Modified OTC Protein mRNA for Stable Mitochondrial Enzyme Delivery
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for Ornithine Transcarbamylase (OTC) deficiency, such as dietary restrictions, medications, and liver transplantation, are cumbersome and risky, and there is a need for more effective and stable gene therapy approaches to deliver OTC enzyme to mitochondria.
Innovation Solution
Development of a modified human OTC protein (SEQ ID NO: 4) with optimized ubiquitination sites and codon-optimized mRNA constructs to enhance stability and efficiency of OTC protein delivery to mitochondria, using a heterologous mRNA construct with a 5'UTR derived from Arabidopsis thaliana for improved expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gene therapy approaches are used to deliver OTC enzyme to mitochondria, then treatment efficacy is improved, but delivery stability and efficiency are insufficient
Solution Approach 1:
The patent modifies the OTC protein sequence by changing specific amino acid residues to create a stabilized variant with improved mitochondrial targeting and reduced ubiquitination. This parameter change in the protein structure directly addresses the delivery stability issue while maintaining treatment efficacy.
Solution Approach 2:
The patent removes ubiquitination sites from the OTC protein sequence to prevent degradation by ubiquitin ligases. By extracting these problematic sites, the protein achieves greater stability during delivery while maintaining its therapeutic function.
2Object-generated harmful factors
If dietary restrictions are imposed to limit protein intake, then ammonia accumulation is reduced, but patient growth and nutrition are compromised
Solution Approach 1:
The patent enables the patient's own cells to produce functional OTC enzyme through gene therapy, allowing the body to self-regulate ammonia metabolism without external dietary restrictions. The endogenous enzyme production eliminates the need for protein limitation while maintaining ammonia control.
3Object-generated harmful factors
If medications are administered to stimulate nitrogen removal, then alternative nitrogen excretion pathways are activated, but patient compliance and quality of life deteriorate
Solution Approach 1:
The gene therapy approach enables the body to naturally produce functional OTC enzyme, eliminating the need for external medication administration. Patients achieve nitrogen removal through restored endogenous enzyme function, improving compliance and quality of life.
4Reliability
If liver transplantation is performed to cure hyperammonemia, then OTC enzyme function is restored, but surgical risks and immunosuppression requirements increase
Solution Approach 1:
The patent extracts the problematic ubiquitination sites from the OTC protein sequence, creating a stabilized variant that achieves therapeutic efficacy without requiring liver transplantation. This eliminates surgical risks and immunosuppression requirements while maintaining the cure for hyperammonemia.
Data Source
AI summary
The present disclosure provides a modified human OTC protein having improved properties for the treatment of OTC deficiency in a patient. Preferably, the protein of the disclosure is produced from a codon optimized mRNA suitable for administration to a patient suffering from OTC deficiency wherein upon administration of the mRNA to the patient, the protein of the disclosure is expressed in the patient in therapeutically effective amounts to treat OTC deficiency. The present disclosure also provides codon optimized mRNA sequences encoding wild type human OTC comprising a 5′ UTR derived from a gene expressed by Arabidopsis thaliana for use in treating OTC deficiency in a patient.