CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

Overview

• Study Title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
• Publication: The New England Journal of Medicine, August 5, 2021
• Authors & Institutions: Researchers from University College London, University of Auckland, Intellia Therapeutics, Regeneron Pharmaceuticals, and others.

Background

• Transthyretin Amyloidosis (ATTR): A life-threatening disease caused by the accumulation of misfolded transthyretin (TTR) proteins in tissues, affecting nerves and heart.
• Hereditary and Wild-type ATTR: Can be hereditary (hATTR) or acquired (wild-type), with the hereditary form being autosomal dominant and causing amyloid polyneuropathy or cardiomyopathy.
• Current Treatments: Aim to stabilize TTR or inhibit its synthesis, but require long-term administration and have limitations.

Study Objective

• Investigate NTLA-2001, a CRISPR-Cas9-based therapeutic for ATTR amyloidosis.
• NTLA-2001: Uses CRISPR-Cas9 system to reduce TTR concentration in serum via gene editing. Delivered using lipid nanoparticles encapsulating mRNA for Cas9 and specific sgRNA targeting TTR.

Methods

• Preclinical Studies: In vitro and in vivo studies in human hepatocytes, mice, and cynomolgus monkeys showing TTR knockdown.
• Clinical Study Design: Phase 1 trial with escalating doses (0.1 mg/kg and 0.3 mg/kg) in patients with hATTR amyloidosis with polyneuropathy.
• Participants: Six patients with hereditary ATTR amyloidosis were treated.

Results

• Preclinical Findings: Demonstrated durable TTR knockout and significant protein reduction in animal models.
• Safety & Adverse Events: Mild adverse events with no serious complications observed in humans.
• Pharmacodynamics: Dose-dependent reduction in serum TTR protein; 52% reduction at 0.1 mg/kg dose and 87% reduction at 0.3 mg/kg dose by day 28.

Conclusions

• Efficiency: NTLA-2001 showed promising results in reducing TTR protein levels with minimal adverse effects, supporting further development for treating ATTR amyloidosis.
• Significance: Represents a potential shift towards in vivo gene editing as a therapeutic strategy, providing long-term benefits without the need for continued treatments.
• Next Steps: Continued follow-up and further trials aimed at confirming these findings and evaluating long-term outcomes.

References

• Various studies and publications on ATTR amyloidosis, CRISPR-Cas9 technology, and related therapeutic strategies.

Acknowledgments

• Sponsored by Intellia Therapeutics and Regeneron Pharmaceuticals.
• Contributions from numerous researchers and institutions.

This study indicates a potential breakthrough in treating hereditary ATTR amyloidosis using CRISPR-Cas9 technology, offering a more targeted approach with reduced treatment burdens.