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CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
Quick Takes
- NTLA-2001 is an in vivo gene-editing therapeutic agent based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating mRNA for Cas9 protein and a single guide RNA targeting TTR selectively in hepatocytes.
- In vitro and in vivo preclinical studies show NTLA-2001 leads to >90% knockdown of TTR expression and protein production. In six patients with hereditary ATTR amyloidosis, NTLA-2001 at 0.3 mg/kg dose dramatically reduced circulating TTR levels without severe adverse effects.
- This study is an example of the promise of CRISPR-Cas9, and paves the way forward in exploring gene-editing technology for the treatment of numerous otherwise untreatable diseases and a revolution in health care.
Study Questions:
Is a gene-editing approach using CRISPR-Cas9 effective and safe at reducing blood transthyretin (TTR) protein levels in patients with hereditary ATTR amyloidosis?
Methods:
NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA (mRNA) for Cas9 protein and a single guide RNA targeting TTR.
The investigators first performed preclinical studies investigating the effectiveness, specificity, and pharmacokinetics of NTLA-2001 in knocking out TTR, in both in vitro (hepatocytes) and in vivo models (mice and the cynomolgus monkey). They then assessed NTLA-2001’s effectiveness and safety in targeting TTR in six adult patients with hereditary ATTR amyloidosis and evidence of polyneuropathy; three in each of the two initial dose groups (0.1 mg/kg and 0.3 mg/kg), within an ongoing phase 1 clinical study.
Results:
In primary human hepatocytes, NTLA-2001 resulted in >90% reductions in TTR mRNA expression and ≥95% reductions in TTR protein production. In transgenic mice, the effect was dose-dependent and durable with serum TTR protein levels reaching a nadir by 4 weeks after receipt of the dose, remaining suppressed for ≥12 months.
In the phase 1 trial portion of the studies, six patients with hereditary ATTR amyloidosis and peripheral neuropathy were included. The patients were 46-64 years of age. Three patients had a p.T80A mutation, two a p.S97Y mutation, and one a p.H110D mutation. None of the patients had heart failure. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47-56) in the group that received a dose of 0.1 mg/kg and was 87% (range, 80-96) in the group that received a dose of 0.3 mg/kg.
Conclusions:
Knocking down TTR using CRISPR-Cas9-derived NTLA-2001 in a small group of patients with hereditary ATTR amyloidosis is safe and associated with a dramatic reduction in serum TTR.
Perspective:
The advent of clustered regularly interspaced short palindromic repeat DNA sequence (CRISPR)-based technologies has revolutionized the life sciences and is finally making a breakthrough in clinical care. CRISPR-editing involves the use of CRISPR-associated (Cas) enzymes that target and cleave specific nucleic acid sequences. Different CRISPR systems have distinct nucleic acid binding requirements and enzymatic activities, allowing targeted approaches to gene editing. In the clinical world, CRISPR has been used to edit genes ex vivo to select cells, which would be reintroduced in the patient, for example, in the treatment of cancer of sickle cell disease. For a long time, in vivo use of CRISPR was dreaded for the risk of off-target editing and inducing counterproductive immune response. This study is proof that CRISPR can be used safely and effectively in a targeted fashion: the mRNA for the Cas9 protein and guide RNA were encapsulated in lipid nanoparticles selectively absorbed by hepatocytes; the main site of TTR production, leading to a sustained decrease in serum TTR while minimizing toxic effects. These findings represent nothing less than a breakthrough, which will undoubtedly push forward a revolution in health care, albeit along with justifiable fears of the risks of misuse of this technology.
Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Acute Heart Failure
Keywords: Amyloid Neuropathies, Familial, Amyloidosis, Familial, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, Heart Failure, Hepatocytes, Lipids, Mutation, Nanoparticles, Polyneuropathies, Prealbumin, RNA, Messenger
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