NTLA-2001 gene-editing therapy shows potential for transthyretin amyloid cardiomyopathy

NTLA-2001 gene-editing therapy shows potential for transthyretin amyloid cardiomyopathy

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

The latest 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 study lead author Julian D. Gilmore, MD, PhD. , University College London Center for Amyloidosis in a statement. . “Recently, clinical trials investigating therapy with mRNA-targeted gene silencing agents have found that reducing TTR protein levels produces cardiac benefits.”

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

Gilmore and the team of researchers evaluated the safety, tolerability, and efficacy of NTLA-2001. Gene-editing therapy can delete the TTR gene in the liver of people with ATTR amyloid cardiomyopathy.

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

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

Findings indicated a consistent and durable reduction in TTR achieved with 0.7 and 1.0 mg/kg doses of NTLA-2001.

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

Additionally, 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 full study dose of NTLA-2001.

The investigators noted that a single grade 3 infusion-related reaction was reported at the 0.7 mg/kg dose in a NYHA class III patient, but it resolved without clinical sequelae. No other patient reported a treatment-related adverse event greater than Grade 1.

Gilmored added that the main limitation in interpreting these results is that this is an original Phase 1 dose-escalation study in patients with ATTR amyloid cardiomyopathy.

“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 both possible and safe in the short term,” Gilmore said. “We were impressed by the significant and consistent reductions in serum TTR protein levels in patients.”

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

However, the researchers added that more research is required to establish the long-term safety of NTLA-2001. They suggest the need for continued monitoring and evaluation of the potential effects of markedly reduced TTR levels on clinical patient outcomes.

“First human CRISPR/Cas9 in vivo editing of the TTR gene by NTLA-2001 in transthyretin amyloidosis patients with cardiomyopathy,” was presented at AHA 2022.

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