Title of Abstract
Hereditary tyrosinemia type I (HT1) is an autosomal recessive inborn error of metabolism caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. We previously developed a porcine model of HT1 that closely resembles the human phenotype. In the absence of nitisinone (NTBC), FAH-/- pigs undergo acute liver failure that is characterized by diffuse and severe hepatocellular damage or they progress to chronic liver disease characterized by fibrosis and cirrhosis. Recently, we have used this model to test the efficacy of ex vivo gene therapy in primary autologous hepatocytes. Using a lentiviral vector, we were able to demonstrate that ex vivo gene therapy is curative in FAH-/- pigs and that normal metabolic function is restored. The goal of the present study was to further test the clinical relevance of ex vivo gene therapy in a larger cohort of animals by utilizing a number of novel reporters and noninvasive approaches for determining safety and biodistribution of transplanted lentiviral vector-transduced cells.
Since coming to Mayo Clinic in 2012, my research has focused exclusively on liver-directed regenerative medicine. Specifically, my research interest has been on developing novel gene and cell therapies for metabolic liver diseases. During this time, I have been able to expand and develop a unique skill set that includes in vivo and ex vivo gene manipulation with viral vectors, stem cell and differentiated cell transplantation, and noninvasive cell imaging in small and large animals using nuclear imaging.
Raymond Hickey; Clara Nicolas; Zeji Du; Kari Allen; Rebekah Guthman; Aditya Bansal; Bruce Amiot; Timothy DeGrado; Scott Nyberg; Joseph Lillegard.
All Author Affiliations
Mayo Clinic, Rochester, Minnesota.