Diagnosis of urea cycle disorders.
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Amino Acids↗
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Results for “Urea cycle disorder”
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Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.
Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea-cycle disorder, results in hyperammonemia initiating a sequence of adverse events that can lead to coma and death if not treated rapidly. There is a high unmet need for an effective therapeutic for this disorder, especially in early neonatal patients where mortality is excessive. However, development of an adeno-associated virus (AAV)-based approach is hampered by large cDNA size and high protein requirement. We developed an oversized AAV vector as a gene therapy to treat CPS1 deficiency. In order to constrain genome size, we utilized small liver-specific promoter/enhancers and a minimal polyadenylation signal. Long-term survival (9 months, end of study) with ammonia control was achieved in AAV8.CPS1-administered Cps1flox/flox mice, while all null vector-injected controls died with marked hyperammonemia; female mice demonstrated improved survival over treated males. While glutamine remained elevated compared to controls, ammonia was controlled in surviving animals. Mice maintained their weights and were not sarcopenic. While drinking water did contain carglumic acid, no nitrogen scavengers were administered. Although there were concerns with vector genomic integrity, these findings demonstrate proof of concept for an oversized gene-therapy approach for a challenging urea-cycle disorder where high-level hepatic protein is essential for survival.
MT: Delivery Strategies↗
A brief history of gene therapy for ornithine transcarbamylase deficiency.
Gene therapy encompasses the use of nucleic acids, including DNA and RNA, as therapeutic agents. This broad category includes approaches that permanently modify the genome to correct pathogenic variants, as well as strategies that restore gene expression without altering genomic DNA. In ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder, the goal of somatic gene therapy is to restore hepatic expression of functional OTC enzyme and thereby reestablish urea cycle activity. Both viral and non-viral delivery platforms have been investigated in preclinical models and clinical studies to achieve therapeutic OTC expression. Despite contemporary medical therapy, individuals with OTC deficiency (OTCD) remain at risk for recurrent hyperammonemia which may result in neurocognitive impairment and reduced quality of life. Novel therapy that restores liver OTC expression and lessens chronic disease burden is highly desired. In this manuscript, we summarize the history of gene therapy development for OTC deficiency, spanning early preclinical investigations to contemporary clinical trials. Although a definitive cure through gene therapy has not yet been achieved, substantial progress has been made toward the development of safe and effective liver-directed nucleic acid therapeutics for this disorder.
Adeno-associated virus vector↗
Management of heritable disorders of the urea cycle and of Refsum's and Fabry's diseases.
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Adult↗
Argininosuccinic aciduria: assignment of the argininosuccinate lyase gene to the pter to q22 region of human chromosome 7 by bioautography.
Argininosuccinic aciduria, an autosomal recessive disorder of the urea cycle in humans, is associated with a deficiency of argininosuccinate lyase (ASL; L-argininosuccinate arginine-lyase, EC 4.3.2.1). ASL activity was visualized on gels after electrophoresis by a new method, termed bioautography. Bioautography involves the use of mutant bacteria to visualize the location of mammalian enzymes after zone electrophoresis. By this technique, human ASL migrated to a position different from mouse ASL, while a survey of mouse strains, tissues, and tissue culture cell extracts demonstrated the same electrophoretic form and no genetic variants of mouse ASL. Identifying human ASL, by bioautography in human-mouse somatic cell hybrids has made it possible to regionally locate the ASL gene on human chromosome 7. The human ASL phenotype segregated concordantly with the human enzyme beta-glucoronidase (GUS; beta-D-glucoronide glucuronosohydrolase, EC 3.2.1.31) in cell hybrids, but showed discordant segregation with 32 other enzyme markers representing 23 linkage groups. The gene for GUS has been assigned to chromosome 7 in humans, and cosegregation (synteny) of ASL and GUS demonstrates the assignment of ASL to chromosome 7. Regional location of ASL and GUS to the pter to q22 region of chromosome 7 was achieved in hybrids segregating a 7/9 translocation.
Amino Acid Metabolism, Inborn Errors↗
Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity.
Six subjects from three sibships with hyperornithinemia, homocitrullinuria, and hyperammonemia are described. Assays of liver biopsy in one showed decreased CPS I and leukocyte assays indicate a similar defect in all six. Loading studies with ornithine and citrulline are consistent with a block early in the urea cycle between ornithine and citrulline. They thus support the results of the enzymatic assays. Similar studies with lysine and homocitrulline indicate there is excessive homocitrulline biosynthesis that is related to lysine intake, but there is no evidence of a block in the main lysine catabolic pathway. The younger more severely affected patients require protein restriction to 1.2 and 1.5 g/kg/24 hr to control hyperammonemia; hyperornithinemia remains unaffected. Adult subjects avoid large protein meals but tolerate a diet that is almost normal. The mode of inheritance of this disorder appears to be autosomal recessive. The fine structure of liver shows the presence of large and abnormally configurated mitochondria. There is a peculiar periodic structure situated closely to the inner mitochondrial membrane, and it is possible that the presence of this may be related to the impairment of transport of ornithine into the mitochondria; this in turn may give rise to hyperornithinemia. This disorder adds to the metabolic errors that suggest that there are close links of lysine metabolism to the urea cycle but the details are yet to be defined.
Adolescent↗
Enzymatic screening of genetic diseases. (Including hyperammonemia).
The application of the techniques of clinical enzymology to the study of human biochemical genetics has laid the foundations for the practice of clinical genetics. In the study of inborn errors of metabolism of the urea cycle, these investigations have resulted in an understanding of the pathophysiology of hyperammonemia as well as delineating additional information on the molecular mechanisms of ammonia detosification. Insight has been obtained through recent investigations of another group of genetic disorders, hypercholesterolemia, which has resulted in opening new horizons relating to metabolic regulation of enzyme action through effector-receptor interactions at cell surfaces.
Ammonia↗
Studies of renal urea cycle enzymes. I. Renal concentrating ability and urea cycle enzymes in the rat during protein deprivation.
Activities of renal urea enzymes were studied in normally fed (21% dietary protein) rats and rats deprived of protein (6% dietary protein) for 3 weeks. Protein deprivation resulted in growth retardation and defective urine concentrating ability. Compared to rats on an optimal diet containing 21% of protein, the protein starved animals had decreased concentrations of protein and urea in serum, reduced urinary excretion of urea and decreased levels of all five urea cycle enzyme activities in the liver. In the kidney, however, protein malnutrition resulted in a significant increase in arginase specific activity from 11.5 +/- 1.1 to 16.3 +/- 1.5 (M +/- SD) whereas the other urea cycle enzymes remained unchanged. It is postulated that this increase in renal arginase might be an early compensatory mechanism to preserve a net synthesis of urea in a situation involving arginine deficiency, thereby preserving an intact hypertonic gradient in the renal medulla.
Animals↗
Studies of renal urea cycle enzymes. II. Human renal arginase activity and location of the adaptive changes of renal arginase in the protein deprived rat.
Rats fed 6% protein for 3 weeks with growth retardation and urinary concentration defect had 3 times higher arginase activity in the kidney cortex (10.8 +/- 28, M +/- SD) compared with controls fed 21% protein (3.3 +/- 0.9, M +/- SD). In the outer medulla there was a 50% increase of arginase activity whereas no change was observed in the inner medulla and papilla. Arginase activity in fresh human cortical tissue was of the same magnitude as in the rat. The results are in agreement with the hypothesis that intrarenal urea synthesis contributes to the maintenance of the intrarenal urea gradient in the protein deprived state. The response in the protein deprived rat might thus be an adaptation to a situation with substrate deficiency.
Adaptation, Physiological↗