The project: Gene therapy is a promising strategy for the treatment of inborn errors of metabolism, but difficulties with instability of gene expression in some target tissues currently limit this approach. We propose that, if stable gene expression in a specific target tissue cannot be accomplished, a metabolic disorder can be treated by producing the deficient gene product in a heterologous tissue. Using the Pahenu2 hyperphenylalaninemic mouse, a model of human phenylketonuria (PKU), we will evaluate the efficacy and limitations of heterologous gene therapy as a treatment for inherited enzyme deficiencies. The specific hypothesis we will test is that heterologous expression of phenylalanine hydroxylase (PM') in skeletal muscle or in hematopoietic tissues will cure hyperphenylalaninemia in the Pahenu2 mouse. We have developed two model systems for evaluating heterologous gene expression: germline-modified mice with constitutive expression of PAH in muscle or in hematopoietic tissues which we will use to evaluate the effects of heterologous PAH expression in vivo, and cultured primary myotubes which we will use in vitro to explore the limiting factors potentially inhibiting phenylalanine hydroxylation in muscle. Heterologous gene expression, if successful in the treatment of the Pahenu2 mouse, will be generally applicable as a therapeutic approach to other inborn errors of metabolism. This study will provide important information regarding the choice of target tissue in gene therapy protocols.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002405-04
Application #
2872167
Study Section
Special Emphasis Panel (SRC)
Program Officer
Hyde, James F
Project Start
1996-02-01
Project End
1999-06-30
Budget Start
1999-03-15
Budget End
1999-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715