Lipid Nanoparticle TTR Base Editing for Amyloidosis
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Solution Overview
Problem
There is a need for effective treatments for amyloidosis, particularly transthyretin amyloidosis, as liver transplant is the current standard but limited by organ donor availability, and existing methods are inadequate.
Innovation Solution
Compositions and methods using lipid nanoparticles (LNPs) containing guide polynucleotides and amino lipids to edit the transthyretin (TTR) gene, employing a base editor and guide RNAs to modify or edit the TTR gene sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If liver transplant is used to treat transthyretin amyloidosis, then treatment effectiveness is improved, but availability is limited due to organ donor scarcity
Solution Approach 1:
The patent creates a functional copy of the therapeutic effect without using actual organ transplants. By delivering gene editing components (Cas9 protein, guide RNA, and donor TTR gene) via lipid nanoparticles to patient hepatocytes, the therapy produces a functional replacement of defective TTR protein synthesis, achieving treatment effectiveness without requiring physical organ donation
Solution Approach 2:
The patent replaces the mechanical/biological process of organ transplant with a molecular biology approach. Instead of physically replacing the liver organ, the therapy uses gene editing mechanisms to correct the underlying genetic defect (TTR gene mutations) at the molecular level, substituting a complex surgical procedure with a targeted molecular intervention
2Adaptability or versatility
If conventional treatments for amyloidosis are used, then treatment options are limited, but disease progression continues
Solution Approach 1:
The patent performs preliminary gene editing of the TTR gene in hepatocytes before the defective protein can cause further amyloid deposition. By introducing the corrected TTR gene sequence and Cas9/guide RNA complex early in the disease process, the therapy prevents further mutation-induced protein misfolding and amyloid formation, addressing the root cause rather than treating symptoms
Solution Approach 2:
The patent changes the genetic parameter of the TTR gene by introducing specific nucleotide edits (e.g., A80V mutation correction) that alter the protein's amino acid sequence. This parameter change at the molecular level restores proper protein folding and eliminates the propensity for amyloid formation, fundamentally altering the disease trajectory
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The LNP-based gene editing approach provides a potential treatment for conditions associated with transthyretin amyloidosis, including hereditary polyneuropathy and cardiomyopathy, offering an alternative to liver transplant.
Implementation Method 1
a guide polynucleotide containing a sequence selected from any one or more of the following SEQ ID NOs: 472-476, 479-497, 499-504, 506-532, 534-571, 573-638, 653-677, 707-711, 713-731, 733-784, 1044, 1045, 1214, and 1215
Implementation Method 2
Compositions and methods directed to editing the TTR gene using an editing system, such as one comprising a base editor and guide RNAs are disclosed
Implementation Method 3
a lipid nanoparticle (LNP) containing a guide polynucleotide
Data Source
AI summary
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.