EXTON, PA — Castle Creek Biosciences announced the recent publication of a preclinical study that found that its experimental in vivo gene therapy treatment resolved biochemical and hepatic histological markers of hereditary tyrosinemia type-1 (HT1) in a large animal model of the disease. The findings appear in the August 25 edition of Nature Communications.
Researchers at Mayo Clinic administered a therapeutic lentiviral vector designed to integrate a functional human fumarylacetoacetate hydrolase (FAH) transgene into the liver of the pig model of HT1. The direct in vivo delivery of a single intraportal dose of the vector carrying the human FAH gene normalized liver function 78-98 days post-treatment, according to the published study.
“This preclinical research demonstrated that lentiviral vector gene therapy was active in a large animal model of HT1 and the pigs did not experience adverse events from the integrating vector,” said senior author Joseph Lillegard, MD, PhD, Castle Creek Biosciences chief scientific officer. “We saw a complete resolution of the biochemical and histologic features of tyrosinemia in the liver and demonstrated the benign integration pattern of the vector into the pig genome.”
“Interestingly, at 12-months post-treatment, the liver was repopulated with healthy, FAH-positive hepatocytes,” said co-author Stephen J. Russell, MD, PhD, of the Mayo Clinic Comprehensive Cancer Center. “This latest finding builds on a six-year series of preclinical studies that we hope will lead to an initial clinical trial in patients with HT1.”
Hereditary tyrosinemia type-1 (HT1) is an autosomal recessive inborn error of metabolism characterized by the inability to completely metabolize tyrosine. Caused by a deficiency of the terminal enzyme of the pathway, FAH, HT1 causes an accumulation of toxic metabolites in the liver resulting in severe oxidative damage.
Patients who are untreated commonly experience high rates of fibrosis, cirrhosis, liver failure and hepatocellular carcinoma (HCC) at a very young age. Patients with HT1 are currently treated with medication that reduces the toxic metabolites responsible for liver disease progression.
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