AAV NAGLU Vectors With Codon Optimization for MPS IIIB
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Solution Overview
Problem
Current treatments for mucopolysaccharidosis IIIB (MPS IIIB), a devastating autosomal recessive lysosomal storage disease, are limited to supportive care, and there is an urgent need for a treatment that can effectively target the root cause by delivering recombinant α-N-acetylglucosaminidase (NAGLU) to the central nervous system and peripheral tissues to address the accumulation of undegraded heparan sulfates.
Innovation Solution
The use of AAV vectors containing codon-optimized NAGLU nucleic acid sequences for enhanced expression and secretion, which leads to improved therapeutic efficacy by increasing NAGLU levels in infected cells and bystander effects in non-infected cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV vectors with wild-type NAGLU sequence are used for gene therapy, then the treatment can be delivered to CNS and peripheral tissues, but the expression level and secretion of NAGLU are insufficient to effectively reduce GAG accumulation
Solution Approach 1:
The patent applies codon optimization to the NAGLU coding sequence, which changes the nucleotide parameters (codon usage) while maintaining the same amino acid sequence. This parameter change increases translation efficiency and protein expression levels, directly resolving the contradiction between reliable delivery and sufficient productivity of NAGLU enzyme in treated tissues
2Adaptability or versatility
If gene therapy is delivered systemically to achieve broad tissue coverage, then both CNS and peripheral tissues can be treated, but the secretion of NAGLU to non-infected cells is insufficient for optimal bystander effects
Solution Approach 1:
By optimizing codon usage in the NAGLU gene sequence, the patent enhances both intracellular expression and secretory efficiency. The increased secretion quantity enables effective bystander effects in non-infected cells, while the AAV vector maintains its ability to deliver therapy to both CNS and peripheral tissues, thus resolving the contradiction between broad adaptability and sufficient quantity of secreted enzyme
Data Source
AI summary
Recombinant nucleic acid comprising nucleotides encoding α-N-acetylglucosaminidase (NAGLU). Vectors comprising the recombinant nucleic acid for delivery to a subject. In an aspect the NAGLU sequences optimized for expression in human cells. Methods of using the vector to increase secretion of NAGLU from a cell and for treatment and prevention of mucopolysaccharidosis IIIB.