Optimized PBGD Gene Therapy via AAV Vector
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Solution Overview
Problem
Current treatments for acute intermittent porphyria (AIP), such as liver transplantation, have limitations due to donor availability and morbidity, and existing gene therapy approaches show only transient efficacy, necessitating improved vectors and protocols for delivering functional porphobilinogen deaminase (PBGD) to address the enzyme deficiency.
Innovation Solution
Development of a parvoviral virion comprising a nucleic acid construct with a nucleotide sequence coding for human porphobilinogen deaminase, combined with an AAT promoter and mouse albumin gene enhancer, and AAV serotype 5 capsid proteins, to create an efficient AAV vector for targeted gene therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If liver transplantation is used to treat AIP, then the enzyme deficiency is corrected, but donor availability is limited and morbidity is high
Solution Approach 1:
The patent extracts the essential therapeutic function (PBGD enzyme replacement) from the complex liver transplantation procedure, delivering only the necessary gene therapy component via AAV vectors to correct the enzyme deficiency without requiring organ transplantation
Solution Approach 2:
The patent introduces AAV vectors as an intermediary delivery system to transport the PBGD gene into hepatic cells, serving as a bridge between the therapeutic goal and the cellular target, thereby avoiding the complexity of direct liver transplantation
2Reliability
If existing gene therapy approaches are used, then PBGD delivery is attempted, but efficacy is only transient
Solution Approach 1:
The patent changes critical parameters of the gene delivery system by selecting AAV serotype 5 capsid proteins with enhanced stability and liver tropism, and optimizing the promoter-enhancer configuration (AAT promoter with mouse albumin gene enhancer) to achieve sustained long-term expression of PBGD enzyme
Solution Approach 2:
The patent creates a composite gene therapy vector combining multiple functional elements: AAV serotype 5 capsid proteins for targeted delivery, AAT promoter for tissue-specific expression, mouse albumin gene enhancer for enhanced expression levels, and the human PBGD coding sequence, achieving synergistic sustained therapeutic efficacy
Data Source
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AI summary
The present invention relates to nucleotide sequences coding for human porphobilinogen deaminase that are optimised for higher expression in mammalian cells. The invention further relates to DNA constructs comprising such optimised synthetic coding sequences for use in gene therapy of conditions caused by a deficiency in porphobilinogen deaminase, such as acute intermittent porphyria. Accordingly, the present invention relates to anucleic acid or a nucleic acid construct comprising a nucleotide sequence coding for a human porphobilinogen deaminase, wherein at least 320 of the codons coding for the human porphobilinogen deaminase are identical to the codons in SEQ ID NO: 1 or wherein at least 305 of the codons coding for the human porphobilinogen deaminase are identical to the codons in SEQ ID NO: 3.