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Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency
S E Raper1, J M Wilson, M Yudkoff
1Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, USA.
Abstract:
There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy with an adenoviral vector. Using the partially OTC-deficient sparse fur mouse we found transduction and expression could be achieved using an intravenous infusion of a recombinant adenovirus containing the OTC cDNA. The results were transient as a result of immune activation in response to the vector and vector-transduced cells. By modifying the adenoviral construct, creating an E1 deletion-E2 temperature-sensitive mutation, we blunted the cytotoxic T lymphocyte immune response and achieved correction of biochemical abnormalities for 2-3 months. We also found that transduction and expression following gene transfer occurred sufficiently rapidly to protect against acute hyperammonaemia within 24 h. Subsequent preclinical studies in mice and non-human primates demonstrated that E1-E4-deleted vectors had a substantially improved safety profile and similar efficacy. With this evidence of efficacy and safety of adenoviral vectors, we are embarking on a phase I trial of intravascular gene transfer using an E1-E4-deleted vector in adults with partial OTC deficiency.
Insights
Gene therapy using modified adenoviral vectors shows promise for ornithine transcarbamylase (OTC) deficiency. This approach successfully corrected biochemical abnormalities in animal models, paving the way for human clinical trials.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Ornithine transcarbamylase (OTC) deficiency is a common genetic disorder with poor clinical outcomes.
- Gene therapy presents a potential treatment strategy for OTC deficiency due to available cloned genes, animal models, and the disorder's prevalence.
Purpose of the Study:
- To evaluate the efficacy and safety of in vivo gene therapy using adenoviral vectors for ornithine transcarbamylase (OTC) deficiency.
Main Methods:
- Adenoviral vectors containing OTC cDNA were administered intravenously to OTC-deficient mice.
- Vector modifications, including E1 deletion-E2 temperature-sensitive mutations and E1-E4 deletions, were used to mitigate immune responses and enhance safety.
- Biochemical abnormalities and protection against hyperammonaemia were assessed.
Main Results:
- Initial studies showed transient transduction and expression due to immune activation.
- Modified vectors (E1 deletion-E2 temperature-sensitive) blunted immune responses, achieving biochemical correction for 2-3 months and rapid protection against hyperammonaemia.
- Further preclinical studies with E1-E4-deleted vectors demonstrated improved safety and sustained efficacy in mice and non-human primates.
Conclusions:
- Adenoviral vectors, particularly E1-E4-deleted constructs, show significant potential for treating ornithine transcarbamylase (OTC) deficiency.
- The demonstrated efficacy and improved safety profile support the initiation of a Phase I clinical trial for intravascular gene transfer in patients with partial OTC deficiency.