麻豆传媒

It is possible for transthyretin amyloid cardiomyopathy (ATTR-CM, also called cardiac ATTR amyloidosis) to be reversed with antibody treatment, as suggested by rare cases of patients who had their ATTR-related heart failure resolve spontaneously, with cardiac structure and function restored to almost normal.

In a small case series, three men (ages 68, 82, and 76) started out with a characteristic hypertrophic phenotype of the usually progressive ATTR-CM. All three had Perugini grade 2 cardiac uptake on 99mTc-DPD scintigraphy, reported Julian Gillmore, MD, PhD, of the National Amyloidosis Centre at University College London (UCL), and colleagues.

Over follow-up, each patient reported a reduction in symptoms without receiving any new or potentially disease-modifying treatments. Their clinical recovery was corroborated by substantial improvement or normalization of findings from echocardiography, serum biomarker levels, 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.

All three recovering patients turned out to have had an anti-amyloid immune response, as researchers confirmed high-titer circulating polyclonal IgG antibodies to human ATTR amyloid in these individuals, per their letter to the editor published in the.

"This is a proof of principle that if the amyloid is cleared from the heart, then the heart can recover its function and strongly suggests that the means by which amyloid is cleared from the heart is via antibodies [that] bind to amyloid. It opens the door to antibody therapy for cardiac ATTR amyloidosis," Gillmore told 麻豆传媒.

Indeed, over the last decade, researchers have been trying to develop antibodies against amyloid and these products are now entering clinical trials for ATTR-CM, commented Rodney Falk, MD, director of the cardiac amyloidosis program at Brigham and Women's Hospital and Harvard Medical School in Boston.

Recently, a small early-phase trial showed that the has promise to reduce cardiac amyloid load. Other amyloid fibril antibodies in development include the and the .

"Antibodies are not designed to stop progression, but to take out the amyloid," Falk explained in an interview.

For now, no therapy has been proven to reverse the disease process of ATTR-CM, a disease characterized by extracellular myocardial accumulation of plasma ATTR amyloid. For asymptomatic patients diagnosed with early-stage disease, it can take just a few years to progress to clinical heart failure or other cardiovascular complications.

The pricey TTR stabilizer, tafamidis (Vyndaqel or Vyndamax), merely slows disease progression. It doesn't get rid of existing amyloid in the heart and does not lead to clinical improvement, according to Gillmore.

Even the next line of drugs expected to clear FDA review -- gene silencers like patisiran (Onpattro), vutrisiran (Amvuttra), and eplontersen -- would stay in the realm of stopping or slowing disease progression. They would not be expected to reverse cardiac amyloidosis.

Gillmore and colleagues had been led to search for anti-ATTR amyloid antibodies after an endomyocardial biopsy on patient 3 showed an unusual infiltrate of macrophages and giant cells surrounding amyloid deposits, indicating myocardial inflammation. Mass spectrometry of amyloid material from this biopsy sample showed transthyretin, IgG, and complement C3.

Notably, none of the three recovering patients had had recent vaccinations, notable infections, or any clinical suggestion of myocarditis.

Furthermore, none of the comparison group -- 350 consecutive ATTR-CM patients who had a typical clinical course -- harbored the seemingly protective antibodies.

"It's fair to say these auto-antibodies, which are there for reasons that are unclear, were the cause of the resolution of the cardiac amyloid in these patients," said Falk.

Ahmad Masri, MD, MS, director of the cardiac amyloidosis program and the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University in Portland, pointed out that the antibodies' effects were seen across wild and variant ATTR-CM. He observed that two of the three recovered patients in the report had variant ATTR-CM -- which disproportionately affects individuals of African descent -- and one was wild-type.

"Whether these antibodies caused the patients' recovery is not conclusively proven," Gillmore cautioned in a press release.

"However, our data indicate that this is highly likely and there is potential for such antibodies to be recreated in a lab and used as a therapy. We are currently investigating this further, although this research remains at a preliminary stage," he said.

For a few years, Gillmore's group has also been involved in developing the to stop disease progression by inactivating a target gene in the liver, where TTR protein is made.

The new findings raise expectations for full-blown disease reversal instead.

"We have seen for the first time that the heart can get better with this disease. That has not been known until now and it raises the bar for what might be possible with new treatments," said co-author Marianna Fontana, MD, PhD, a cardiac amyloidosis specialist at University College London, in a statement.

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