Novel gene-editing therapy reduces circulating TTR protein levels in patients with ATTR amyloid cardiomyopathy

Novel gene-editing therapy reduces circulating TTR protein levels in patients with ATTR amyloid cardiomyopathy

A single intravenous infusion of NTLA-2001, a new CRISPR/Cas9-based gene-editing therapy, significantly reduced levels of circulating transthyretin (TTR) protein in patients with ATTR amyloid cardiomyopathy, a progressive and fatal cause of heart failure, according to a late-breaking research study presented today at the American Heart Association Scientific Sessions 2022. The meeting, held in person in Chicago and virtually, November 5-7, 2022, is a premier global exchange of the latest scientific advances, research, and evidence-based clinical practice updates in cardiovascular science.

Transthyretin is a protein that is produced by the liver and transports retinol, also known as vitamin A, and the thyroid hormone thyroxine in circulation throughout the body. Transthyretin amyloidosis (ATTR) is caused by the accumulation of fibrils composed of misfolded transthyretin protein in organs, including the heart. The fibrils disrupt normal organ function and lead to progressive organ failure.

Despite the availability of TTR protein stabilizers as a treatment option for people with ATTR amyloidosis, it remains a progressive and universally fatal disease. Recently, clinical trials investigating therapy with mRNA-targeted gene silencing agents have found that reducing levels of TTR protein produces cardiac benefits.”


Julian D. Gillmore, MD, Ph.D., Senior Study Author, Professor, University College London Center for Amyloidosis, UK

The researchers evaluated the safety, tolerability, and efficacy of NTLA-2001, which precisely deletes the TTR gene in the liver of people with ATTR amyloid cardiomyopathy. A single IV dose of NTLA-2001 is designed to minimize the production of abnormal TTR proteins.

The study included 12 participants with ATTR amyloidosis and varying levels of heart failure requiring treatment. Patients received a single infusion of NTLA-2001. TTR protein concentration levels in the bloodstream were measured at the beginning of the study and also at periodic intervals (two, four and six months) after the single intravenous dose of NTLA-2001.

The results found that circulating serum TTR proteins were rapidly and profoundly reduced by at least 90% in all patients 28 days after administration of a single intravenous dose of NTLA-2001. These benefits were maintained until the last study visit four to six months after receiving the therapeutic infusion. Additionally, NTLA-2001 was generally well tolerated (meaning there was only one serious adverse event, which resolved), and most adverse events, such as infusion-related reactions, were mild.

The main limitation to the interpretation of this study is that it is an original Phase 1 dose-escalation study in patients with ATTR amyloid cardiomyopathy, Gillmore said.

“This is the first human gene editing trial. live, or in the body, and our study shows that gene editing in the human body is possible and also safe in the short term. We were impressed by the significant and consistent reductions in patients’ serum TTR protein levels,” said Gillmore. “These results indicate that IV NTLA-2001 is a potential new treatment option that may halt disease progression in patients with ATTR amyloid cardiomyopathy or even achieve improvement. However, more research is needed to establish the long-term safety of NTLA-2001 and to continue to monitor and evaluate the potential effects of markedly reduced TTR levels on clinical patient outcomes.”

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