CELL THERAPY: Xenotransplants for Spinal Injuries

A number of recent developments suggest that pig cells can be used successfully to treat injuries and degenerative diseases of the nerve system. Alexion Pharmaceuticals, in collaboration with Harvard Medical School researchers have reported the successful engraftment and function of pig neurons in a primate model of Parkinson’s disease. The same company, working with Yale University School of Medicine scientists, was able to regenerate the myelin sheath around an injured spinal cord using transplanted pig myelin forming cells.

Meanwhile, Biotranplant, Inc. along with researchers from Massachusetts General Hospital (MGH) reported on immune system manipulations that allow long term tolerance to xenotranplants. On the other hand, Cytotherapeutics, Inc. (CTII) would like to circumvent the need for foreign tissue, by expanding populations of human neural stem cells.

The Parkinson’s disease study, titled “Xenotransplantation of Transgenic Fetal Pig Dopamine Neurons Into Monkey with Complement Inhibition,” comes from the laboratories of Dr. Ole Isacson of the Neuroregeneration Laboratories, Harvard Medical School, and McLean Hospital (Belmont, MA) working in collaboration with scientists from Alexion. Results of the study were presented at the 29th Meeting of the Society for Neuroscience in Miami Beach.

Parkinson’s disease is caused by the degeneration of the dopamine- producing neurons in the substantia nigra of the brain, resulting in decreased dopamine availability. In the study, these scientists demonstrated that transplantation of neurons from Alexion’s transgenic pigs restored dopamine production locally and selectively in the affected part of the brain in primates with Parkinson’s-like disease. Additionally, the results show that the activity of Alexion’s pharmaceutical C5 Inhibitor, 5G1.1, further improved the engraftment and survival of the neurons.

5G1.1 is a fully humanized monoclonal antibody, designed to deliver potent anti-complement and anti-inflammatory activity to patients suffering from chronic inflammatory diseases, including rheumatoid arthritis, membranous nephritis and systemic lupus. 5G1.1 is currently in phase II safety and efficacy trials in rheumatoid arthritis and membranous nephritis patients.

Specific antibody binding to the surface of a foreign cell initiates the complement cascade, which results in the destruction of the foreign cell. Previously, these Harvard and Alexion researchers had reported that pig neurons were sensitive to destruction by complement proteins. Alexion’s technologies address this problem in three ways. First, pig cells are modified to reduce or eliminate the expression of certain pig sugars that are targeted by the complement-triggering antibodies. Second, dopamine-producing pig cells are further modified to express a protective shield of human complement inhibitor proteins. Third, the transplant recipient is administered the C5 complement inhibitor drug.

“Tapping the full breadth of our immunoregulatory technologies, a combination of our C5 Inhibitor drug and our modified pig neurons may provide a novel therapy aimed at restoring function to Parkinson’s disease patients,” says Leonard Bell, president and CEO of Alexion. “We are now focusing on optimizing manufacturing and beginning to explore the process of initiating human clinical trials.”

A report presented at the Fifth Congress of the International Xenotransplantation Society, titled “Xenotransplantation of Transgenic Pig Myelin Forming Cells Promotes Axonal Regeneration and Restores Conduction Across the Transected Spinal Cord,” was based on research conducted in the laboratories of Jeffrey D. Kocsis, M.D., of the Dept. of Neurology, Yale University School of Medicine, and Dr. William L. Fodor, senior director of xenotransplantation at Alexion Pharmaceuticals, Inc. and their colleagues.

“This particular study showed that, following transplantation, these engineered cells survived, restored nerve cell function, produced myelin and ensheathed the damaged nerve fibers,” says Kocsis. “We have seen successful engraftment of Alexion’s immunoprotected transgenic pig cells and remyelination of damaged nerve fibers in four out of five primates studied. Furthermore, we are encouraged that our results obtained with transgenic pig cell transplantation into injured primate spinal cords reflect the results we’ve seen earlier in rodent models of spinal injury.” Pig cells both engrafted and restored conductance in rodent spinal cords.

BioTransplant and MGH researchers presented studies at the Fifth Congress of the International Xenotransplantation Association held in Nagoya, Japan demonstrating methods that decrease the immune response of primates to pig tissues. BioTransplant and MGH investigators have taken several fundamental approaches toward our goal of achieving acceptance of xenografts,” says David Sachs, of MGH. “These approaches are focused on modifying recipient systems to induce tolerance to porcine grafts either by creating a state of mixed chimerism or via porcine thymus transplantation.” Mixed chimerism in mouse models of xenotransplantation has allowed the permanent acceptance of donor hearts in the absence of immunosuppressive drugs.

Investigators also suggested that various protocols designed to enhance mixed chimerism increase the tolerance to pig tissues. These therapeutic approaches effectively block the sensitization of primate immune reactivity to the pig cells. MGH and BioTransplant researchers described procedures to enhance the establishment of hematopoietic cell grafts through the sustained expression of porcine cytokines. Using a transgenic mouse model, substantial numbers of porcine cells were present at 20 weeks post-transplant in the porcine cytokine- expressing mice, while none were detected in the absence of porcine cytokines.

Additional presentations were made showing that induction of mixed hematopoietic chimerism may overcome the hyperacute rejection of pig xenografts caused by production of natural human antibodies to an epitope found on pig tissues. Antibodies directed against cells that produce natural antibody have been shown to remove at least half of the pig-specific natural antibodies in primates.

Xenotransplantation may not be necessary to fix damaged nervous systems, if Cytotherapeutics, Inc. (CTII) is able to carry out its program for obtaining human neural stem cells. Nobuko Uchida, Ph.D., director of the neural stem cell program at the company’s wholly owned subsidiary StemCells, Inc., reported results from a study related to the isolation and expansion of human neural stem cells at the 29th Annual Meeting of the Society for Neuroscience in Miami, Florida.

Uchida used a set of monoclonal antibodies to mark the surface of a subset (less than 5%) of freshly isolated human brain cells, which were separated into a highly pure population by cell-sorting technology. In culture conditions, non-genetically modified cells isolated in this fashion initiate the formation of neurosphere structures, which have previously been established to grow well and to produce important cells of the brain, including neurons and supporting glial cells. Following expansion in culture, antibody selected cells were transplanted into the brains of mice with deficient immune systems, and shown to both migrate into appropriate regions of the brain and differentiate into normal appearing neural cells.

“We believe that our ability to isolate and grow human neural stem cells, which are not genetically modified, creates an advantage from both a regulatory and product development perspective,” observes Richard Rose, CEO of Cytotherapeutics. “It should accelerate our ability to move the neural stem cell into the clinic, and speed the development of products aimed at restoring components of the central nervous system damaged by degenerative diseases.”

COPYRIGHT 1999 Business Communications Company, Inc.

COPYRIGHT 2004 Gale Group

You May Also Like

Growing Interest in Microarrays

Growing Interest in Microarrays A joint venture between Molecular Dynamics (880 E. Arques Ave., Sunnyvale, CA 94086; Tel: 408/737-3000) an…

ANTIBODIES: Yeast Library Patents Issued

ANTIBODIES: Yeast Library Patents Issued Genetastix Corp. (780 Montague Expressway, Suite 303, San Jose, CA 95131; Tel: 408/435-8900, Fax…

GENE THERAPY: Engineered Herpes Attacks Cancer Cells

GENE THERAPY: Engineered Herpes Attacks Cancer Cells U.K.’s Medicines Control Agency (MCA) has approved BioVex Limited’s (70 Milton Park,…

Recombinant Hirudin Approved for U.S

INDUSTRY NEWS: Recombinant Hirudin Approved for U.S Hoechst Marion Roussel (10236 Marion Park Dr., Kansas City, MO 64134; Tel: 816/966-500…