Tippi MacKenzie, MD
	Tolerance induction after in utero stem cell transplantation or gene therapy
	Phone: (415) 476-4086 Email: mackenziet@surgery.ucsf.edu Websites: Pediatric Surgery
Selected Publications | Complete Publications

Fetal surgery started at UCSF over two decades ago as a way of treating rare, fatal congenital anomalies.  With our growing understanding of the molecular basis of disease, we now have an opportunity to design less invasive methods such as stem cell transplantation or gene therapy to treat a variety of prenatally diagnosed disorders.  For example, in utero stem cell transplantation can be used to treat diseases in which stem cells are missing or mutated, such as immunodeficiencies, inborn errors of metabolism, or muscular dystrophy.  Prenatal gene transfer can be used to introduce missing proteins in single-gene disorders such as hemophilia or cystic fibrosis.  The main advantage of this strategy is that early in gestation, the fetus is immunologically immature, which gives an opportunity to transplant allogeneic or xenogeneic cells without an immune response.  In addition, the proliferative state of the fetus would nurture the migration and differentiation of transplanted (or genetically modified) stem cells. 

My lab, in collaboration with Dr. Abul Abbas, studies in utero transplantation in the fetal mouse model with the goal of elucidating mechanisms of engraftment and tolerance induction.  Recent experience in the mouse model has shown that there are barriers to engraftment in a fetus that remain poorly understood.  We are currently examining immune responses after fetal stem cell transplantation in a TCR transgenic mouse model with a specific focus on the role of regulatory T cells in establishing and maintaining tolerance. 

We are also examining the role of in utero gene transfer for diseases such as hemophilia.  Early gestational expression of a transgene may be used to induce tolerance to a foreign protein such as a clotting factor.  Transduction of stem cells with an integrating vector may lead to widespread gene expression throughout the life of the animal.  We are working on methods to optimize gene expression and tissue targeting using ultrasound-guided injection of viral vectors in fetal mice. 

Selected Publications

Liechty KW, MacKenzie TC, Shaaban AF, Radu A, Moseley AB, Deans R, Marshak DR, Flake AW.  Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep.  Nature Medicine 2000, 6(11), 1282-1286.

MacKenzie TC, Kobinger GP, Kootstra NA, Radu A, Sena-Esteves M, Bouchard S, Wilson JM, Verma IM, Flake AW. Efficient transduction of liver and muscle after in utero injection of lentiviral vectors with different pseudotypes. Molecular Therapy 2002;6:349-358

MacKenzie TC, Kobinger GP, Louboutin JP, Radu A, Wilson JM, Flake AW.  Transduction of satellite cells after prenatal intramuscular injection of lentiviral vectors.  Journal of Gene Medicine, 2005, 7(1), 50-8.

Sabatino D, MacKenzie TC, Peranteau W, Edmonson S, Campagnoli C, Liu Y-L, Flake AW, High KA.  Persistent expression of hFIX after tolerance induction by in utero or neonatal administration of AAV-1-F.IX in hemophilia B mice.  Molecular Therapy, 2007, 15(9), 1677-85.

Information last updated October 2007