Katherine P. Ponder, M.D.

DEPARTMENT OF Internal Medicine
Keywords: blood coagulation, immunology, bone biology, genetics, virology

Our lab uses hepatic gene therapy to treat recessive genetic deficiencies. Intravenous injection of a retroviral vector to newborn mice and dogs results in transduction of >10% of hepatocytes, therapeutic levels of expression of coagulation Factor IX and Factor VIII, and markedly reduced bleeding manifestations in animals with hemophilia B and A, respectively. Similarly, delivery of a retroviral vector expressing b-glucuronidase or iduronidase to newborn mice and dogs that are deficient in these lysosomal enzymes has markedly reduced the cardiac, eye, bone, and joint manifestations of these multisystemic lysosomal storage diseases. In this case, the liver produces enzyme with a mannose-6 phosphate tag, which can be taken up by cells throughout the body via the mannose-6 phosphate receptor. Further experiments will attempt to understand the mechanism of bone disease in MPS, which may involve loss of fibroblast growth factor-mediation signaling. We are also trying to improve delivery to some tissues such as cartilage and brain that are difficult to correct by modification of the protein. Although the neonatal gene therapy approaches is effective and results in tolerance to the therapeutic protein, immune responses usually develop after gene transfer to adults. We are currently trying to define the mechanism of tolerance in the animals that received neonatal gene therapy, and determine if tolerance can be achieved in adult mice via a variety of approaches.