Robert Cywes, M.D., Ph.D

Research Interests

 

Fetal Surgery

Pediatric and neonatal advanced minimally invasive surgery

 





Current Research

Fetal Therapy For Inborn Errors Of Metabolism Using Selective Cell Transplantation

Inborn Errors Of Metabolism
Variations and abnormalities have been described for virtually every known gene. Certain abnormalities with known devastating consequences occur when gene expression (or non-expression) is localized to a particular organ. In such instances, it may be feasible to overcome the genetic defect by transplanting tissue or organs that contain the normally functioning gene into the defective host. Several candidate genetic abnormalities ideally suited to this approach have been described, many of which are categorized as inborn errors of metabolism. Tissue or organ transplantation after birth usually requires some form of recipient immunosuppression, which may be devastating to the host. In addition, several of the genetic defects have an effect prior to birth in the fetus or at birth before tissue replacement can occur. Therefore, it would be advantageous to introduce normally functioning tissue into the recipient prior to injury.

Fetal Therapy
Most organ-specific genetic defects are only expressed after organogenesis in the developing fetus. Furthermore, the effects of certain organ-specific enzyme pathway genetic defects only become injurious to the host late in development or after birth because in utero, the placenta dialyses the fetal circulation. This creates a therapeutic window during fetal development where an intervention may correct a genetic defect prior to it affecting the fetus. In addition, during the late first and second trimester, this therapeutic window overlaps the time period when the fetus is immunologically tolerant to foreign antigens, presenting the ideal opportunity for tissue transplantation without requiring immunosuppression.

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The most simplistic fetal therapy protocol involves the transplantation of normal cells into the affected fetal liver. More complex therapies include the replacement of defective fetal bone marrow with immature but normal fetal liver cells that contain hematopoietic stem cells, or the introduction of viral vectors used to insert normal genes into the defective fetal genome. Such gene therapy is currently ongoing in our and other experimental laboratories. Several human trials involving fetal bone marrow replacement for genetic defects are currently ongoing with moderate early success. Further research is aimed at the induction of tolerance by cell transplantation during the fetal period, which would allow for organ transplantation without immunosuppression in the neonatal period.

Transplantation Immunology
Tolerance to fetal cell transplantation is currently under investigation in our laboratory. The longevity of the tolerant period and methods to extend this period as well as the ability to induce tolerance in the fetus by cell transplantation that would subsequently support whole organ transplantation in the postnatal period is being investigated. This direction has particular application in the field of xenotransplantation.

Several strategies have been proposed to increase the transplanted cell mass. A two pronged approach to these investigations is required. Firstly, a structured cellular environment needs to be created using a biodegradable scaffold that allows neovascularization of a large mass of transplanted cells to recreate an organ-like complex attached to the omentum or bowel mesentry. Such neo-organogenesis would comprise of donor parenchymal cells maintained by a recipient non-parenchymal cell structural network. The development of a biodegradable microskeleton for this purpose is currently ongoing. Secondly, a strategy for trophic support of the transplanted cell mass needs to be developed. Such strategy should not only stimulate the cell mass to rapidly increase in size, but should also stimulate neovascularization of the cell mass.

Research Goal
By exploiting the immune "naïve" window in the fetus, when there is no immune distinction between self and non-self, cells which contain the missing gene may be placed in the defective fetus without the need for immunosuppression. Such transplantation would also occur prior to the need for functional gene products within the fetus. Postnatally, these transplanted cells would produce enough product to maintain normal or near-normal functional levels. In addition, if the fetus has become tolerant to the donor cells, but there is attrition of these cells, a boost infusion of same-donor cells may be feasible in the early neonatal period should the fetus have been made tolerant by the initial transplant.

Fetal liver stem cells may induce tolerance which may preclude booster doses postnatally. Such protocols have already been successfully implemented in humans to replace defective bone marrow. However, simultaneous cellular grafts have not been investigated in detail. The emphasis in this work has been on the development of chimerism within the immune system.

Our work is specifically directed at cellular fetal transplantation to organ-specific inborn errors of metabolism because we have all the tools necessary at our disposal. Once the technique for correcting the defect is established in the laboratory, the final step is to put it into clinical practice. The method may also then be extended to other forms of inborn errors in metabolism with minor modifications.

 

Education

Dr. Cywes received his M.D. degree from the University of Cape Town, in Cape Town, South Africa in 1987.

In 1989 Dr. Cywes was a resident in anesthesiology and general surgery at Groote Schuur Hospital in Cape Town, South Africa. In 1990 he was a pediatric surgery resident at Columbus Children's Hospital, Ohio State University. From 1990-1996 he was a resident in general surgery in the Gallie Surgical Scientist Program at the University of Toronto. During this time he earned the M.S. and Ph.D. for studies pertaining to liver transplantation and completed his training in general surgery. In 1997 he served as an elective fellow in neonatal /pediatric intensive care at the Hospital for Sick Children, Toronto. From 1997 through June 1999 he served as a fellow in pediatric surgery at C.S. Mott Children's Hospital, University of Michigan.

Contact

Telephone: (615) 322-2343
FAX: (615) 334-4251
E-mail Dr. Cywes: rob.cywes@mcmail.vanderbilt.edu

 

 

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