Introduction

Degenerative central nervous system (CNS) diseases are characterized by the continuous deterioration of cognitive and motor functions leading to prolonged periods of increasing incapacity. Among the most problematic and prevalent neurological disorders are those associated with the loss of specific populations of brain neurons. Approximately 12 million people in the United States suffer from such neurological disorders resulting in public expenditures and secondary medical expenses that exceed $400 billion annually (1). Beyond monetary costs to the health care economy, however, the medical, societal, familial, and personal costs cascading from these diseases defy calculation.

Advances in molecular biology, genetic engineering, pro-teomics, and genomics are making available an increasing number of proteins, peptides, and other compounds with enormous treatment potential. Most of these compounds are, however, not active following systemic administration, largely because the brain uses the blood-brain barrier (BBB) to modulate the local and global exchange between the vascula-ture and brain parenchyma. The BBB provides an exquisite regulation of the internal chemical environment of the CNS by regulating the internal environment with a mechanism of low passive permeability, combined with a highly selective transport system between the blood and the brain (2,3). It has also been a source of frustration for researchers and clinicians searching for a means of introducing drugs to the brain.

A number of strategies have been described to circumvent the BBB. Some of the techniques currently available for delivering therapeutic molecules directly into the brain include (1) carrier- or receptor-mediated transcytosis (4,5); (2) osmotic opening (6,7); (3) direct infusion with stereotactic guidance (8-10); (4) osmotic pumps (11,12); (5) sustained-release poly mer systems (13-15); (6) cell replacement/cell therapy (16-18); and, (7) direct gene therapy (19-22). A presentation outlining these techniques was recently reviewed (23). In recent years, one iteration of cell-based therapy proposes to use xenogeneic cells that are encased within a selectively permeable polymeric membrane, known as immunoisolation. Immunoisolation was originally described in 1933 by V. Bisceglie (24) with the demonstration that encapsulated xenograft cells survived beyond the limit for humoral rejection. The further application of immunoisolation for the CNS owes much of its foundation to investigators focused on peripheral diseases, particularly diabetes (25,26) and Parkinsons's disease (PD), using dopamine secreting cells (27). Immunoisolation is based on the observation that xenogeneic cells can be protected from host rejection by encapsulating, or surrounding them within an immunoisolatory, semipermeable membrane. Single cells or small clusters of cells can be enclosed within a selective, semipermeable membrane barrier which admits oxygen and required nutrients and releases bioactive cell secretions, but restricts passage of larger cytotoxic agents from the host immune defense system. The selective membrane eliminates the need for chronic immunosuppression of the host and allows the implanted cells to be obtained from nonhuman sources, thus avoiding the constraints associated with cell sourcing, which have limited the clinical application of unencapsulated cell transplantation.

In this chapter, I track the use of immunoisolated cells from the initial cell biology and encapsulation process, through several preclinical research models, and ultimately to human clinical trials (Fig. 1). The preclinical animal model data demonstrating the therapeutic potential of genetically modified, encapsulated cells for Alzheimer' disease (AD), PD, and Huntingtons's disease (HD) will be highlighted. Finally, the current state of initial clinical trials using encapsulated cells therapy is discussed.

Figure 1 Flow diagram illustrating the steps involved in using genetically modified polymer encapsulated cells for CNS implantation. Cells are cultured and modified in vitro prior to either manual or automated loading into hollow fiber membranes. Following in vitro characterization, the cells are transplanted into the desired region of the brain and in vivo tests are conducted to determine the potential efficacy produced by the products secreted from the encapsulated cells.

Figure 1 Flow diagram illustrating the steps involved in using genetically modified polymer encapsulated cells for CNS implantation. Cells are cultured and modified in vitro prior to either manual or automated loading into hollow fiber membranes. Following in vitro characterization, the cells are transplanted into the desired region of the brain and in vivo tests are conducted to determine the potential efficacy produced by the products secreted from the encapsulated cells.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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