Novel Gene-Editing Therapy Shows Promise for Rare Fatal Heart Disease ATTR-CM
核心洞察
Singapore researchers are leading Asia's first clinical trial of Nexiguran Ziclumeran (nex-z), a groundbreaking gene-editing therapy targeting transthyretin amyloid cardiomyopathy (搜索) (ATTR-CM (搜索)), a rare and potentially fatal heart disease.
The MAGNITUDE study, led by Assistant Professor Lin Weiqin from the National University Heart Centre, Singapore (搜索), uses CRISPR-Cas9 technology to alter DNA and reduce production of disease-causing proteins in patients with ATTR-CM (搜索).
Early phase clinical trials have shown "consistent, rapid, and durable reductions" in abnormal proteins with minimal side effects, offering new hope to approximately 150 diagnosed patients in Singapore and potentially many more undiagnosed cases.
A groundbreaking gene-editing therapy is offering new hope to patients suffering from transthyretin amyloid cardiomyopathy (搜索) (ATTR-CM (搜索)), a rare and potentially fatal heart disease that affects approximately 150 diagnosed patients in Singapore, with experts suggesting the actual number could be significantly higher.
The National University Heart Centre, Singapore (搜索) (NUHCS (搜索)) has become the first in Asia to recruit patients for the international MAGNITUDE study, which is investigating the efficacy of Nexiguran Ziclumeran (nex-z, also known as NTLA-2001) in treating ATTR-CM (搜索).
Understanding ATTR-CM
ATTR-CM (搜索) is caused by the accumulation of misfolded transthyretin (搜索) (TTR (搜索)) proteins in the heart, nerves, and other organs. This protein buildup results in thickened and stiff heart walls, preventing proper relaxation and filling with blood, and reducing the heart's ability to pump efficiently.
"The symptoms of ATTR-CM (搜索) can be vague and may include numbness in the hands and feet, lethargy and dizziness; but left undiagnosed and not treated promptly, it could lead to heart failure and death," explains Assistant Professor Lin Weiqin, Clinical Director for the Heart Failure and Cardiomyopathy Programme at NUHCS (搜索).
Many patients dismiss these symptoms as normal consequences of aging, contributing to underdiagnosis. "Not many patients know about this condition, and not many doctors can diagnose this condition accurately as well," Prof Lin noted.
Revolutionary Gene-Editing Approach
Nexiguran Ziclumeran works by seeking out and removing a portion of the TTR (搜索) gene, effectively slowing down the production of the disease-causing protein. The therapy is based on Nobel Prize-winning CRISPR-Cas9 technology, which allows precise DNA sequence alterations.
"If this trial is successful, it will be the first DNA-altering treatment used in the field of adult cardiology and offers new hope to patients living with ATTR-CM (搜索)," said Prof Lin, who is leading the Singapore arm of the study.
The double-blind trial began recruitment in Singapore in 2024 and has already enrolled eight patients from NUHCS (搜索) and the National Heart Centre Singapore. Researchers aim to recruit a total of 14 patients by the end of 2025.
Patient Experience
One participant in the trial is 61-year-old Chua Ah Hai, whose journey with ATTR-CM (搜索) began after a car accident in 2018 when he experienced numbness and weakness in his hands. Initially diagnosed with carpal tunnel syndrome, an abnormal heart scan and subsequent biopsy revealed ATTR-CM.
"I couldn't carry heavy things after my condition deteriorated. I stopped work in March 2024, as my employers encouraged me to rest," said Mr. Chua, who experienced frequent falls and fractures due to his condition.
His decision to join the trial was driven by hope: "I wanted to give myself a new hope, a new lease of life."
The hereditary nature of the disease became apparent when Mr. Chua's son and daughter, aged 27 and 26, tested positive for the gene mutation, though they currently show no symptoms. According to medical experts, a parent with the gene mutation has a 50 percent chance of passing it to each child, though not everyone with the mutation develops the disease.
Promising Early Results
While the full outcomes of the MAGNITUDE study will only be known in two to three years, early phase clinical trials have shown encouraging results. Findings published in the New England Journal of Medicine in November 2024 demonstrated "consistent, rapid, and durable reductions" in the abnormal protein causing ATTR-CM (搜索), with minimal side effects.
"The patients in Singapore have also not reported any side effects thus far," Prof Lin confirmed.
Eligibility and Future Outlook
Patients in Singapore wishing to participate in the trial must be between 18 and 90 years old, diagnosed with heart failure due to ATTR, and on medication for heart failure with an episode in the past year. As a precaution, only women who can no longer have children are eligible, as edited genes could potentially be passed down.
A parallel trial is also beginning to study nex-z's effectiveness in patients with transthyretin amyloid neuropathy (搜索), where TTR (搜索) protein accumulation results in nerve damage.
Should the trials prove successful, Prof Lin expects the drug to become commercially available by the end of the decade. The study design ensures that participants who initially received a placebo will also receive a free dose of nex-z if the treatment proves effective.
Broader Implications
This pioneering research represents a significant advancement in the treatment of rare genetic heart diseases. While gene editing therapy has been approved in other countries for certain neuromuscular conditions, cancers, and inherited blood disorders, this would mark its first application in adult cardiology.
The NUHCS (搜索), which serves as the coordinating site for the Singapore trial, continues to recruit eligible patients for this landmark study that could potentially transform the treatment landscape for ATTR-CM (搜索) and related conditions.