The identification of an antibody linked to spontaneous reversal of cardiac transthyretin amyloidosis may represent a novel approach to treatment of this normally universally progressive and fatal condition.
Cardiac transthyretin amyloidosis (also called ATTR amyloidosis cardiomyopathy or ATTR-CM) is a progressive disease and a cause of heart failure resulting from accumulation of the protein transthyretin, which misfolds and forms amyloid deposits on the walls of the heart, causing both systolic and diastolic dysfunction.
The condition is progressive and normally fatal within a few years of diagnosis. Treatment options are limited and aimed at slowing progression; nothing has been shown to reverse the course of the disease.
However, an international team of researchers are now reporting the discovery of three patients with ATTR-CM–associated heart failure in whom the condition resolved spontaneously, with reversion to near normal cardiac structure and function. On further investigation, it was found that these three patients had developed circulating polyclonal IgG antibodies to human ATTR amyloid.
They are hopeful that a monoclonal form of these antibodies could be developed and may represent a novel treatment, or even a cure, for the condition.
The researchers report their findings in a letter to the New England Journal of Medicine, published online today.
"We are very optimistic about this discovery of these antibodies. They could become the first treatment to clear the amyloid that causes this horribly progressive and fatal condition," senior author Julian Gillmore, MD, head of the UCL Centre for Amyloidosis, based at the Royal Free Hospital, London, UK, told theheart.org | Medscape Cardiology.
"Obviously, there is a lot of work to do before we can say this is the case, but it is very exciting," he added.
Gillmore explained how the antibodies were discovered. "This disease has a universally progressive course, but we had one patient who on a repeat appointment said he felt better and on detailed cardiac MRI imaging, we found that the amyloid in his heart had reduced. That is totally unheard of," he said.
"We then looked back at our cohort of 1663 patients with ATTR-cardiomyopathy, and we discovered two others who had also improved both on imaging and clinically," Gillmore said.
Each of these three patients reported a reduction in symptoms, although they had not received any new or potentially disease-modifying treatments. None of the patients had had recent vaccinations, notable infections, or any clinical suggestion of myocarditis.
Clinical recovery was corroborated by substantial improvement or normalization of findings on echocardiography, serum biomarker levels, and results of cardiopulmonary exercise tests and scintigraphy.
Serial cardiac MRI scans confirmed near-complete regression of myocardial extracellular volume, coupled with remodeling to near-normal cardiac structure and function without scarring.
The researchers wondered whether the changes in these patients may have been brought about by an antibody response. On further investigation, they found antibodies in the three patients that bound specifically to ATTR amyloid deposits in a transgenic mouse model of the condition, and to synthetic ATTR amyloid. No such antibodies were present in the other 350 patients in the cohort with a typical clinical course.
"The cause and clinical significance of the anti-ATTR amyloid antibodies are intriguing and presently unclear. However, the clinical recovery of these patients establishes the unanticipated potential for reversibility of ATTR-CM and raises expectations for its treatment," the researchers conclude.
Gillmore said they didn't know why these three patients had these antibodies, while all the other patients did not. "There must be something different about these patients. We don't know what that is at present, but we are looking hard."
The researchers are hoping that after this publication, other centers caring for patients with ATTR-cardiomyopathy will look in their cohorts and see if they can identify other cases where there has been improvement.
"It is very plausible that they do have such cases, but they will be rare, as we all think of this disease as universally progressive and fatal," Gillmore noted.
"We haven't absolutely proven that the antibodies have caused the clearance of amyloid in these patients, but we strongly suspect this to be the case," Gillmore said. The researchers are planning to try to confirm this by isolating the antibodies and treating the transgenic mice.
Gillmore attributed the current discovery to the development of novel imaging cardiac MRI techniques. "This allowed us to monitor closely the amyloid burden in the heart. The observation that this had diminished in these three patients was the breakthrough that led us to look for antibodies."
Another antibody product directed against ATTR cardiomyopathy is also in development by Neurimmune, a Swiss biopharmaceutical company. A phase 1 study of this agent was recently published, suggesting that it appeared to reduce the amount of amyloid protein deposited in the heart.
Gillmore said the antibody they have detected is different to the Neurimmune product.
The research was supported by a British Heart Foundation Intermediate Clinical Research Fellowship, a Medical Research Council Career Development Award, and a project grant from the British Heart Foundation. Gillmore reports being a consultant or expert advisory board member for Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Eidos Therapeutics Inc, Intellia Therapeutics, Ionis Pharmaceuticals Inc, and Pfizer Inc.
N Eng J Med. Published June 8, 2023. Correspondence
Lead image: National Institutes of Health
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Cite this: Antibody Linked to Spontaneous Reversal of ATTR-CM - Medscape - Jun 08, 2023.