Engineered Viral Vector for OTC Deficiency Treatment
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Solution Overview
Problem
Current therapies for ornithine transcarbamylase (OTC) deficiency, such as low protein diets and medications, have limitations, including high mortality rates in neonates and challenges in gene therapy due to the cell-autonomous nature of the gene and instability of hOTC mRNA, necessitating alternative approaches for effective treatment.
Innovation Solution
Development of a recombinant viral vector with an engineered nucleic acid sequence encoding human ornithine transcarbamylase (hOTC) that is less than 80% identical to the wild-type sequence, optimized for enhanced transduction, transcription, and translation, using vectors like adeno-associated virus (AAV) with liver-specific promoters to ensure expression in liver cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type hOTC nucleic acid sequence is used in viral vectors, then the sequence is stable and recognizable by cellular machinery, but expression levels are insufficient and mRNA is unstable
Solution Approach 1:
The patent applies parameter changes by modifying the nucleic acid sequence parameters of hOTC - specifically codon optimization to change codon usage frequency and nucleotide composition while maintaining the amino acid sequence. This resolves the contradiction by improving mRNA stability and expression levels through sequence parameter optimization without changing the functional protein product.
Solution Approach 2:
The patent creates an engineered copy of the hOTC nucleic acid sequence that is optimized for viral vector expression. This engineered copy maintains the functional amino acid sequence but incorporates optimized nucleotide sequences that improve mRNA stability and translation efficiency, resolving the contradiction between using wild-type sequence and achieving high expression.
2Ease of manufacture
If conventional therapies (low protein diet and medications) are used, then treatment is non-invasive and avoids surgery, but mortality rate is nearly 50% in neonates and hyperammonemic crises cannot be prevented
Solution Approach 1:
The patent uses a viral vector as an intermediary delivery system to introduce engineered hOTC nucleic acid sequences into liver cells. This intermediary approach enables gene therapy delivery without requiring liver transplantation surgery, resolving the contradiction between treatment accessibility and mortality rate by providing a less invasive but more effective treatment option.
3Reliability
If liver transplantation is performed, then OTCD is cured, but donor liver is limiting, procedure carries significant morbidity, and immunosuppressive drugs are necessary for life
Solution Approach 1:
The patent extracts the therapeutic function (hOTC enzyme production) from the complex liver transplantation procedure by delivering only the necessary nucleic acid sequence via viral vector. This extraction approach achieves the therapeutic effect without requiring donor organ matching, surgical transplantation, or lifelong immunosuppression, resolving the contradiction between cure rate and treatment complexity.
4Productivity
If adenoviral vectors are used to express hOTC, then some reconstitution of liver OTC activity is achieved, but sufficient levels of active human OTC cannot be expressed
Solution Approach 1:
The patent applies parameter changes to the nucleic acid sequence by implementing codon optimization that specifically addresses viral vector expression parameters. The engineered sequence incorporates optimized codon usage and nucleotide composition that enable sufficient expression levels in viral vector systems, resolving the contradiction between partial reconstitution and sufficient expression.
Data Source
AI summary
Viral vectors comprising engineered hOTC DNA and RNA sequences are provided which when delivered to a subject in need thereof are useful for treating hyperammonemia, ornithine transcarbamylase deficiency and symptoms associated therewith. Also provided are methods of using hOTC for treatment of liver fibrosis and/or cirrhosis in OTCD patients by administering hOTC.