New gene-editing therapy shows promise for patients with transthyretin amyloid cardiomyopathy

New gene-editing therapy shows promise for patients with transthyretin amyloid cardiomyopathy

Research Highlights:

  • In a clinical trial, a single intravenous infusion of NTLA-2001, a new CRISPR/Cas9-based gene-editing therapy, significantly reduced abnormal levels of the protein transthyretin in patients with ATTR amyloid cardiomyopathy, a progressive and fatal cause of heart failure. cardiac.
  • Circulating TTR protein, which accumulates in the heart and causes progressive cardiomyopathy, was rapidly and profoundly reduced by more than 90% in all patients after 28 days.
  • Gene editing therapy was generally well tolerated and most adverse events were mild.

CHICAGO, November 5, 2022 – A single intravenous infusion of NTLA-2001, a novel CRISPR/Cas9-based gene-editing therapy, significantly reduced levels of circulating transthyretin (TTR) protein in patients with ATTR amyloid cardiomyopathy, a cause progressive and fatal heart failure, according to breaking research 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 universally fatal and progressive disease,” said study lead author Julian D. Gillmore, MD, Ph.D. ., professor at University College. London Center for Amyloidosis in the UK “Recently, clinical trials investigating therapy with mRNA-targeted gene silencing agents have found that reducing levels of TTR protein produces cardiac benefits.”

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 trial of gene editing in vivo or in the body, and our study demonstrates 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.”

The co-authors are Jörg Taubel, MD; Ed Gane, MBCh.B., MD; Bjorn Pilebro, MD, Ph.D.; Michael Maitland, MD, Ph.D.; Mark Stroh, Ph.D.; Yuanxin Xu, MD, Ph.D.; Adam Boyd, Ph.D.; Jeffrey Cehelsky, MBA; David E. Gutstein, MD; Tina Ho, PharmD; Alison Sonderfan, MS; Liron Walsh, MD; David Lebwohl, MD; and Marianna Fontana, MD, Ph.D. Authors’ declarations are listed in the abstract.

The study was funded by Intellia/Regeneron.

Statements and conclusions of studies presented at American Heart Association scientific meetings are the sole responsibility of the study authors and do not necessarily reflect the policy or position of the Association. The Association does not represent or guarantee its accuracy or reliability. Abstracts presented at Association scientific meetings are not peer-reviewed, but rather are selected by independent review panels and considered based on the potential to add to the diversity of scientific topics and viewpoints discussed at the meeting. . The findings are considered preliminary until they are published as a full manuscript in a peer-reviewed scientific journal.

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