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Novel 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 novel gene-editing therapy based on CRISPR/Cas9, significantly reduced abnormal levels of the protein transthyretin in patients with ATTR amyloid cardiomyopathy, a progressive and fatal cause of heart failure.
  • 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.
  • The gene-editing therapy was generally well-tolerated and the majority of adverse events were mild.

Embargoed until 3:00 p.m. CT/4:00 p.m. ET, Saturday, Nov. 5, 2022

(NewMediaWire) – November 05, 2022 – CHICAGO — A single IV infusion of NTLA-2001, a novel CRISPR/Cas9-based gene editing therapy, significantly 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 Scientific Sessions 2022. The meeting, held in person in Chicago and virtually, Nov. 5-7, 2022, is a premier global exchange of the latest scientific advancements, 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 through the body. Transthyretin amyloidosis (ATTR) is caused by 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,” said lead study author Julian D. Gillmore, M.D., Ph.D., a professor at the University College London Centre for Amyloidosis in the U.K. “Recently, clinical trials investigating therapy with gene-silencing agents targeting mRNA have found that lowering TTR protein levels results in cardiac benefits.”

Researchers evaluated the safety, tolerability and efficacy of NTLA-2001, which precisely knocks out the TTR gene in the liver of people with ATTR amyloid cardiomyopathy. A single IV dose of NTLA-2001 is designed to minimize production of the 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. Levels of TTR protein concentration 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 NTLA-2001 dose.

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

The primary limitation to 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-ever human trial of gene editing in vivo, or in the body, and our study proves 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,” Gillmore said.  “These results indicate that IV NTLA-2001 is a potential new treatment option that may stop disease progression in patients with ATTR amyloid cardiomyopathy or even bring about improvement. However, further research is needed to establish long-term safety of NTLA-2001 and to continue to monitor and evaluate the potential effects of markedly reduced TTR levels on patients’ clinical outcomes.”

Co-authors are Jörg Täubel, M.D.; Ed Gane, M.B.Ch.B., M.D.; Björn Pilebro, M.D., Ph.D.; Michael Maitland, M.D., Ph.D.; Mark Stroh, Ph.D.; Yuanxin Xu, M.D., Ph.D.; Adam Boyd, Ph.D.; Jeffrey Cehelsky, M.B.A.; David E. Gutstein, M.D.; Tina Ho, Pharm.D.; Alison Sonderfan, M.S.; Liron Walsh, M.D.; David Lebwohl, M.D.; and Marianna Fontana, M.D., Ph.D. Authors’ disclosures are listed in the abstract.

The study was funded by Intellia/Regeneron.

Statements and conclusions of studies that are presented at the American Heart Association’s scientific meetings are solely those of the study authors and do not necessarily reflect the Association’s policy or position. The Association makes no representation or guarantee as to their accuracy or reliability. Abstracts presented at the Association’s scientific meetings are not peer-reviewed, rather, they are curated by independent review panels and are considered based on the potential to add to the diversity of scientific issues and views discussed at the meeting. The findings are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.

The Association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific Association programs and events. The Association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and biotech companies, device manufacturers and health insurance providers and the Association’s overall financial information are available here.

Additional Resources:

The American Heart Association’s Scientific Sessions 2022 is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science. The 3-day meeting will feature more than 500 sessions focused on breakthrough cardiovascular basic, clinical and population science updates occurring Saturday through Monday, November 5-7, 2022. Thousands of leading physicians, scientists, cardiologists, advanced practice nurses and allied health care professionals from around the world will convene virtually to participate in basic, clinical and population science presentations, discussions and curricula that can shape the future of cardiovascular science and medicine, including prevention and quality improvement. During the three-day meeting, attendees receive exclusive access to more than 4,000 original research presentations and can earn Continuing Medical Education (CME), Continuing Education (CE) or Maintenance of Certification (MOC) credits for educational sessions. Engage in Scientific Sessions 2022 on social media via #AHA22. 

About the American Heart Association

The American Heart Association is a relentless force for a world of longer, healthier lives. We are dedicated to ensuring equitable health in all communities. Through collaboration with numerous organizations, and powered by millions of volunteers, we fund innovative research, advocate for the public’s health and share lifesaving resources. The Dallas-based organization has been a leading source of health information for nearly a century. Connect with us on heart.org, Facebook, Twitter or by calling 1-800-AHA-USA1.  

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For Media Inquiries and AHA Expert Perspective:

AHA Communications & Media Relations in Dallas: 214-706-1173; ahacommunications@heart.org

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