A novel gene editing therapy reduces circulating TTR protein levels in patients with ATTR amyloid cardiomyopathy

A novel gene editing therapy reduces circulating TTR protein levels in patients with ATTR amyloid cardiomyopathy

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

Transthyretin is a protein produced by the liver that transports retinol, also called vitamin A, and the thyroid hormone thyroxine in the 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 generally fatal disease. Recently, clinical trials investigating therapy with gene silencing agents targeting mRNA have found that lowering TTR protein levels results in cardiac benefits.”

Julian D. Gillmore, MD, Ph.D., lead author of the study, Professor, University College London Center for Amyloidosis, UK

Researchers evaluated the safety, tolerability and effectiveness of NTLA-2001, which precisely switches off the TTR gene in the liver of people with ATTR amyloid cardiomyopathy. A single intravenous dose of NTLA-2001 is designed to minimize production of the abnormal TTR proteins.

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

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The results showed 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 final study visit, which was conducted four to six months after receiving the therapeutic infusion. In addition, NTLA-2001 was generally well tolerated (meaning there was only one serious adverse event, which resolved), and the majority of adverse events, such as: B. infusion-related reactions were mild.

The primary limitation in interpreting 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-ever human attempt at gene editing in vivo or in the body, and our study proves that gene editing in the human body is possible and safe in the short term. We were impressed by the significant and consistent reduction in TTR protein levels in patients' serum," Gillmore said. "These results suggest that IV NTLA-2001 is a potential new treatment option that may halt disease progression or even improve disease progression in patients with ATTR amyloid cardiomyopathy. However, further research is needed to demonstrate the long-term safety of NTLA-2001 and to continue to monitor and assess the potential impact of significantly reduced TTR levels on patients' clinical outcomes." evaluate."

Source:

American Heart Association

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