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  • br Introduction Arginase deficiency is

    2024-07-10


    Introduction Arginase deficiency is a rare metabolic disorder resulting from a loss of arginase 1 (ARG1), the final enzyme in the urea cycle, which is the major pathway for the detoxification of ammonia in terrestrial mammals. ARG1 is expressed most prevalently in hepatocytes and red blood cells. Through ARG1 in the liver, in coordination with the other enzymes of the cycle, nitrogen is sequestered as urea [1]. Arginine undergoes hydrolysis by ARG1 to produce ornithine which then re-enters the Rizatriptan Benzoate as urea and is excreted as waste in the urine. ARG1 deficiency usually presents later in life beginning in late infancy to the second year with microcephaly, spasticity, seizures, clonus, loss of ambulation (often manifesting as spastic diplegia that may be indistinguishable from cerebral palsy), and failure to thrive Rizatriptan Benzoate associated with hyperargininemia [2]. The neurologic manifestations seen in arginase deficiency may arise from the accumulation of arginine metabolites or may result from hyperargininemia, in which multiple guanidino compounds (putative neurotoxins) increase, though the exact cause is not known. Patients typically avoid the catastrophic hyperammonemic crises characteristic of the other urea cycle disorders and thus tend to survive much longer [1]. At present, long-term therapy rests on the provision of a restricted protein diet and administration of nitrogen scavengers. While these treatments together can partially alleviate ARG1 deficiency, there is no completely effective therapy available today. Because of the marginally effective therapies that are available for this disorder, new strategies, including preclinical application of gene therapy to treat this disorder, have been applied and proven successful, albeit with limitations [[3], [4], [5], [6], [7]]. The extensive episomal loss of adeno-associated viral vectors (AAV) in rapidly dividing tissues such as the neonatal liver, results in minimal residual hepatic AAV expression of arginase in adulthood and thus the treated animals remain quite vulnerable to ammonia and at risk for hyperammonemia and death [7].
    Materials and methods
    Results
    Discussion Primary hepatocyte transplantation, engraftment, and expansion have the potential to be an effective therapy for metabolic disorders including those of nitrogen metabolism. Studies of such therapeutic methods for urea cycle disorders in murine models are sparse. The purpose of the present investigation was to examine if hepatocyte transplantation would be effective in treating arginase deficiency in a conditional murine knockout model of the disorder. We sought to examine 1) if hepatocyte transplantation could lead to normal behavioral and cognitive activity in treated animals where endogenous hepatic arginase activity was eliminated knowing that complete loss results in ataxia, listlessness, and death [3,8]; 2) if control of plasma ammonia and amino acids (including arginine and glutamine) was possible in transplanted animals; and 3) to determine the durability of the treated animal's response to ammonium loading with an eye towards understanding if substantial nitrogen vulnerability remains; we have found this to be a marked limitation in our other studies of treating arginase deficiency with AAV due to the substantial hepatic episomal copy loss that occurs [6,20]. While one other group had attempted transplantation of wild type murine hepatocytes to the conditional arginase knockout mouse utilizing the cell inhibitor retrorsine and partial hepatectomy, their results were limited by low enzyme activity, limited lifespan extension and repopulation estimated only to be up to 5% [21]. In our investigations, we sought a different approach. We generated the FRG-CKO arginase mouse by taking advantage of the FRG mouse with T and B cell deficiency allowing for immune suppression, and deficiency in fumarylacetoacetate hydrolase to give a selective advantage to transplanted hepatocytes, as described by the Grompe group [16,17]. Breeding with the conditional arginase knockout and screening for homozygosity, we generated the Fah−/−/Rag2−/−/Il2rγ−/−/Argflox/flox mouse, amenable to hepatic arginase disruption with AAV8-TBG-Cre recombinase, similar to what our group previously reported with tamoxifen induction with a widespread cre deleter [8].