PROJECT 2: HEREDITARY TYROSINEMIA TYPE 1 (HT1)

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Principal Investigator: William H. Peranteau
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2023
Award: $1,069,283
Funding agency: National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive metabolic liver disease that can cause death in
the first months of life and incurs an increased risk of hepatocellular cancer. The current treatment option—strict
adherence to twice daily dosing with NTBC, a repurposed herbicide that inhibits HPD—is limited by high
noncompliance rates. Liver transplant remains the only option for those patients that fail medical management.
Genome editing to inactivate the HPD gene in the tyrosine catabolic pathway provides a potential universal, one-
time, lifelong treatment for HT1 patients. Project 2 will focus on an LNP-based adenine base editing postnatal
treatment of HT1, with the aim to file an IND application and begin a clinical trial, and prenatal base editing
treatment of HT1, with the aim of performing preclinical studies during the five-year funding period to enable an
eventual IND application if the postnatal clinical trial proves successful.

Terms: <1H-Purin-6-amine><4,6-dioxo-heptanoic acid><4,6-dioxoheptanoic acid><Adenine><Adherence><Biodistribution><Birth><Cause of Death><Cell Line><CellLine><Clinical Trials><Clotting><Coagulation><Coagulation Process><Cytosine><Dioxygenases><Disease><Disease model><Disorder><Dose><Drug Kinetics><Drugs><Early treatment><Enzyme Gene><Enzymes><Food and Drug Administration><Fumarylacetoacetase><Funding><Genes><Genetic Alteration><Genetic Change><Genetic defect><Germ-Line Mutation><Germline Mutation><Goals><Guide RNA><Hepatic Cells><Hepatic Disorder><Hepatic Failure><Hepatic Parenchymal Cell><Hepatic Transplantation><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Herbicides><Hereditary Mutation><Hereditary Tyrosinemias><Human><Impairment><Lead><Life><Liver><Liver Cells><Liver Cells Carcinoma><Liver Failure><Liver Grafting><Liver Transplant><Liver diseases><Medical><Medication><Messenger RNA><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modern Man><Murine><Mus><Mutation><Neonatal><Neurologic><Neurological><Nonsense Mutation><Outcome><Ovine><Ovis><Parturition><Pathogenicity><Pathology><Pathway interactions><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology and Toxicology><Phenotype><Phenylalanine><Pre IND FDA meeting><Pre-IND mtg><Primary carcinoma of the liver cells><Prior Therapy><Proteins><Proximal Kidney Tubules><RNA Splicing><Risk><Safety><Sheep><Site><Splicing><Strains Cell Lines><Therapeutic><Thesaurismosis><Tyrosine><Tyrosinemias><USFDA><United States Food and Drug Administration><Vitamin B4><autosome><base editing><base editor><cultured cell line><diet restriction><dietary><dietary restriction><disorder model><drug/agent><early therapy><fetal><fumarylacetoacetate fumarylhydrolase><fumarylacetoacetate hydrolase><gRNA><gene-editing therapy><genome editing><genome editing based therapy><genome editing therapy><genome editing treatment><genome editing-based therapeutics><genome mutation><genomic editing><germline variant><heavy metal Pb><heavy metal lead><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><high risk><in utero><in vivo><lipid based nanoparticle><lipid nanoparticle><liver carcinoma><liver disorder><liver transplantation><mRNA><meeting><meetings><metabolism disorder><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neonatal period><new approaches><non-compliance><non-compliant><non-sense mutation><noncompliance><noncompliant><novel approaches><novel strategies><novel strategy><pathway><pharmacologic><postnatal><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical study><preclinical study><prenatal><renal proximal tubule><renal tubular dysfunction><response><restricted diet><somatic cell gene editing><somatic cell genome editing><somatic gene editing><somatic genome editing><standard of care><succinylacetone><therapeutic editing><therapeutic genome editing><unborn>