RATIONALE: The urea cycle is the process in which nitrogen is removed from the blood and
converted into urea, a waste product found in urine . Urea cycle disorders are inherited
disorders caused by the lack of an enzyme that removes ammonia from the bloodstream. Gene
therapy is treatment given to change a gene so that it functions normally. Studying the
treatment and metabolism of patients with urea cycle disorders may be helpful in developing
new treatments for these disorders.
PURPOSE: Two-part clinical trial to study the treatment and metabolism of patients who have
urea cycle disorders.
PROTOCOL OUTLINE: This protocol involves 2 clinical studies. Part A is a metabolic study of
glutamine conversion to urea at different levels of protein intake, while on and off
medications. Part B is a dose escalation study of a first-generation adenoviral vector with
an E1 deletion and an E3 deletion substitution (d1309) expressing ornithine transcarbamylase
In Part A, diet is controlled for protein and calories. Intravenous glutamine and urea are
administered. Controls are given intravenous arginine, phenylacetate, and benzoate.
In Part B, groups of 3 patients are given a single low, intermediate, or high dose of
intravenous OTC vector. Allopurinol is administered every 12 hours for 12 days. As of
12/10/1999, Part B of the study is closed.
PROTOCOL ENTRY CRITERIA:
Part A. Patients at least 6 months old with ornithine transcarbamylase deficiency (OTC),
i.e.: Hemizygous OTC or homozygous autosomal recessive disorder with evidence of complete
enzyme deficiency Hemizygous OTC male with late presentation and presumed evidence for
residual enzyme activity OTC heterozygotes (molecular diagnosis) with severely symptomatic
to asymptomatic disease Obligate heterozygotes for autosomal recessive disorder (parent or
genotyped sibling) Normal adult volunteers and genotyped siblings entered as controls Part
B. Metabolically stable heterozygous OTC females aged 18 to under 65 Orotic acid level at
least 5 times normal on allopurinol Symptoms ranging from severe to asymptomatic
acceptable No prior hospitalization for hyperammonemia Exclusion criteria (Parts A and B):
Acute or chronic intercurrent illness Pregnancy Acute hyperammonemia