Therapeutic uses of microencapsulated genetically engineered cells

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Abstract

Microencapsulated genetically engineered cells have the potential to treat a wide range of diseases. For example, in experimental animals, implanted microencapsulated cells have been used to secrete growth hormone to treat dwarfism, neurotrophic factors for amyotrophic lateral sclerosis, β-endorphin to decrease pain, factor XI for hemophilia B, and nerve growth factors to protect axotomized neurons. For some applications, microencapsulated cells can even be given orally. They can be engineered to remove unwanted molecules from the body as they travel through the intestine, and are finally excreted in the stool without being retained in the body. This application has enormous potential for the removal of urea in kidney failure, ammonia in liver failure and amino acids such as phenylalanine in phenylketonuria and other inborn errors of metabolism.

Section snippets

Principles of action of microcapsules

Biologically active materials retained inside microcapsules can act on smaller molecules that can diffuse across the membrane of the microcapsule from the outside (Fig. 1). Small molecules produced inside the microcapsules can also diffuse across the membrane into the `extracellular' environment.

A further advantage of microcapsules is that the capsule contents are protected from immune rejection because leukocytes and antibodies cannot penetrate the capsule2, 3, 4(Fig. 1). This allows

The evolution of microcapsule technology

The first semipermeable microcapsules contained hemoglobin (for use as a blood substitute), enzymes (to treat inborn errors of metabolism) or adsorbents (to treat drug overdoses) and were of cellular dimensions (in the micrometer range)1, 2, 3, 4. They were composed of semipermeable polymers such as cellulose nitrate or polyamide, or of crosslinked protein membranes1, 2(Fig. 2). This was followed by the use of silastic—a polymer that is permeable only to lipophilic molecules (Fig. 2). To allow

Implantation of microencapsulated genetically engineered cells

Genetic engineering has made it possible to develop microcapsules that are much more efficient than any of the biologically active materials used in the first-generation artificial cells (reviewed in Ref. [6]). Some examples of the types of genetically engineered, microencapsulated cells used to treat a range of diseases are given in Table 1 (Refs 12, 13, 14, 15, 16, 17, 18, 19). The promising results obtained so far have stimulated further research into the safety and long-term feasibility of

Oral administration of microencapsulated genetically engineered cells

An exciting development is our recent finding that orally administered artificial cells might be suitable for some applications. Orally administered microcapsules avoid the need for implantation24, 25, 26, and therefore obviate many of the problems associated with this approach. During the passage of microcapsules through the gastrointestinal tract, small molecules (such as urea, ammonia or amino acids) from the body enter the microcapsules where they can be metabolized by genetically

Different strategies for different diseases

Long-term implantation of microencapsulated genetically engineered cells for a variety of conditions will probably take several years to perfect. Meanwhile, several groups are looking into other configurations for more immediate clinical application. For example, Aebischer's ingenious use of capillary fibers to encapsulate cells has allowed his group to insert these subcutaneously into the cerebrospinal fluid on a short-term basis[30]. This allows the capsules to be replaced when necessary[30],

Glossary

Alginate–polylysine–alginate—Membrane formed by the interaction of alginate, an anionic gel, with polylysine, a polycation.

Allogeneic—From an unrelated member of the same species.

Hemoperfusion—The process by which a patient's blood is perfused through a column of biologically active particles then returned to the patient.

Semipermeable microcapsules—Microscopic containers enclosing biologically active materials. The encapsulating membrane retains the contents but allows smaller molecules to

The outstanding questions

  • Which other conditions could be treated using oral therapy with microencapsulated cells?

  • Will a combination of microencapsulated E. coli DH5 cells (to remove urea) and oral adsorbents and osmotic agents (to control water, electrolytes and other uremic waste metabolites) remove the need for dialysis in patients with kidney failure?

  • What is the role of complement components and cytokines in the long-term function of implanted, microencapsulated genetically engineered cells?

  • How can the tissue

Acknowledgements

T.M.S.C. acknowledges the grant support and career investigatorship from the Medical Research Council of Canada and the `Virage' Center of Excellence Award from the Quebec Ministry of Higher Education, Science and Technology.

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