Deadly heart condition reversed in 3 patients using CRISPR

• Transthyretin cardiac amyloidopathy (ATTR-CM) is a rare but severe and progressive heart condition where sticky, toxic proteins build up in the heart muscle and cause heart failure.
• Current treatments can relieve the symptoms but cannot cure the disorder.
• Now, in an unprecedented finding, scientists have reported that three patients have spontaneously recovered from the condition.
• They believe this finding may lead to new treatments and possibly even a cure.

Although rare, with around 5,000-7,000 cases diagnosed in the United States each year, transthyretin cardiac amyloidopathy (ATTR-CM) is a devastating condition. Previously, symptoms were often thought to be due to aging, but improved imaging techniques have made diagnosing the condition much more straightforward.

Transthyretin (TTR) is a protein that is highly conserved through the animal kingdom. TTR is made in the liver and transports the thyroid hormone thyroxine and retinol (vitamin A) around the body. However, mutations in this protein can make it form insoluble amyloid fibrils in the heart muscle. These make the heart muscle stiff and rigid, leading to congestive heart failure.

As well as heart failure, the condition, which is more common in men over the age of 60, can cause irregular heartbeat (cardiac arrhythmias, atrial fibrillation) and other symptoms, such as carpal tunnel syndrome.

Around half of those diagnosed with ATTR-CM die within four years of diagnosis. Early diagnosis and treatment may slow the progression of the disease, and people with the condition are treated to relieve the symptoms of heart failure and arrhythmias and to slow the buildup of TTR.

However, as yet, no therapy has been found that can reverse the condition.

Now, researchers led by scientists from University College London have, for the first time, reported the spontaneous recovery of 3 patients with ATTR-CM. They believe that the recovery may have been due to an immune response, suggesting that antibody treatments could be effective against the condition.

The findings are published in the New England Journal of Medicine.

“This New England journal communication represents the Holy Grail of amyloidosis treatment: proof of concept that a long-hoped-for cure of cardiac amyloidosis is not just speculation but is attainable and occurs in nature.”
— Dr. Richard Wright, M.D., cardiologist at Providence Saint John’s Health Center in Santa Monica, California.

Spontaneous improvement

The three patients were unrelated, older men. Patient 1 was 68 years old, patient 2 was 82, and patient 3, 76. They all presented with class 2 heart failure, which had been causing symptoms for more than six months.

In addition, patients 1 and 2 had a prior history of bilateral carpal tunnel syndrome, patient 2 had atrial fibrillation, and patient 3 had been fitted recently with a pacemaker. Following further investigations, all three were diagnosed with ATTR-CM.

They were followed up at 1, 2, and 3 years. At follow-up, all three reported improvements in their symptoms, despite not having any potentially disease-modifying treatments. Investigations — including blood tests, several imaging techniques including echocardiography (a type of ultrasound), cardiac magnetic resonance (CMR) imaging scans, and scintigraphy (a nuclear medicine bone scan) — confirmed that the amyloid had almost completely cleared and heart function was back to near-normal.

“Cured is obviously a ‘big’ word but the disease has reversed and they have little in the way of remaining symptoms.”
— Prof. Julian Gillmore, senior author, UCL Division of Medicine, head of the UCL Centre for Amyloidosis

Why did the patients improve?

The researchers suggest that the improvement might be due to an immune response.

They found antibodies in the three men that specifically targeted amyloid deposits. These amyloid-targeting antibodies were not found in other patients whose condition progressed as normal.

A biopsy on the heart muscle of one of the patients showed an atypical inflammatory response surrounding the amyloid deposits. The researchers did not find this in biopsies on 286 patients with typical disease progression.

“Previous antibody treatment studies confirmed that amyloid deposits could be removed from abdominal viscera, but this is the first firm evidence that transthyretin cardiac deposits are susceptible to removal by harnessing the body’s intrinsic way to rid itself of unwanted invaders,” Dr. Wright told Medical News Today.

A potential treatment

The researchers suggest that if these antibodies can be harnessed, they could be combined with new therapies being trialed that suppress TTR protein production. This would enable clinicians to clear away amyloid as well as prevent further amyloid deposition.

Dr. Wright was enthusiastic about the potential of these findings:

“This is a stunning observation and one that should be able to be replicated with manufactured antibodies or through ‘immunization’ of amyloidosis patients against their own amyloid protein.”

“Whether these antibodies caused the patients’ recovery is not conclusively proven. However, our data indicates that this is highly likely and there is potential for such antibodies to be recreated in a lab and used as a therapy.”
— Prof. Julian Gillmore

“So long as this can be undertaken safely, for example, without inducing severe cardiac inflammation, such treatment could remove all amyloid deposits and “cure” amyloidosis, perhaps for a long period of time. Since amyloid takes years to deposit, such immune therapy might need to be used only once in a particular patient,” he added.

More research underway

The team at UCL is currently investigating a therapy that may prevent the progression of this disease.

Prof. Gillmore explained how the therapy works:

“It is a gene editing therapy (the first of its kind) which knocks out the TTR gene, reduces circulating concentration of TTR protein, and thereby slows ongoing amyloid formation.”

Early results of their trial have suggested that it may be effective.

The findings of this study and the early trial results may well lead to better treatments, giving hope to those with this progressive, fatal condition.

As Dr. Wright noted:

“The implications of this are vast, and if achieved, could render all current amyloidosis therapies obsolete.”

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