although neural stem cells have also been proposed as a potential source of replacement neurons and astrocytes to repopulate injured or degenerating neural circuits, the challenges involved in rebuilding damaged brain architecture are substantial and remain an active area of investigation. In contrast, the use of NSCs as biological minipumps does not rely on neuronal differentiation, axonal targeting, or synaptogenesis. This strategy may be a faster route to cell-based therapy of the CNS and is poised to move into human clinical trials. This review considers two types of neurologic disease that may be suitable targets for this alternative approach to NSC therapy: glial brain tumors and traumatic brain injury. We examine some of the key scientific and technical issues that must be addressed for the successful use of NSCs as minipumps.

Evaluation of pharmacological treatment strategies in traumatic brain injury.

Traumatic brain injury (TBI) is a devastating disease, predominately affecting young people. Although the prognosis for TBI victims has improved in recent years, many survivors of TBI suffer from emotional, cognitive and motor disturbances and a decreased quality of life. In recent years, there has been a rapid increase in the number of pharmacological targets evaluated in clinically-relevant experimental TBI models, showing improved cognitive and motor outcome and decreased loss of brain tissue. Despite the completion of several recent clinical trials using compounds showing neuroprotection in preclinical studies, pharmaceutical treatment strategies with proven clinical benefit are still lacking. This paper reviews the preclinical pharmacological treatment studies evaluated to date in experimental models of TBI. Although human TBI is a complex and multifaceted disease, these studies provide encouraging translational data suggesting that pharmacological compounds, delivered in a clinically-relevant time window, may improve the outcome of TBI patients.

Neural progenitor cells engineered to secrete GDNF show enhanced survival, neuronal differentiation and improve cognitive function following traumatic brain injury.

We sought to evaluate the potential of C17.2 neural progenitor cells (NPCs) engineered to secrete glial cell line-derived neurotrophic factor (GDNF) to survive, differentiate and promote functional recovery following engraftment into the brains of adult male Sprague-Dawley rats subjected to lateral fluid percussion brain injury. First, we demonstrated continued cortical expression of GDNF receptor components (GFRalpha-1, c-Ret), suggesting that GDNF could have a physiological effect in the immediate post-traumatic period. Second, we demonstrated that GDNF over-expression reduced apoptotic NPC death in vitro. Finally, we demonstrated that GDNF over-expression improved survival, promoted neuronal differentiation of GDNF-NPCs at 6 weeks, as compared with untransduced (MT) C17.2 cells, following transplantation into the perilesional cortex of rats at 24 h post-injury, and that brain-injured animals receiving GDNF-C17.2 transplants showed improved learning compared with those receiving vehicle or MT-C17.2 cells. Our results suggest that transplantation of GDNF-expressing NPCs in the acute post-traumatic period promotes graft survival, migration, neuronal differentiation and improves cognitive outcome following traumatic brain injury.

Caspase-mediated cell death predominates following engraftment of neural progenitor cells into traumatically injured rat brain.

Neural progenitor cells (NPCs) have been shown to be a promising therapy for cell replacement and gene transfer in neurological diseases including traumatic brain injury (TBI). However, NPCs often survive poorly after transplantation despite immunosuppression, and the mechanisms of graft cell death are unknown. In this study, we evaluated caspase- and calpain-mediated mechanisms of cell death of neonatal mouse C17.2 progenitor cells, transplanted at 24 h following lateral fluid percussion brain injury (FP) in rats. Adult Male Sprague-Dawley rats (n = 30) were subjected to lateral FP injury (n = 18) or sham surgery (n = 12). C17.2 cells labeled with green fluorescent dye (CMFDA) were engrafted in the perilesional deep cortex, and animals were sacrificed at 24 h, 72 h and 1 week post-transplantation. Pro-apoptotic caspase-mediated cleavage products (Ab246) and calpain-mediated cleavage products (Ab38) were detected in the engrafted cells using immunohistochemistry. Only 2 to 4.5% of grafted NPCs were found to survive at 24 h post-transplantation, regardless of injury status of the host brain, although brain-injured animals had significantly fewer graft cells than sham-injured animals. Limited caspase and calpain-mediated graft cell death was observed in both sham- and brain-injured animals, and caspase-mediated graft cell death was significantly greater than calpain-mediated graft cell death in all animals. Brain-injured animals had significantly increased caspase-mediated graft cell death compared to sham-injured animals. These results suggest that both the caspase and calpain family of proteases are involved in graft cell death, and that caspase-mediated apoptotic graft cell death predominates in the acute post-traumatic period following TBI.

Neuroendoscope-assisted evacuation of large intracerebral hematomas: introduction of a new, minimally invasive technique. Preliminary report.

OBJECT: The aim of this study was to describe a new, minimally invasive technique for the endoscopic evacuation of intracerebral hematomas (ICHs) and the clinical and radiological outcomes in patients who underwent the procedure. The authors used a multifunctional three-in-one endoscopic instrument that combines a 0 degrees, 4-mm rigid telescope, an irrigation cannula, and a cautery electrode. METHODS: In 13 patients a small keyhole craniotomy was made through noneloquent cortex to gain access to the hematoma. After opening the dura mater, a small cortical tunnel (approximately 6 mm in diameter) was created using bipolar forceps and suction to enter into the clot. The three-in-one endoscope was then introduced to provide illumination and irrigation inside the cavity. The clot was safely aspirated under endoscopic vision and constant irrigation by performing microsurgical suction with the other hand. Hemostasis could be achieved using electrocautery and Surgicel. This technique eliminates the use of an endoscopic sheath, thus providing more maneuverability to the neurosurgeon. The brilliant illumination provided by the endoscope and the possibility of using electrocautery in the depths of the brain combined with the increased maneuverability make this technique valuable. Near-complete hematoma evacuation was achieved in 11 (85%) of 13 patients. There were four deaths (30%). CONCLUSIONS: Safe and effective evacuation of large ICHs is possible by using the three-in-one endoscopic device. Appropriate indications for surgery in patients with large intracerebral hemorrhage must be developed.

A multifunctional, modified rigid neuroendoscopic system: clinical experience with 83 procedures. Technical note.

The authors combined a monopolar electrode and a suction/irrigation channel with a 0 degrees, 4-mm Hopkins rigid telescope into a single multifunctional unit. This three-in-one instrument is inserted through a lightweight 7.5-mm outer sheath, which is fixed separately. A fourth instrument (for example, a balloon catheter or a biopsy forceps) can be introduced and manipulated independently with the other hand. All endoscopic procedures were performed with a trephine to create a 15-mm craniotomy. After opening the dura mater, ventricles were tapped with a brain needle, which was followed by the insertion of the rigid scope for visualization. The telescope was then withdrawn momentarily; the outer sheath was introduced into the ventricle and fixed over the area of interest. The definitive procedure was then performed with ease by using the multifunctional three-in-one instrument in one hand and a fourth instrument in the other hand. This novel neuroendoscopic system has been used in clinical testing at the Vidyasagar Institute of Mental Health and Neurosciences since May 1998. Thus far, 83 neuroendoscopic procedures have been successfully performed with the aid of this instrumentation system, which has proven to be safe, versatile, and cost-effective, allowing a greater degree of freedom for the neurosurgeon.

Gamma-linolenic acid therapy of human gliomas.

OBJECTIVES: We investigated the effect of intratumoral administration of gamma-linolenic acid (GLA) in human gliomas. METHODS: We evaluated the effect of the administration of 1 mg of GLA for 7 d via a cerebral reservoir placed into the tumor bed or by direct intratumoral delivery in nine patients who had grade 4 disease and recurrent glioma after surgery, radiation, or chemotherapy. RESULTS: There was some, but not dramatic, improvement in patients' survival. No significant prolongation of life span was expected considering the advanced nature of the disease. Nevertheless, it was encouraging that GLA produced no significant side effects in any patient. Regression of the cerebral gliomas was visualized on computed tomography and magnetic resonance imaging. CONCLUSIONS: Based on results of the present and previous studies, we believe that GLA is a safe antitumor agent and that higher doses of GLA should be investigated in future studies.