A single-dose gene editing therapy has shown the potential to halt the progression of a rare, debilitating nerve disease. In a clinical trial, the therapy, nexiguran ziclumeran, led to the stabilization or improvement of neuropathy symptoms in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). The treatment uses CRISPR-Cas9 technology to reduce the production of a protein that misfolds and damages nerves.
Hereditary transthyretin amyloidosis is a life-threatening disease caused by a gene mutation that results in the buildup of abnormal protein deposits in the nerves and other organs. These deposits cause progressive damage, leading to a decline in neurological function. The new therapy, formerly known as NTLA-2001, is designed to be a one-time treatment that permanently edits the target gene in the liver, thereby reducing the levels of the disease-causing protein in the bloodstream.
Mechanism of Gene Editing Therapy
The therapy is administered as a single intravenous infusion. It utilizes a lipid nanoparticle delivery system to transport two key components to the liver: a guide RNA that targets the transthyretin (TTR) gene and a messenger RNA that encodes the Cas9 enzyme. The guide RNA directs the Cas9 enzyme to the specific location on the TTR gene, where it makes a precise cut, effectively disabling or “knocking out” the gene. This process prevents the liver from producing the mutated TTR protein, thus halting the accumulation of amyloid deposits that cause nerve damage.
Clinical Trial and Patient Outcomes
Neuropathy Score Stabilization
The ongoing Phase 1 study has demonstrated promising results in patients with ATTRv-PN. After two years of follow-up, the therapy showed evidence of disease modification, with favorable trends indicating stability or improvement in neuropathy. Clinical and biomarker measures, including the Neuropathy Impairment Score (NIS) and the modified Neuropathy Impairment Score +7 (mNIS+7), were used to assess the therapy’s effectiveness. Among 18 patients who completed a 24-month assessment, 14 showed a clinically meaningful improvement in their mNIS+7 score. Notably, this included five of six patients who had previously been progressing on an existing therapy before entering the study.
Reduction in Disease-Causing Protein
The clinical benefits observed in the trial are supported by significant and lasting reductions in the serum TTR protein levels. Across patients who received a dose of 0.3 mg/kg or higher, the mean serum TTR reduction was 90% by day 28. These reduced levels remained consistent for at least two years, suggesting a durable effect from the single-dose treatment. The profound and sustained reduction of the TTR protein is a key indicator of the therapy’s potential to halt disease progression.
Safety and Tolerability
The gene editing therapy was generally well-tolerated by patients in the clinical trial. The most common adverse events were mild and included headache, infusion-related reactions, back pain, rash, and nausea. No clinically significant liver issues were observed. The encouraging safety profile supports the continued development of the therapy for the treatment of ATTR amyloidosis.
Future Research and Development
Based on the positive results from the Phase 1 trial, a global Phase 3 study, known as MAGNITUDE-2, is planned to further evaluate the efficacy and safety of nexiguran ziclumeran. The primary endpoints of this study will be the change in the modified neuropathy impairment score and the change in serum TTR levels. The company developing the therapy expects to be able to support a biologics license application for the treatment of ATTRv-PN by 2028.
Broader Implications for Gene Editing
The success of this trial represents a significant milestone for the field of gene editing. It is the first study to provide clinical data supporting the safety and efficacy of in vivo CRISPR genome editing in humans, where the gene editing is performed directly inside the body. This approach has the potential to revolutionize the treatment of a wide range of genetic diseases by offering a one-time, potentially curative therapy. The ongoing research into nexiguran ziclumeran will continue to provide valuable insights into the long-term effects and broader applications of this groundbreaking technology.
