Stabilization of neuropathy scores seen after gene editing therapy for rare nerve disease

University College London’s National Amyloidosis Center leads a multinational team reporting that a single infusion of an in vivo gene-editing therapy (nexiguran ziclumeran) produced rapid, deep, and durable reductions in serum transthyretin for hereditary transthyretin amyloidosis with polyneuropathy, with disease measures largely stable or improved through 24 months.

Hereditary transthyretin amyloidosis with polyneuropathy is a rare, multisystem, progressive, debilitating, and fatal disease characterized by deposition of misfolded transthyretin (TTR) protein in peripheral nerves.

In the bloodstream, TTR assembles as a four-part protein complex, or tetramer, that normally transports thyroxine and a retinol-binding protein. Pathogenic variants destabilize this complex and drive its dissociation into monomers that misfold and accumulate in tissues.

Median survival from disease onset ranges from six to 12 years and varies with age at onset, TTR variant, cardiac involvement, and promptness of treatment. Current treatments require repeated lifelong administration and do not always halt disease progression.

In the study, “Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy,” published in The New England Journal of Medicine, researchers conducted a Phase I, single-group, open-label trial to assess the safety and pharmacodynamics of nexiguran ziclumeran and evaluate effects on neurologic function.

Enrollment included 36 patients with a mean Neuropathy Impairment Score of 31. Treatments took place at four sites in France, New Zealand, Sweden, and the United Kingdom, with a mean follow-up of 27 months. The primary pharmacodynamic measure was serum TTR level.

A single infusion produced rapid and deep reductions in serum transthyretin, with mean change of -90% at day 28 and -92% at month 24, sustained through month 36 in participants with available data.

Polyneuropathy disability score stayed stable in 27 participants, improved in five, and worsened in two. Familial amyloid polyneuropathy stage stayed stable in 29 patients, improved in two, and worsened in two at month 24. Biomarkers and patient-reported measures shifted in the direction of clinical benefit by prespecified scales.

Adverse events occurred in all patients. The most frequent were infusion-related reactions in 21 patients, headache in 10, diarrhea in eight, decreased thyroxine in eight without hypothyroidism or elevated thyrotropin, and increased aspartate aminotransferase in six.

Serious adverse events were reported in 11 patients. One death from cardiac amyloidosis occurred on study day 273, and one participant discontinued due to motor decline judged unrelated by investigators.

Authors conclude that one-time nexiguran ziclumeran yields profound and durable transthyretin lowering, supporting further investigation for hereditary transthyretin amyloidosis with polyneuropathy.

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