rAAV Vector Expression Control for GM1 and GM2 Gene Therapy
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Solution Overview
Problem
Current AAV vectors deliver high levels of gene expression that result in adverse events such as cytotoxicity, and there are no effective therapies for lysosomal storage disorders like GM1 gangliosidosis and Tay Sachs disease.
Innovation Solution
Recombinant AAV vectors with engineered regulatory elements modulate transgene expression levels to provide therapeutic amounts without adverse events, using a capsid containing a nucleic acid with a promoter operably linked via a chimeric intron to a transgene encoding lysosomal storage disorder-associated proteins like HEXA, HEXB, or GLB1, and include a chicken beta-actin promoter and rabbit beta globin intron.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current AAV vectors are used to deliver high levels of gene expression, then therapeutic enzyme levels are achieved, but cytotoxicity and adverse events occur
Solution Approach 1:
The patent modifies the regulatory elements controlling transgene expression to achieve optimal therapeutic enzyme levels without cytotoxicity. By engineering specific promoter-intron-transgene configurations, the patent tunes gene expression parameters to a therapeutic window that avoids adverse events while maintaining sufficient enzyme activity for treatment
Solution Approach 2:
The patent introduces engineered regulatory elements as intermediaries between the promoter and transgene. These regulatory sequences act as mediators that control the level of transgene expression, allowing therapeutic enzyme production without the harmful effects of uncontrolled high-level expression
2Reliability
If no effective therapy is available for lysosomal storage disorders, then disease progression continues, but introducing gene therapy may cause adverse events
Solution Approach 1:
The patent applies partial action by delivering gene therapy at controlled expression levels rather than maximum possible levels. By using engineered regulatory elements to modulate transgene expression to therapeutic (not supraphysiological) levels, the patent achieves disease treatment efficacy while avoiding the adverse events associated with excessive gene expression
3Productivity
If high levels of transgene expression are achieved, then therapeutic effect is enhanced, but cytotoxicity increases
Solution Approach 1:
The patent changes the parameters of gene expression control by engineering specific regulatory element configurations. This allows optimization of transgene expression productivity to achieve therapeutic effects while maintaining expression levels within a safe range that does not cause cytotoxicity
Data Source
AI summary
Aspects of the disclosure relate to compositions and methods for the treatment of lysosomal storage disorders, such as GM1 gangliosidosis, Tay Sachs disease, and Sandhoff disease. In some embodiments, the compositions comprise viral vectors encoding beta-galactosidase. In some embodiments, the compositions comprise viral vectors encoding beta-hexosaminidase subunits (e.g. HEXA, HEXB, or combinations thereof).