In Vivo CRISPR Liver Editing via Lipid Nanoparticles for Durable TTR Reduction
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Solution Overview
Problem
Current treatments for ATTR amyloidosis, such as TTR stabilization and mRNA degradation, require chronic administration and are limited by side effects and disease progression, necessitating a need for long-lasting gene editing therapies that can sustainably reduce TTR production.
Innovation Solution
Systemic administration of a CRISPR/Cas9-based therapeutic using a lipid nanoparticle (LNP) composition containing mRNA encoding a Cas nuclease and a guide RNA targeting the TTR gene for in vivo liver editing, achieving durable reduction of TTR protein levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for ATTR amyloidosis (TTR stabilization or mRNA degradation) are used, then symptom relief and functional improvement are achieved, but chronic administration is required and side effects occur
Solution Approach 1:
The patent applies preliminary action by using CRISPR/Cas9 gene editing to permanently modify the TTR gene in hepatocytes before disease progression occurs or at early stages. The gene editing creates heritable changes in the liver cells that continuously produce reduced TTR levels without requiring repeated administrations, thus achieving long-lasting effect from a single or limited treatment intervention.
Solution Approach 2:
The patent employs copying by using mRNA encoding Cas9 and guide RNA that can be replicated and delivered systemically via lipid nanoparticles. The edited genes in hepatocytes serve as permanent templates that continuously produce the desired effect, eliminating the need for chronic re-administration of therapeutic agents.
2Quantity of substance
If current treatments for ATTR amyloidosis are used, then TTR production is reduced, but lifelong administration is required to maintain knockdown
Solution Approach 1:
The CRISPR/Cas9 system performs preliminary gene editing action that permanently alters the TTR gene sequence in hepatocytes. This preliminary modification establishes a permanent state of reduced TTR production that persists throughout the patient's life without requiring continuous treatment, thus resolving the contradiction between achieving low TTR levels and avoiding lifelong administration.
Solution Approach 2:
The patent implements self-service by engineering the patient's own liver cells to permanently perform the therapeutic function. The edited hepatocytes autonomously maintain reduced TTR production through their modified genes, eliminating the need for external continuous intervention or chronic medication administration.
3Reliability
If TTR knockdown is intensified to improve neuropathy endpoints, then greater clinical improvement is achieved, but biosafety concerns increase
Solution Approach 1:
The patent applies local quality by using tissue-specific liver-targeted delivery of CRISPR components via lipid nanoparticles that selectively deliver Cas9 and guide RNA to hepatocytes. This localized delivery ensures that TTR knockdown occurs specifically in the liver where TTR is produced, minimizing off-target effects and biosafety risks while achieving sufficient clinical improvement.
Solution Approach 2:
The patent employs parameter changes by carefully controlling the degree of TTR knockdown through optimized CRISPR guide RNA design and dosing regimens. The treatment aims to achieve a balanced reduction in TTR levels that is sufficient for clinical benefit while maintaining safety margins, thus resolving the contradiction between intensive knockdown for improved outcomes and biosafety constraints.
Data Source
AI summary
The first systemic administration of a CRISPR/Cas9-based therapeutic for in vivo editing in a clinical trial is described. Described herein are methods for in vivo editing of a liver gene by systemically administering a lipid nanoparticle composition comprising an mRNA encoding a Cas nuclease and a guide RNA that targets the gene. For example, disclosed herein are methods for in vivo editing of a transthyretin gene by systemically administering a lipid nanoparticle composition comprising an mRNA encoding a Cas nuclease and a guide RNA that targets the TTR gene. Assessment of biosafety metrics and clinical efficacy metrics, as well as methods of treatment, are also described herein.