AI Article Synopsis

  • Ornithine transcarbamylase deficiency (OTCD) is a serious X-linked liver disorder leading to high ammonia levels, causing neurological issues and potentially death, with liver transplantation being the most effective treatment to date.
  • AAV-mediated gene-replacement therapy using an AAV2/8 vector has shown promise in correcting OTCD symptoms by enhancing mRNA translation and restoring liver function in animal models.
  • The study indicated that the AAV8-hOTC-CO gene transfer is safe, offering sustained treatment benefits and supporting future clinical applications for OTCD patients.

Article Abstract

Ornithine transcarbamylase deficiency (OTCD) is an X-linked liver disorder caused by partial or total loss of OTC enzyme activity. It is characterized by elevated plasma ammonia, leading to neurological impairments, coma, and death in the most severe cases. OTCD is managed by combining dietary restrictions, essential amino acids, and ammonia scavengers. However, to date, liver transplantation provides the best therapeutic outcome. AAV-mediated gene-replacement therapy represents a promising curative strategy. Here, we generated an AAV2/8 vector expressing a codon-optimized human cDNA by the α1-AAT liver-specific promoter. Unlike standard codon-optimization approaches, we performed multiple codon-optimization rounds via common algorithms and ortholog sequence analysis that significantly improved mRNA translatability and therapeutic efficacy. AAV8-hOTC-CO (codon optimized) vector injection into adult OTC mice (5.0E11 vg/kg) mediated long-term complete correction of the phenotype. Adeno-Associated viral (AAV) vector treatment restored the physiological ammonia detoxification liver function, as indicated by urinary orotic acid normalization and by conferring full protection against an ammonia challenge. Removal of liver-specific transcription factor binding sites from the AAV backbone did not affect gene expression levels, with a potential improvement in safety. These results demonstrate that AAV8-hOTC-CO gene transfer is safe and results in sustained correction of OTCD in mice, supporting the translation of this approach to the clinic.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786024PMC
http://dx.doi.org/10.1016/j.omtm.2020.11.005DOI Listing

Publication Analysis

Top Keywords

ornithine transcarbamylase
8
transcarbamylase deficiency
8
aav vector
8
long-term correction
4
correction ornithine
4
deficiency spf-ash
4
spf-ash mice
4
mice translationally
4
translationally optimized
4
optimized aav
4

Similar Publications

Maternal and Newborn Care for Ornithine Transcarbamylase Deficiency.

MCN Am J Matern Child Nurs

December 2024

Sharon Anderson is an Associate Professor, Division of Advanced Nursing Practice, Rutgers School of Nursing, Newark, NJ; and Advanced Practice Nurse, Medical Genetics, Rutgers Health, Rutgers Robert Wood Johnson Medical School, Child Health Institute of New Jersey, New Brunswick, NJ. Dr. Anderson can be reached at and

Article Synopsis
  • Ornithine transcarbamylase (OTC) deficiency is the most common disorder affecting the urea cycle, which can lead to serious health issues like brain damage and even death if untreated.
  • The condition is caused by genetic mutations in the OTC gene and has varying symptoms depending on the age of onset and severity.
  • The overview also discusses diagnostic testing and provides treatment guidelines, especially for both carrier females and affected male newborns throughout their prenatal, natal, and postpartum phases.
View Article and Find Full Text PDF

Strategies for Modifying Adenoviral Vectors for Gene Therapy.

Int J Mol Sci

November 2024

Laboratory of Genome Editing, Research Centre for Medical Genetics, Moskvorechye, 1, 115522 Moscow, Russia.

Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, large capacity, and high transduction efficiency, making them widely used as oncolytic vectors and for creating vector-based vaccines. This review also considers the application of adenoviral vectors in oncolytic virotherapy and gene therapy for inherited diseases, analyzing strategies to enhance their efficacy and specificity. However, despite significant progress in this field, the use of adenoviral vectors is limited by their high immunogenicity, low specificity to certain cell types, and limited duration of transgene expression.

View Article and Find Full Text PDF

A novel de novo missense OTC mutation in an Iranian girl: a case report.

J Pediatr Endocrinol Metab

November 2024

Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran.

Objectives: Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle, caused by mutations in the OTC gene located on the X chromosome. OTCD presents in early and late-onset forms, with variable severity. Despite the high genetic heterogeneity, genotype-phenotype correlations help in prognosis and treatment planning.

View Article and Find Full Text PDF

Hyperammonemia is a serious metabolic condition marked by elevated ammonia levels in the blood, leading to neurological damage and systemic complications if untreated. While often associated with liver dysfunction, inborn metabolic errors such as fatty acid oxidation defects, pyruvate metabolism disorders, urea cycle disorders (UCDs), urea splitting bacterial infections, hemato-oncological disorders, and portosystemic shunts are less commonly recognized but significant causes, particularly outside neonatal populations. These metabolic errors, due to partial enzyme deficiencies, may present later in life with atypical symptoms.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!

A PHP Error was encountered

Severity: Notice

Message: fwrite(): Write of 34 bytes failed with errno=28 No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 272

Backtrace:

A PHP Error was encountered

Severity: Warning

Message: session_write_close(): Failed to write session data using user defined save handler. (session.save_path: /var/lib/php/sessions)

Filename: Unknown

Line Number: 0

Backtrace: