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Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency

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Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency Journal of Pediatrics and Neonatal Care Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency Abstract Review Article Volume 7 Issue 1 - 2017 Carbamoyl phosphate synthetase 1 (CPS1) is the first and rate-limiting enzyme in the urea cycle. CPS1 deficiency is a devastating condition, which is clinically characterized by periodic episodes of life-threatening hyperammonemia. Currently, 1Associate at Department of Genetic Medicine, Children’s there is no cure for CPS1 deficiency except for liver transplantation, which is limited Research Institute, Children’s National Health System, USA on the progress to date, cell-based therapies—including hepatocyte or stem cell 2 by a severe shortage of donors and significant risk of mortality and morbidity. Based Washington Institute for Health Sciences, Department of transplantation—and new approaches for gene therapy have become the promising Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, USA curative treatments for CPS1 deficiency. This review outlines the current progress and *Corresponding author: Bin Li, MD, Washington Institute Keywords:challenges of cell and gene therapies for CPS1 deficiency. for Health Sciences, 4601 N Fairfax Drive, Arlington, VA therapy; Gene therapy 22203; Georgetown University Medical Center, 4000 Urea cycle defects; Carbamoyl phosphate synthetase 1 deficiency; Cell Reservoir Road, N.W., Washington D.C. 20057, United States. Tel: 202-687-6484, Fax: (202) 687-1800, Email: Abbreviations: AAVs: Adeno-Associated Viruses; ADA: Received: July 03, 2017 | Published: July 14, 2017 Adenosine Deaminase; ADHLSCs: Adult-Derived Human Liver Stem Cells; ASL: Argininosuccinate Lyase; ASS: Argininosuccinate Synthetase; CPS1: Carbamoyl Phosphate Synthetase 1; CRISPR/ Cas9: Clustered, Regularly Interspaced, Short Palindromic Repeats/ CRISPR-associated protein 9; ESCs: Embryonic Stem Cells; iPSC: now, more than 240 CPS1-associated genetic changes have been Induced Pluripotent Stem Cell; iHLCs: iPSC-Derived Hepatocyte- of approximately 1 to 9 in 1,000,000 (http://www.orpha.net/ L-Glutamate; OAs: Organic Acidemias; OLT: Orthotopic Liver consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=147identified [1]. CPS1 deficiency is a rare disease with an incidence) and Transplantation;like Cells; NAGS: N-AcetylglutamateOTC: Ornithine Transcarbamylase; Synthase; NCG: N-Carbamyl- UCDs: Urea Cycle Defects any other physical stressor, such as injury or surgery, can cause lethal1/1,300,000 hyperammonemic live births in crises the USA in neonates[2]. Infection or youngwith fever infants or Introduction The urea cycle is a series of biochemical reactions that occurs with CPS1 deficiency. The symptoms of neonatal-onset form in the liver and converts highly toxic ammonia to urea. There are toof death.CPS1 deficiencyBeyond the include newborn lethargy, period, unwillingness patients can topresent feed, vomiting, hypothermia, hypotonia, seizures, coma, and can lead synthase (NAGS), carbamyl phosphate synthetase 1 (CPS1), ornithinesix enzymes transcarbamylase involved in this (OTC),cycle, includingarginase, N-acetylglutamateargininosuccinate confusion and cognitive disability. hyperammonemia with irritability, lethargy, headache, seizures, synthetase (ASS), and argininosuccinate lyase (ASL). Urea cycle defects (UCDs) are a group of inherited diseases caused by a transplantation. To avoid acute hyperammonemia, which is the Currently, there is no cure for CPS1 deficiency except for liver strategies include promoting toxic ammonia excretion and mutation that results in a deficiency in one of the above six major treatment focus for this disease, additional key therapeutic effects,enzymes. especially In these conditions,for the central the excess nervous ammonia system. produced CPS1 is from the Hemodialysis and ammonia scavenger medications (sodium breaking down protein accumulates in the body and causes toxic reducing dietary protein intake/optimizing caloric intake. location of CPS1 gene is at 2q34, which is the long (q) arm of facilitate ammonia excretion. A balanced diet can limit excess chromosomefirst and rate-limiting 2 at position enzyme 34 (Homo in the sapiensurea cycle. Annotation The cytogenetic Release dietarybenzoate, protein, sodium reverse phenylbutyrate, endogenous catabolism arginine, andcitrulline) decrease canthe Other experimental therapeutic approaches are also under study. 108, GRCh38.p7) (NCBI). CPS1 deficiency is one of the less Recently,excess ammonia basic studies produced have fromshown the that breakdown N-carbamyl-L-glutamate of protein [1]. disorder,frequent UCDswhich and means is caused both bycopies a complete of the geneor partial in each deficiency cell have in (NCG), the chemical analog of CPS1’s essential activator, can mutations.the enzyme IfCPS1. an individual This disease only is an carry autosomal one copy recessive of the metabolic mutated improve and protect the function of mutant CPS1. Clinical studies gene, he or she typically do not show signs and symptoms of CPS1 patients with some special mutations, such as the p.Glu1034Gly diagnosed in a few less severely affected patients later in life. Until have also shown that NCG had beneficial effects on CPS1-deficient deficiency. This condition often is found in newborns but may be mutation [3]. The treatment outcomes depends on disease Submit Manuscript | http://medcraveonline.com J Pediatr Neonatal Care 2017, 7(1): 00273 Copyright: Cell and Gene Therapy for Carbamoyl Phosphate Synthetase 1 Deficiency ©2017 Zhang et al. 2/5 severity. About 50% of children with newborn onset UCDs did not concluded that although hepatocyte transplantation is not a permanent therapeutic option, it is suitable to bridge patients to have a worse prognosis. Episodes of hyperammonemic coma ofsurvive long durationto age 5 years.are associated Neonatal-onset with cognitive CPS1 deficiencies disability (seemedhttp:// www.nucdf.org/ucd_faqs.htm). byuntil 2011. liver Most transplantation of these cases [9]. had A verygroup few of technical 10 patients complications with UCDs who had undergone hepatocyte transplantation was summarized In patients whose symptoms cannot be controlled by the treatments described above, orthotopic liver transplantation andAccording encouraging to clinicalthe database results [10].Clinicaltrials.gov, there are two clinical trials studying hepatocyte transplantations. One is an Organ Sharing for 2002-2012 described 293 patients with UCDs open, prospective, uncontrolled, multicenter study to evaluate and(OLT) organic is the final acidemias curative (OAs) option. who Data received from the liver United transplantation. Network for Within 5 years after transplantation, the graft survival rate was the safety and efficacy of a liver cell suspension infused into the byportal repetitive vein of application children with of humanUCDs [11]. liver In cells. this Thestudy, aim neonates of this new and 78% for children < 2 years old at the time of transplantation and infants within the first 3 months of life with UCDs were treated liver88% fortransplants children ≥ 2 in childrenyears old with at theUCDs time are of antransplantation approximate cells to compensate for the metabolic defect and to reduce the 90%[4]. Foschi survival et al.rate, summarized normal mental that the development, advantages ofand orthotopic a better therapeutic option is to supply a sufficient amount of healthy liver a single-center study at Children’s Hospital of Pittsburgh at the risk of neurological deterioration while awaiting OLT. Another is associatedquality of life with [5]. major However, surgery, whole and liver the transplantationrequirement for for lifelong these clinical study is to determine whether partial irradiation of the immunosuppressivedisorders is limited bytherapy. a severe Currently, shortage approximately of donors, the 17,000 risks liverUniversity and subsequent of Pittsburgh liver Medical cell transplantation Center [12]. The can purpose provide of help this adults and children are waiting for donated livers in United States, for patients with life-threatening liver-based metabolic diseases, and the waiting list continues to grow. Every year, more than 1,500 people die waiting for a donated liver to become available physiologic function will be assessed 6 months after infusing (http://www.liverfoundation.org/patients/organdonor/about/). allogeneicincluding UCDs.donor hepatocytesIn this study, through the improvementthe portal vein in following enzyme Therefore, there is certainly an urgent need for novel curative preparative hepatic irradiation. Currently, there are no study therapies. Based on the progress to date, cell-based therapies results posted. and new approaches in gene therapy have become the promising The major challenges for hepatocyte transplantation are the low rates of engraftment (from 0% to a maximum of 12%) and current progress and challenges of cell and gene therapies for curative treatments for CPS1 deficiency. This review outlines the short-term survival of transplanted hepatocytes due to rejection or senescence. Most patients lose their graft after several months CPS1 Cell therapiesdeficiency. for CPS1 deficiency another major limitation. Therefore, increasing engraftment Hepatocyte transplantation was proposed as a treatment for ratesto years. and Inliver addition, repopulation the lack are of importantgood-quality research donor topicsorgans for is orthotopic liver transplantation, hepatocyte transplantation has somemetabolic advantages, diseases including
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