Onpattro eases symptom reemergence in brothers: Study

Siblings with hATTR previously had liver transplants decades ago

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Onpattro (patisiran), a liver-directed gene-silencing therapy, successfully slowed progression of symptoms that emerged in two brothers with hereditary transthyretin amyloidosis (hATTR) decades after their disease was stabilized by liver transplants, a study showed.

In the reemergence of disease symptoms, the brothers showed also brain and eye problems that were not previously present. This is likely due to the fact that the transthyretin protein, which is mainly produced in the liver and is faulty in hATTR, also is generated in these tissues.

While it is too soon to tell what the very long-term effects of this relatively new gene-silencing therapy will be for patients, the researchers hypothesize that symptoms affecting the central nervous system (CNS; brain and spinal cord) may be likely to emerge just as they did after a liver transplant.

“Novel future therapeutic strategies are demanded to guarantee a better long-term stabilization of symptomatology,” the researchers wrote.

The report, “Central nervous system involvement in two siblings affected by hereditary transthyretin amyloidosis 30 years after liver transplantation: a model for gene-silencing therapies,” was published in Neurological Research.

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Transthyretin accumulation can affect peripheral nerves and heart

hATTR is marked by the toxic accumulation of clumps of an abnormal form of the transthyretin protein in the body’s tissues as a consequence of mutations in the TTR gene.

Transthyretin can accumulate all over the body, leading to symptoms that most often affect the peripheral nerves, or those outside the CNS, and the heart.

hATTR with polyneuropathy, also called familial amyloid polyneuropathy (FAP), is a form of hATTR marked mostly by damage to peripheral nerves, while hATTR with cardiomyopathy is characterized by damage to the heart.

Because TTR is mainly produced in the liver, a liver transplant was the first treatment that was found to slow nerve damage, or neuropathy, and improve survival as it prevented production of the problematic protein.

However, this approach may not lead to permanent suppression of symptoms due to two events. One, called the nest effect, is the potential binding of new liver-produced healthy transthyretin to already present toxic clumps, further perpetuating the aggregation process.

The other is the fact that some transthyretin is produced outside the liver, particularly in a brain region and in a specific layer of the eye that’s also part of the CNS. That could also mean that CNS symptoms may be particularly likely to emerge in the years after a transplant.

More recently, gene-silencing therapies for hATTR and FAP have emerged. Including Onpattro, Tegsedi (inotersen), and Amvuttra (vutrisiran), these treatments work to block the activity of the TTR gene, thereby lowering the production of abnormal transthyretin and easing symptoms of nerve damage or neuropathy.

These therapies also reduce the production of healthy transthyretin, which can help prevent the nest effect and further nerve damage.

Still, given their relatively recent emergence, the real-world, long-term effects of these therapies — particularly on CNS symptoms — remain relatively under-explored.

Study of two brothers

Now, a team of researchers in Italy described the cases of two brothers in central Italy with hATTR who were treated with Onpattro due to symptom reemergence years following a liver transplant.

The younger brother was 21 years of age when his symptoms emerged, which included erectile dysfunction, abnormal sensations in his limbs, and gastrointestinal problems. A liver transplant at age 24 led to resolution of all symptoms, except for sexual issues.

More than two decades later, at age 46, symptoms re-appeared and were accompanied by visual problems, reduced kidney function, and shortness of breath. In the span of a few years, he had also experienced four episodes of aphasia, or temporary periods when he lost the ability to understand or produce speech.

He reached the researchers’ clinic at age 48, where additional exams showed signs of reduced muscle strength, a loss of reflexes, neuropathy, and eye abnormalities. Brain MRI and heart evaluation were unremarkable.

The man was started on Onpattro, administered via into-the-vein infusions once every three weeks, after which he remained stable as of a one-year follow-up appointment.

His older brother had begun to experience abnormal sensations, leg weakness, erectile dysfunction, and diarrhea at age 30. A liver transplant at age 39 eased all symptoms.

He was stable for many years, but at age 52, the man experienced electrical abnormalities in the heart that required a pacemaker implantation. The next year, he began experiencing eye problems that required surgery, abnormal sensations, loss of sensation in some areas, and stomach pain.

At the researchers’ clinic three years later, additional exams revealed signs of reduced muscle strength, poor reflexes, neuropathy, some abnormalities on brain MRI, and eye problems.

As with his brother, the man was started on Onpattro, and no disease progression was found a year later.

Little known about long-term effects of treatment

These cases highlight the potential occurrence of the nest effect in patients undergoing a liver transplant that lead to symptom reemergence and the development of CNS and eye symptoms due to the continuous production of abnormal transthyretin in these tissues.

While Onpattro benefited both brothers, “little is known about the long-term effect of these treatments on disease progression,” the researchers wrote.

The team noted, however, that as with a liver transplant, these gene-silencing therapies target transthyretin production in the liver. Because they don’t readily cross into the brain, it is possible that CNS and eye symptoms may progress despite treatment, as they did after transplant.

“Despite the existence of these innovative drugs, [hATTR] treatment deserves an even more challenging approach for the next years: newer drugs able to stop [transthyretin] synthesis in central nervous system and to degrade the already existent deposits throughout the body are needed for the best management of our patients,” the team concluded.