In Utero Gene Therapy for the Correction of Congenital Genetic Anomalies

Students

2020
College

Faculty

Assistant Professor of Surgery

Project Summary

This summer, I have had the exciting opportunity to conduct research in Dr. Peranteau’s Lab at the Abramson Pediatric Cancer Research Center within the Children’s Hospital of Philadelphia. My main project focuses on studying the mechanisms behind the genetic disorder, hereditary tyrosinemia type I (HT-1), in a mouse model and exploring the potential for gene therapy to provide a cure for the disease. Tyrosinemia type I is an autosomal recessive disorder resulting in severe disease of the liver, kidney, and peripheral nerves that causes organ damage. It results from a disruption in the metabolic breakdown pathway of the amino acid tyrosine, which results in accumulation of hepatotoxic catabolites. Specifically for type I of the disease, the enzyme fumarylacetoacetate (FAA) hydrolase is rendered dysfunctional. Type I is also the most severe form of tyrosinemia, manifesting in infants through a variety of symptoms, including failure to thrive, vomiting, diarrhea, jaundice, and increased risk of hepatocellular carcinoma. If left untreated, patients do not typically live past the age of 10.

Existing treatments for this genetic disorder include the drug, nitisinone (NTBC), and strict management of a low-tyrosine diet, which excludes meat, poultry, eggs, dairy, and whole grain products. However, both can be burdensome for patients and their families, with the disorder’s presence constantly pervading their lives. In addition, NTBC is an incomplete pharmacological block, so that although the treatment reduces the risk of HT-I patients developing hepatocellular carcinoma, the incidence of this cancer is still significantly greater in this population. The ultimate goal of our project is to genetically engineer the same therapeutic effect as the NTBC drug. We hope to induce a nonsense mutation via a Cas9 base-editor in the FAH gene so that we therapeutically delete the enzyme and prevent build-up of the hepatotoxic catabolites.

My research experience has proved invaluable in not only the hands-on bench work and animal handling techniques but also the opportunity to interact and engage with lab members who are in all different stages of their educational or career paths. It has been eye-opening to speak with attending physicians, medical students, research fellows, residents, and even fellow undergraduates attending different schools about their experiences and perspectives on a life dedicated to medicine and biological sciences.

Throughout the course of my project, I have had the opportunity to help plan, execute, and adjust our experiment, which has been an enlightening view into the scientific method at work. In addition, it is incredible to see how all our work is founded on the basic science concepts I learned in biology and chemistry high school and college courses. It is so gratifying to see these theoretical textbook concepts come to life in the context of research work that holds the potential to provide cures and save lives. Every small milestone achieved is encouraging, every setback is a lesson learned for the future, and I have never been so excited to continue pursuing my research and studies on the medical path.