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Patient selection may affect gene therapy success. Dominant negative effects observed for ornithine transcarbamylase
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
We have achieved significant improvement of ornithine transcarbamylase deficiency (OTCD) in a mouse model through adenoviral-mediated gene transfer of the human ornithine transcarbamylase cDNA. Substantial reduction in orotic aciduria was observed within 24 h of treatment. Metabolic correction was later associated with phenotypic correction and moderate increase in enzymatic activity. In an effort to identify the level of gene expression required to achieve wild-type levels of enzyme activity we uncovered a dominant negative effect of the endogenous mutant protein on the activity of the delivered recombinant wild-type protein. This phenomenon is relevant to homomultimeric protein defects such as OTCD, represent a challenging category of disorders for gene therapy. Thus, although our findings indicate that adenoviral-mediated gene transfer may have potential as a short-term treatment for OTCD in humans and may be effective especially during catabolic crisis, the observations in this study suggest that careful patient selection based on mutation class may be essential for initial OTCD gene therapy trials, and perhaps, for other homomultimeric enzyme deficiencies being considered as gene therapy targets.
Insights
Adenoviral gene therapy improved ornithine transcarbamylase deficiency (OTCD) in mice, reducing orotic aciduria and correcting metabolic and phenotypic issues. However, mutant protein interference necessitates careful patient selection for future human trials.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Ornithine transcarbamylase deficiency (OTCD) is a genetic urea cycle disorder.
- OTCD is caused by mutations in the OTC gene, leading to hyperammonemia.
- Gene therapy offers a potential treatment strategy for genetic disorders like OTCD.
Purpose of the Study:
- To evaluate the efficacy of adenoviral-mediated gene transfer of human ornithine transcarbamylase cDNA in a mouse model of OTCD.
- To investigate the gene expression levels required for wild-type enzyme activity.
- To identify potential challenges for gene therapy in homomultimeric protein defects.
Main Methods:
- Adenoviral-mediated gene transfer of human ornithine transcarbamylase cDNA in an OTCD mouse model.
- Monitoring of orotic aciduria levels.
- Assessment of metabolic and phenotypic correction.
- Enzymatic activity assays.
- Analysis of endogenous mutant protein effects on recombinant protein activity.
Main Results:
- Significant reduction in orotic aciduria within 24 hours post-treatment.
- Metabolic and phenotypic correction observed.
- Moderate increase in enzymatic activity.
- Discovery of a dominant negative effect of the endogenous mutant protein on the wild-type enzyme.
- Identification of challenges for gene therapy in homomultimeric protein defects.
Conclusions:
- Adenoviral gene transfer shows potential for short-term OTCD treatment, particularly during catabolic crises.
- The dominant negative effect of mutant proteins in homomultimeric defects complicates gene therapy.
- Careful patient selection based on mutation class is crucial for OTCD gene therapy trials.
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