TTR Gene Base Editing With Lipid Nanoparticle Delivery
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Solution Overview
Problem
Current treatments for hereditary transthyretin amyloidosis, such as liver transplantation, kinetic stabilizers, and gene-silencing drugs, are inadequate in providing a durable solution for conditions like polyneuropathy and cardiomyopathy caused by transthyretin amyloidosis.
Innovation Solution
A base editing system comprising a guide RNA and a codon-optimized Cas9 protein fusion is used to modify the transthyretin (TTR) gene, employing a lipid nanoparticle delivery system to achieve targeted gene editing and reduce amyloid deposition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If liver transplantation is performed to treat hATTR amyloidosis, then TTR protein production is replaced, but the treatment requires lifelong immunosuppression and has significant surgical risks
Solution Approach 1:
The patent extracts and corrects only the defective TTR gene in the liver using base editing technology, rather than replacing the entire liver organ. This removes the problematic gene mutation while preserving the rest of the liver's function, avoiding the need for lifelong immunosuppression and major surgery.
Solution Approach 2:
The base editing system changes the nucleotide parameters of the TTR gene at specific positions (such as position 119) to correct pathogenic mutations. This precise parameter change at the DNA level transforms the defective gene into a functional one, providing a durable cure without organ replacement.
2Stability of the object's composition
If kinetic stabilizers like tafamidis are administered to stabilize TTR tetramers, then protein misfolding is reduced, but the treatment requires continuous lifelong medication with limited durability
Solution Approach 1:
The base editing system performs preliminary correction of the TTR gene mutation before amyloid formation occurs. By fixing the genetic defect upfront, the liver will produce normal TTR proteins throughout life, eliminating the need for continuous stabilizer medications.
Solution Approach 2:
The corrected TTR gene enables the liver to self-produce functional TTR proteins without external intervention. The liver's own transcription and translation machinery will generate stable, non-amyloidogenic TTR tetramers autonomously, replacing the need for exogenous kinetic stabilizers.
3Object-generated harmful factors
If gene-silencing drugs like patisiran are used to suppress TTR protein synthesis, then amyloid deposition is reduced, but the treatment does not address the underlying genetic mutation and requires continuous administration
Solution Approach 1:
Instead of merely silencing the gene to reduce harmful protein production, the base editing system converts the harmful mutated gene into a beneficial functional gene. The same TTR gene that was causing amyloidosis is now corrected to produce healthy proteins, turning the source of harm into a source of benefit.
Solution Approach 2:
The patent performs preliminary correction of the TTR gene mutation before amyloid pathology develops or progresses. By fixing the genetic defect in advance, the treatment prevents rather than just manages the disease, providing curative potential that gene-silencing therapies lack.
4Reliability
If base editing is used to correct TTR gene mutations, then a potentially one-time curative treatment is achieved, but the delivery system complexity increases with lipid nanoparticle formulation
Solution Approach 1:
Lipid nanoparticle (LNP) formulations serve as intermediary vehicles to deliver the base editing components (Cas9 protein, guide RNA, and base editor mRNA) into liver cells. The LNP protects the delicate biological molecules during circulation and facilitates cellular uptake, enabling in vivo gene correction without requiring complex surgical procedures.
Data Source
AI summary
Provided herein are compositions for gene modification related to base editor systems, and methods of using the same to treat or prevent conditions associated with the extracellular deposition in various tissues of amyloid fibrils formed by the aggregation of misfolded transthyretin (TTR) proteins. Such conditions include, but are not limited to, polyneuropathy due to hereditary transthyretin amyloidosis (hATTR-PN) and hereditary cardiomyopathy due to transthyretin amyloidosis (hATTR-CM), both associated with autosomal dominant mutations of the TTR gene, and an age-related cardiomyopathy associated with wild-type TTR proteins (ATTRwt), also known as senile cardiac amyloidosis.