Behavioral Effects of Gangliosides: Anatomical Considerations

Gangliosides are endogenous sialic acid containing glycospingolipids which are highly concentrated in the central nervous system. Although they were first characterized over 40 years ago, the function(s) played by this unique class of lipids remain largely unknown. Gangliosides have been suggested to play a prominent role in both normal and abnormal developmental processes. In addition, several lines of convergent evidence have indicated that gangliosides exert pronounced trophic effects following damage to peripheral and central nerves. Gangliosides have been shown to (1) enhance cell survival and outgrowth in cultured and developing neurons; (2) promote the regeneration of damaged peripheral and central nerves, and (3) facilitate behavioral recovery by altering the pattern, extent and persistence of the biochemical, morphological and behavioral changes induced by neural trauma. Little is known, however, concerning the neurobiological mechanisms which subserve the. behavioral protection afforded by ganglioside treatment. This review focuses on the evidence suggesting that gangliosides mediate functional recovery by minimizing primary or secondary cell loss or promoting the regeneration or sprouting of damaged central nerves subsequent to injury. An understanding of the mechanisms, by which gangliosides produce their effects may lead to the development of more efficacious and rational primary or adjunct pharmacological treatments for central nervous system disorders

Encapsulated Cell Therapy for The Treatment of Epilepsy

Contemporary antiepileptic drugs are ineffective in approximately 30% of the patients. These patients continue to experience seizures and, in many cases, seizures increase in frequency and are associated with significant cognitive decline and psychiatric disorders. The delivery of trophic factors such as glial cell-derived neurotrophic factor (GDNF) to the CNS has tremendous potential for treating a range of diseases including epilepsy. We have recently tested a clinically-validated, implantable cell encapsulation system (EC) that delivers high levels of GDNF in a selective, long-term and stable manner to the epileptogenic area of pilocarpine treated rats. As such, this therapeutic technology platform combines the potency of de novo in situ synthesis of cell-derived GDNF with the safety of an implantable, biocompatible, and retrievable medical device. The de novo synthetized source of very high levels of GDNF in the brain region of interest proved able to significantly reduce generalized seizures frequency, improved cognitive performance and normalized anatomical alterations associated with chronic epilepsy

Relationship of vaccine efficacy to the kinetics of DC and T-cell responses induced by PLG-based cancer vaccines

Cancer vaccines are typically formulated for bolus injection and often produce short-lived immunostimulation resulting in poor temporal control over immune cell activation and weak oncolytic activity. One means of overcoming these limitations utilizes immunologically active biomaterial constructs. We previously reported that antigen-laden, macroporous PLG scaffolds induce potent dendritic cell (DC) and cytotoxic T-lymphocyte (CTL) responses via the controlled signaling of inflammatory cytokines, antigen and toll-like receptor agonists. In this study, we describe the kinetics of these responses and illustrate their fundamental relationship to potent tumor rejection when implanted subcutaneously in a mouse B16 model of melanoma. By explanting scaffolds from mice at times ranging from 1–7 d, a seamless relationship was observed between the production of controlled CTL responses, tumor growth and long-term survival in both prophylactic and therapeutic models. Scaffolds must be implanted for > 7 d to augment CTL responses via the prolonged presentation of tumor antigen, and the benefits included a notable regression of established tumors. Host DC infiltration into the porous material persisted for 12 days (peaking at day 5 ~1.4 x 106 cells), and a sharp attenuation in DC numbers coincided with peak CD8+ CTL infiltration at day 12 (~8 x 105 cells). Importantly, these PLG systems enhanced DC numbers in the draining lymph node, resulting in increased CD8(+) CTL subsets at days 10–16 of vaccination. These results indicate that material systems can finely control innate and adaptive immune cell responses to kill typically untreatable melanoma tumors and provide critical kinetic data for the design of vaccine carriers.Engineering and Applied Science

Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson'sDisease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19cells to deliver of GDNF to the brain. In vivostudies demonstrated sustained delivery of GDNF to the rat striatumover 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigraldopaminergic neurons were preserved in neuroprotection studies and dopaminergicfibers were restored inneurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen ofG\u20acottingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significantupregulation of tyrosine hydroxylase immunohistochemistry. These results are thefirst to provide clear evidencethat implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts ofGDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson'sdiseas

Effect of Fetal Striatal and Astrocyte Transplants into Unilateral Excitotoxin-Lesioned Striatum

Studies have suggested that neurotrophic mechanisms may underlie transplant-induced functional recovery. Astrocytes have been reported to be a source of neurotrophic factors. The present study examined the possible role of cultured astrocytes in promoting recovery of apomorphine-induced rotation behavior in rats with unilateral kainic acid (KA) lesions of the striatum. Five weeks after the lesions, one group of rats received fetal striatal tissue (E17) transplants, another group received transplants of cultured astrocyte suspension, and the remaining rats received sham transplants and served as controls. Apomorphine-induced rotation behavior was tested 4 weeks after the KA lesions, and 5 and 10 weeks following the transplantation. The KA-induced rotation behavior was reduced by the striatal transplants but not by the cultured astrocyte transplants 5 and 10 weeks following the transplantation. Histochemicai analysis indicated that the striatal transplants had survived and grown and contained neurons and glia with similar morphology to those in the host brain. Immunocytochemical analysis of the astrocyte transplant sites revealed heavy glial fibrillary acidic protein and OX-42 staining in the transplant areas, suggesting that the transplanted astrocytes may have survived in the host brain. Although fetal striatal transplants can ameliorate apomorphine-induced rotation behavior, transplants of astrocytes alone may not be sufficient to reverse the functional deficits produced by KA lesions

Advances in cell-laden hydrogels for delivering therapeutics

Almost six decades ago, a visionary scientist reported a new method for encapsulating aqueous solutions of protein within semipermeable polymer membranes [1]. This approach was successfully tested in the 1970s and 1980s by immobilizing xenograft islet cells to control glucose metabolism in small animal models [2,3]. Since then, the concept of cell-laden hydrogels has evolved and progressed but still those pioneering works are perfect examples of the theoretical advantages that this approach may offer in terms of long-term delivery and immune protection [4]. In its most basic form, cell-laden hydrogels or bioartificial organs consist of a polymeric or synthetic membrane structure that entraps a wide range of cells releasing bioactive drugs or proteins [5,6]. The three-dimensional (3D) constructs, typically either shaped as a microcapsule or a hollow-fiber, will regulate with different efficiency the permeability and mechanical stability of the cell-based medicine [7]. The semipermeable membrane is responsible for preventing high molecular weight molecules, antibodies and other immunologic components from entering within the construct but also controls the inward/outward diffusion of critical agents for cell survival and therapeutic efficacy including nutrients, oxygen, waste agents and therapeutic protein products (Figure 1). Even though the journey from theory to practice has been demanding and challenging, recent progress in the field is creating new avenues of hope to use this approach in several unmet clinical needs ranging from diabetes to ophthalmological disorders or rare diseases

Cell-laden alginate hydrogels for the treatment of diabetes

Diabetes mellitus is an ever-increasing medical condition that currently suffers 1 of 11 adults who may have lifelong commitment with insulin injections. Cell-laden hydrogels releasing insulin may provide the ultimate means of correcting diabetes. Here, we provide insights of this cell-based approach including latest preclinical and clinical progress both from academia and industry