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In patients with transthyretin amyloidosis, a progressive and fatal disease, amyloid fibrils of misfolded transthyretin (TTR) protein accumulate in tissues, especially the nerves and heart. Transthyretin amyloidosis, which is also known as ATTR amyloidosis, may be acquired or hereditary, with more than 100 pathogenic variants in TTR contributing to the disease. Patients primarily experience amyloid polyneuropathy and/or cardiomyopathy although other organ systems may also be affected. Current treatment strategies focus on reducing amyloid formation. As a monogenic disease, however, ATTR amyloidosis is an ideal target for CRISPR–Cas9 in vivo gene editing. In a recently reported study in The New England Journal of Medicine (https://doi.org/10.1056/NEJMoa2107454), Gillmore and colleagues presented interim results of a phase I trial testing the safety and efficacy of an intravenously administered CRISPR–Cas9-based in vivo gene editing therapy known as NTLA-2001, which edits TTR in hepatocytes where it is nearly exclusively produced. The therapy resulted in decreased production of wild-type and mutant TTR after a single administration. Preclinical studies revealed a dose-dependent and durable effect of NTLA-2001 in murine and primate animal models. In transgenic mice, circulating serum TTR protein levels dropped to the lowest levels within 4 weeks and remained there for 12 months following the single dose administration. The researchers saw a similar effect in cynomolgus monkeys, with a greater than 94% reduction in serum TTR protein levels. Possible off-target editing sites were minimal, and no evidence of off-target editing was seen in primary human hepatocytes when treated with NTLA-2001. In addition, the treatment was not associated with any adverse events. The researchers then initiated an open-label, single-dose, proof-of-concept study of hereditary ATTR amyloidosis patients with polyneuropathy. Three of the six enrolled patients experienced mild adverse events during or after the treatment, and one patient had an infusion-related reaction. No serious adverse events were seen. In the three patients who received a dose of 0.1 mg per kilogram, mean TTR serum levels dropped by half compared with baseline. In the remaining three patients who received a dose of 0.3 mg per kg, serum levels fell to nearly 90% below baseline by day 28. The study is ongoing, but together the results provide clinical proof-of-concept data for in vivo CRISPR–Cas9-mediated gene editing as a therapeutic strategy for ATTR amyloidosis. —V. L. Dengler, News Editor

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