However, highly
regulated expression of several enzymes present in the urea cycle occurs also
in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin,
and glucocorticoids are major regulators of the expression of urea cycle
enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic
cells are regulated by a wide range of pro- and antiinflammatory cytokines and
other agents.
Molecular
Genetics and Metabolism
September–October, 2003 Volume
80, Issues 1-2, Pages 148–158
Fatal
systemic inflammatory response syndrome in a ornithine transcarbamylase
deficient patient following adenoviral gene transfer
Frank S Lee
Nelson A Wivel
Received: May 30, 2003;
Received in revised form: August 8, 2003; Accepted: August 11, 2003;
Fig. 1
Relevant clinical
pathology parameters during hospital course. Note the improvement in laboratory
parameters at a time when pulmonary function began to deteriorate. CVVHD,
continuous veno-venous hemodialysis; ECMO, extracorporeal membrane oxygenation.
The arrows indicate the start and end of vector infusion, and institution of
intubation, CVVHD, and ECMO. Normal ranges are represented in shaded bars.
Units for clinical and laboratory parameters are as follows: NH4—μmol/L; bilirubin—mg/dl; alanine aminotransferase (ALT)—U/L;
prothrombin time (PT)–s; platelets–×103/μl; fibrin split
products (FSP)—μg/ml; fraction of oxygen in inspired air (FiO2)—%.
(A) Microscopic
appearance of normal lung parenchyma (left) compared to microscopic appearance
of lung parenchyma from OTC.019 (right). For detailed description, see text.
(B) Microscopic appearance of normal liver (L) compared to the microscopic
appearance of liver, with necrosis, from OTC.019 (R). Arrow indicates central
vein of hepatic lobule: note centrilobular necrosis. For detailed description,
see text. (C) Microscopic appearance of normal spleen (L) compared to the
microscopic appearance of spleen, with necrosis, from OTC.019 (R). Arrow
indicates scattered lymphocytes in area of widespread necrosis. For detailed
description, see text. (D) Immunohistochemical evaluation of normal bone marrow
(L) demonstrating presence of erythroid precursors compared to bone marrow from
OTC.019 (R), demonstrating absence of hemoglobin A+ erythroid precursors. Arrows indicate normal erythroid
precursors.
Serum levels of two
cytokines in all 18 subjects dosed with recombinant adenoviral vector. (A) Time
course of IL-6 elevation in cohorts 5 and 6. (B) Average peak IL-6 level by cohort.
(C) Time course of IL-10 elevation in cohorts 5 and 6. (D) Average peak IL-10
level by cohort
Biodistribution of OTC
vector in OTC.019. Real-time PCR shows the number of copies of vector DNA
detected in each organ at the time of post-mortem examination.
Abstract
We report the death of
an 18-year-old male with partial ornithine transcarbmaylase (OTC) deficiency
who participated in a pilot (safety) study of gene therapy. The vector used for
this trial was based on human adenovirus type 5, deleted in E1 and E4, and
contained human OTC cDNA. It was infused into the right hepatic artery at a
dose of 6×1011particles/kg. Approximately 18h. following
gene transfer the subject was noted to have altered mental status and
jaundice—clinical signs not seen in any of the first 17 subjects in this study.
Subsequently, his clinical course was marked by systemic inflammatory response
syndrome, biochemically detectable disseminated intravascular coagulation, and
multiple organ system failure, leading to death 98h following gene transfer.
Post-mortem examination was consistent with the clinical course, and vector DNA
sequences were readily detectable in most tissues. The subject had high serum
levels of IL-6 and IL-10 but normal TNFα immediately after infusion of the
vector. This experience points to the limitations of animal studies in
predicting human responses, the steep toxicity curve for replication defective
adenovirus vectors, substantial subject-to-subject variation in host responses
to systemically administered vectors, and the need for further study of the
immune response to these vectors.
HEPATIC ARTERY
INJECTION WOULD YIELD IMMEDIATE PRODUCT ELEVATION AT TOXIC LEVELS POSSIBLY An oral route with first pass through live
would be better. Like a post- ischemic correction of arterial insufficiency at
cardiac level leading to arrhythmias, a pathology may require a more sensitive
replacement of deficiencies
