Gene-Editing Therapy NTLA-2001 Shows Potential for Transthyretin Amyloid Cardiomyopathy


A single intravenous dose of NTLA-2001 significantly reduced abnormal levels of transthyretin in patients with ATTR amyloid cardiomyopathy, reports new data from AHA 2022.

Julian D. Gilmore, MD, PhD

Julian D. Gilmore, MD, PhD

A single intravenous infusion of NTLA-2001, a novel CRISPR/Cas90-based gene editing therapy, significantly reduced abnormal transthyretin (TTR) protein levels in patients with ATTR amyloid cardiomyopathy.

The late-breaking research was presented at the American Heart Association Scientific Sessions 2022 in Chicago.

“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. Gilmore, MD, PhD, University College London Centre for Amyloidosis in a statement. “Recently, clinical trials investigating therapy with gene-silencing agents targeting mRNA have found that lowering TTR protein levels results in cardiac benefits.”

A protein that is produced by the liver, transthyretin transports retinol 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. These fibrils then disrupt normal organ function and can lead to progressive organ failure.

Gilmore and the team of investigators evaluated the safety, tolerability, and efficacy of NTLA-2001. The gene editing therapy can eliminate the TTR gene in the liver of individuals with ATTR amyloid cardiomyopathy.

The single intravenous dose of NTLA-2001 was thus designed to minimize production of the abnormal TTR proteins. A total of 12 participants with ATTR amyloidosis and varying levels of heart failure requiring treatment were included in the study and received a single infusion of NTLA-2001.

Investigators measured the levels of TTR protein concentration in the bloodstream at the beginning of the study and also at periodic intervals (two, four, and six months) after the single intravenous NTLA-2001 dose.

The findings indicated a consistent and durable TTR reduction achieved at both 0.7 and 1.0 mg/kg doses of NTLA-2001.

Circulating serum TTR proteins were both rapidly and significantly reduced by at least 90% in all patients 28 days after the administration of a single intravenous dose of NTLA-2001. The benefits were sustained to the last study visit conducted at four and six months after receiving the therapeutic infusion.

Moreover, the gene editing therapy was considered generally well-tolerated, with 25% (n = 3) of patients reporting no adverse events and 67% (n = 8) reporting mild or moderate adverse events. All patients received a complete study dose of NTLA-2001.

Investigators noted a single Grade 3 infusion-related reaction was reported at the 0.7 mg/kg dose in a NYHA Class III patient, but was resolved without any clinical sequelae. No other patients reported a treatment-related adverse event higher than Grade 1.

Gilmore added that the primary limitation in the interpretation of these results is that it is an original, Phase 1 dose escalation study in patients with ATTR amyloid cardiomyopathy.

“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,” Gilmore said. “We were impressed by the significant and consistent reductions in patients’ serum TTR protein levels.”

The findings indicate the potential for a new treatment option that may stop disease progression in patients with ATTR amyloid cardiomyopathy and potentially lead to improvement

However, investigators added that further research is required to establish long-term safety of NTLA-2001. They suggest the need to continue to monitor and evaluate the potential effects of markedly reduced TTR levels on patient’s clinical outcomes.

“First-in-Human in vivo CRISPR/Cas9 Editing of the TTR Gene by NTLA-2001 in Patients With Transthyretin Amyloidosis With Cardiomyopathy,” was presented at AHA 2022.

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