University College London’s National Amyloidosis Center, leading a multinational consortium, reports that a single in‑vivo gene‑editing infusion (nexiguran ziclumeran) produced rapid, profound, and long‑lasting decreases in serum transthyretin (TTR) for patients with hereditary transthyretin amyloidosis (hATTR) that involves polyneuropathy. Neurological outcomes remained stable or improved through 24 months.
Hereditary transthyretin amyloidosis with polyneuropathy is a rare, progressive, multisystem disorder that ultimately becomes fatal. It is triggered by the accumulation of misfolded TTR protein in peripheral nerves.
In the bloodstream, TTR normally assembles as a tetramer that transports thyroxine and retinol‑binding protein. Pathogenic variants destabilize this complex, causing it to dissociate into monomers that misfold and build up in tissues.
Median survival after disease onset ranges from six to 12 years and depends on age at onset, specific TTR mutation, cardiac involvement, and how quickly treatment begins. Current therapies require continuous lifelong administration and do not always stop the disease’s advance.
In the study titled Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy, published in The New England Journal of Medicine, investigators conducted a Phase I, open‑label, single‑group trial to evaluate the safety, pharmacodynamics, and neurological effects of nexiguran ziclumeran.
The trial screened 36 patients, who had a mean Neuropathy Impairment Score (NIS) of 31. Treatment was delivered at four sites (France, New Zealand, Sweden, and the United Kingdom), and patients were followed for an average of 27 months. The primary pharmacodynamic endpoint was serum TTR concentration.
After a single infusion, serum TTR fell dramatically – an average decrease of 90 % by day 28 and 92 % by month 24 – and the reduction remained steady through month 36 in those with available data.
Neuropathy disability scores stayed unchanged in 27 participants, improved in five, and worsened in two. Functional stage of familial amyloid polyneuropathy was stable for 29 patients, improved for two, and deteriorated for two at month 24. Biomarkers and patient‑reported outcomes all moved toward clinically meaningful improvement per predefined scales.
All patients experienced an adverse event. The most common were infusion‑related reactions (21 patients), headache (10), diarrhea (8), transient low thyroxine (8) without hypothyroidism or TSH rise, and elevated aspartate aminotransferase (6).
Serious adverse events occurred in 11 patients. One death from cardiac amyloidosis was reported on study day 273, and one participant discontinued due to motor decline deemed unrelated by the study investigators.
Authors conclude that a single dose of nexiguran ziclumeran induces sustained, significant lowering of transthyretin, supporting further study of this approach in hereditary transthyretin amyloidosis with polyneuropathy.
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