Three elderly men diagnosed with the previously irreversible heart disease transthyretin cardiac amyloidosis experienced an unprecedented spontaneous recovery confirmed by medical scans, leading researchers at UCL and the Royal Free Hospital to identify a unique immune response targeting amyloid in these patients. This breakthrough raises the potential for new treatments and the possibility of using these antibodies combined with gene-editing therapies to clear toxic protein buildups in the heart and stop further deposition.
In an extraordinary turn of events reported by a research team from University College London (UCL) and the Royal Free Hospital, three men who previously suffered from heart failure due to a build-up of sticky, toxic proteins are now symptom-free after their condition spontaneously reversed .
This condition is a form of amyloidosis affecting the heart, is progressive and was previously thought to be irreversible. Historically, the prognosis has been grim, with half of people dying within four years of diagnosis.
The new study, published as a letter in The New England Journal of Medicine, reported on three men aged 68, 76, and 82 years who were diagnosed with transthyretin cardiac amyloidosis but who later recovered. Their own reports of improvement in symptoms were confirmed by objective assessments, including cardiovascular magnetic resonance (CMR) scans showing that amyloid protein buildup in the heart had cleared.
Lead author Professor Mariana Fontana (UCL Department of Medicine) said: “This is the first time we have seen that the heart can improve with this disease. This was not known before and raises the bar for what could be possible with new treatments.
The researchers also found evidence of an immune response in the three men that specifically targeted amyloid. Amyloid-targeting antibodies were not detected in other patients whose condition progressed normally.
Senior author Professor Julian Gilmore (UCL Department of Medicine), head of the UCL Amyloidosis Centre, based at the Royal Free Hospital, said: “It has not been conclusively proven whether these antibodies caused the patients to recover. However, our data show that this is very likely, and there is potential for such antibodies to be recreated in the laboratory and used as therapy. We are currently investigating this further, although this research remains at a preliminary stage.
Transthyretin (ATTR) amyloidosis is caused by amyloid deposits made up of a blood protein called transthyretin (TTR). It can be heritable or non-heritable (“wild type”). The accumulation of these protein deposits in the heart is called ATTR amyloid cardiomyopathy (ATTR-CM). Current NHS treatments aim to relieve symptoms of heart failure (which can include fatigue, swelling of the legs or abdomen and shortness of breath with activity) but do not tackle amyloid (although a number of ‘gene silencing’ treatments are currently being trialled therapies that reduce the concentration of TTR protein in the blood and thereby delay the formation of amyloid).
Advances in imaging techniques – some of which were first introduced at the UCL Amyloidosis Center – mean that significantly more people are being diagnosed with the disease than was the case 20 years ago. Before the diagnosis required a biopsy (involving tissue taken from the heart).
Imaging techniques also indicate the burden of amyloid on the heart, and therefore the progression of the disease can be more precisely monitored, making it easier to detect cases where the condition has reversed rather than simply remained stable.
The latest study, supported by the Royal Free Charity, began when a 68-year-old man reported that his symptoms were improving. This led the research team to review the records of 1,663 patients diagnosed with ATTR-CM. Two more cases were identified from these patients.
The three men’s recovery was confirmed by blood tests, several imaging techniques, including echocardiography (a type of ultrasound), CMR scanning and scintigraphy (a nuclear medicine bone scan) and, for one patient, an assessment of exercise capacity. A CMR scan showed that the heart’s structure and function had returned to almost normal, and the amyloid had almost completely cleared.
A thorough review of the records and assessments for the rest of the 1663 cohort showed that these three patients were the only ones whose condition reversed.
One of the three men underwent a heart muscle biopsy, which revealed an atypical inflammatory response around the amyloid deposits (including white blood cells known as macrophages), suggesting an immune response. No such inflammatory response was found in 286 biopsies from patients whose disease followed normal progression.
Probing this further, the researchers found antibodies in the three patients that bind specifically to ATTR amyloid deposits in mouse and human tissues and to synthetic ATTR amyloid. There were no such antibodies in 350 other patients in the cohort with a typical clinical course.
If these antibodies can be used, they could be combined with new therapies being tested that suppress the production of the TTR protein, allowing clinicians to clear the amyloid as well as prevent further amyloid deposition.
One such promising therapy is a single intravenous infusion of NTLA-2001, a novel CRISPR/Cas9-based gene editing therapy. Early results from the trial, led by Professor Gilmour, show it can stop the progression of the disease.
The UCL Amyloidosis Center is one of the world’s leading centers for amyloid research. It includes the NHS National Amyloidosis Centre, the UK’s only center specializing in amyloidosis.
John Spiers, chief executive of the Royal Free Charity, said: “As an NHS charity, we are proud to support this research. Our priority is to drive early-stage research that brings innovative treatments to patients sooner.
“This work not only represents a major breakthrough in our understanding of cardiac amyloidosis, but crucially opens new avenues for more effective treatment options.” This is an extremely significant development, which we welcome on behalf of all patients of the National Amyloidosis Center and their families, many of whom have contributed to the funding of our research through their own fundraising efforts.
Reference: “Antibody-Associated Reversal of ATTR Amyloidosis-Related Cardiomyopathy” by Mariana Fontana, Janet Gilbertson, Guglielmo Verona, Mattia Riefolo, Ivana Slamova, Ornella Leone, Dorota Rouchenio, Nicola Bocher, Adam Ioannou, Rishi K. Patel, Yusuf Razvi, Ana Martinez-Najaro, Carol J. Whalen, Lucia Veneri, Amanda Duchlin, Diana Canetti, Stefan Elmerich, James C. Moon, Peter Kelman, Raya Al-Shawi, Laura McCoy, J. Paul Simons, Philip N. Hawkins, and Julian D. Gilmore, 8 Jun 2023 , New England Journal of Medicine.
DOI: 10.1056/nejmc2304584
The Royal Free Charity is the NHS charity partner of the Royal Free London NHS Foundation Trust and the only charity in the UK to directly support the work of the National Amyloidosis Centre.
This is the first human trial in which CRISPR/Cas9, a Nobel Prize-winning technology that makes a cut in cells DNA and inserts new genetic code, is infused intravenously as a drug to inactivate a target gene in a specific organ—in this case, the liver, where TTR protein is produced.