A1AT Base Editing With ABE8 for Liver and Lung Pathology
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Solution Overview
Problem
Current treatments for Alpha-1 Antitrypsin Deficiency (A1AD) fail to address both lung pathology and liver toxicity, with gene therapies being counterproductive due to the liver's severe disease burden and protein replacement therapies not targeting the underlying genetic defect.
Innovation Solution
A modified adenosine deaminase, termed ABE8, is used to edit deleterious mutations in the alpha-1 antitrypsin gene with high efficiency and specificity, converting A·T to G·C to correct the SNP associated with A1AD, thereby producing functional alpha-1 antitrypsin polypeptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If gene knockout or knockdown methods are used to address liver toxicity, then liver damage is reduced, but pulmonary pathology is not corrected
Solution Approach 1:
The invention segments the treatment approach by using tissue-specific gene editing: CRISPR/Cas9 is applied to hepatocytes to correct the A1AT gene and reduce liver toxicity, while separately applying protein replacement therapy to the respiratory system to address pulmonary pathology. This segmentation allows each treatment to optimize for its specific target organ without interfering with the other.
Solution Approach 2:
The invention uses an intermediary approach by introducing a third party (ex vivo gene editing of hepatocytes) that mediates between the two pathologies. The edited hepatocytes are then reconstituted into the patient's liver, serving as a mediator that simultaneously addresses liver toxicity through corrected A1AT production while the systemic effect also benefits the respiratory system.
2Object-affected harmful factors
If protein replacement therapy is used to address pulmonary pathology, then lung function is improved, but liver toxicity is not mitigated
Solution Approach 1:
The invention segments the treatment approach by using tissue-specific gene editing: CRISPR/Cas9 is applied to hepatocytes to correct the A1AT gene and reduce liver toxicity, while separately applying protein replacement therapy to the respiratory system to address pulmonary pathology. This segmentation allows each treatment to optimize for its specific target organ without interfering with the other.
Solution Approach 2:
The invention uses an intermediary approach by introducing a third party (ex vivo gene editing of hepatocytes) that mediates between the two pathologies. The edited hepatocytes are then reconstituted into the patient's liver, serving as a mediator that simultaneously addresses liver toxicity through corrected A1AT production while the systemic effect also benefits the respiratory system.
3Quantity of substance
If gene therapy is used to increase A1AT in the liver, then A1AT levels are improved, but the existing liver disease burden is not addressed and may be exacerbated
Solution Approach 1:
The invention extracts the defective hepatocytes from the patient's liver through apheresis, removes them from the systemic circulation, and replaces them with genetically corrected hepatocytes. This extraction approach allows the removal of toxic aggregates and defective cells while introducing functional A1AT-producing cells, thereby reducing liver disease burden rather than exacerbating it.
Solution Approach 2:
The invention converts the harmful effect of endogenous A1AT (which causes toxicity through misfolded protein aggregates) into a benefit by using the same A1AT production pathway to generate corrected, functional protein. The gene editing transforms the toxic A1AT into beneficial A1AT, converting the harmful liver disease burden into a therapeutic opportunity.
Data Source
AI summary
The present invention features compositions and methods for editing deleterious mutations associated with alpha-1 anti-trypsin (A1AT) deficiency. In particular embodiments, the invention provides methods for correcting mutations in an A1AT polynucleotide using an adenosine deaminase base editor. ABE8, having unprecedented levels of efficiency.