European Primary Care Cardiovascular Society

CRISPR/Cas9-based gene editing in patients with transthyretin amyloid cardiomyopathy

News - Nov. 6, 2022

First-in-Human in vivo CRISPR/Cas9 Editing of the TTR Gene by NTLA-2001 in Patients With Transthyretin Amyloidosis With Cardiomyopathy

Presented at the AHA Scientific Sessions 2022 by: Prof. Julian D. Gillmore, MD, PhD - London, UK

Introduction and methods

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) have impaired systolic and diastolic function and conduction disorders. The disease leads to poor quality of life, high morbidity and if left untreated it can be fatal within 3 to 10 years. The current treatment option requires lifelong administration and only slows disease progression. Recent clinical trials showed that RNAi targeting TTR may result in cardiac benefits. The current study investigated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of NTLA-2001 in patients transthyretin amyloidosis with cardiomyopathy.

NTLA-2001 is an investigational CRISPR/Cas9-based in vivo gene editing therapy. It consist of a lipid nanoparticle which encapsulates mRNA for the SpCas9 protein and a single-guide RNA (sgRNA) targeting the TTR gene. NTLA-2001 is administered by a single intravenous infusion after which it is taken up by LDL receptors on hepatocytes, followed by endocytosis of the particle. The Cas9 mRNA is translated in the cytoplasm. The formed Cas9 protein subsequently interacts with the sgRNA targeting the TTR gene. This complex enters the nucleus, where the sgRNA binds to the complementary sequence of the DNA. Endogenous DNA repair subsequently leads to indels in the TTR gene that prevent production of TTR protein

A total of 12 patients (median age 75, all male) were enrolled in the cardiomyopathy arm of the NTLA-2001 phase 1 study. Enrolled patients had either hereditary transthyretin amyloidosis with cardiomyopathy or wild-type cardiomyopathy, and NYHA class I-III. Part I of the study consisted of 3 dosing cohorts: 1.0 mg/kg, NYHA Class I/II (n=3); 0.7 mg/kg, NYHA Class III (n=6); and 0.7 mg/kg NYHA Class I/II (n=3). All patients received a single dose administered via intravenous infusion. Circulating serum TTR was measured at baseline, days 7, 14, and 28, and after 2, 4 and 6 months.

Main results


TTR reduction


This phase 1 study with the investigational CRISPR/Cas9-based in vivo gene editing therapy NTLA-2001 showed a TTR reduction of ≥90% by day 28 which was sustained through month 4-6 in patients with transthyretin amyloidosis with cardiomyopathy. The majority of reported adverse events were mild and there were no clinically significant laboratory findings.

-Our reporting is based on the information provided at the AHA Scientific Sessions-

Watch a video by Prof. Julian Gillmore

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