CRISPR Gene Editing for Transthyretin Amyloidosis Safe, Effective


Interim data from a phase 1 study from Intellia Therapeutics and Regeneron Pharmaceuticals is the first to support in vivo CRISPR genome editing in humans.

The first in-human systemic administration of a CRISPR-Cas9 gene editing therapy has shown promising safety and efficacy in patients with hereditary transthyretin (ATTR) amyloidosis with polyneuropathy.1

The investigational agent, NTLA-2001, which is delivered via single intravenous infusion, targets the TTR gene in liver cells to effectively inactivate it in order to prevent the production of misfolded TTR protein, the accumulation of which is associated with serious and potentially fatal central and autonomic nervous system complications.

“These are the first ever clinical data suggesting that we can precisely edit target cells within the body to treat genetic disease with a single intravenous infusion of CRISPR. The interim results support our belief that NTLA-2001 has the potential to halt and reverse the devastating complications of ATTR amyloidosis with a single dose,” said Intellia president and chief executive officer John Leonard, MD, in a statement.2 “Solving the challenge of targeted delivery of CRISPR/Cas9 to the liver, as we have with NTLA-2001, also unlocks the door to treating a wide array of other genetic diseases with our modular platform, and we intend to move quickly to advance and expand our pipeline. With these data, we believe we are truly opening a new era of medicine.”

The data, which were presented at the 2021 Peripheral Nerve Society Annual Meeting and simultaneously published in the New England Journal of Medicine,1 were on the first 6 patients (age 46 to 64; 4 men)—all of which had sensory polyneuropathy without motor symptoms and class-I heart failure—to receive one of either 2 doses of NTLA-2001: 0.1 mg/kg or 0.3 mg/kg. Three patients each were assigned to the single-ascending dose groups and monitored for safety and serum TTR levels at weeks 1, 2, and 4. All adverse events that occurred were mild in nature, occurring in 3 of 6 patients, and included a grade-1 infusion-related reaction, nausea, headache, decreased thyroxine, and rhinorrhea. Within 4 to 24 hours post-infusion, 5 of 6 patients had elevated D-dimer levels that returned to baseline by day 7. In addition, coagulation measures were within 1.2 times the upper limit of reference ranges while fibrinogen and platelet counts were above the lower limit. Notably, liver enzymes remained within normal limits.

Reductions in serum TTR were observed as soon as day 14 and increased by day 28, at which point NTLA-2001 was associated with a 52% and 87% mean reduction of TTR in the 0.1 mg/kg and 0.3 mg/kg groups, respectively. The dose-dependent, durable reductions in serum TTR ultimately ranged from 47% to 56% in the lower-dose group, and 80% to 96% in the higher-dose group over the 28-day period. Long-term, serial measurements of serum TTR and safety measures are planned while investigators explore further dose escalation in hopes of producing greater reductions in serum TTR than are currently achievable with available therapeutics, which is approximately 80%.

Based on these results, investigators are currently enrolling eligible participants in cohort 3, which will evaluate a 1 mg/kg dose of NTLA-2001. After a recommended dose is identified, the study sponsors will launch part 2 of the phase 1 study as a single-dose expansion cohort. The successful completion of the phase 1 study will be followed by pivotal studies in patients with ATTR amyloidosis with polyneuropathy and/or cardiomyopathy.

Safety and efficacy of a single dose of NTLA-2001 was previously demonstrated in preclinical mouse and cynomolgus monkey studies, in which treatment resulted in near-elimination of serum TTR protein at doses associated with no adverse events. Notably, while RNA-targeting gene-silencing agents have been associated with reductions in TTR protein levels and in turn, clinical benefits, these require serial infusions. Based on preclinical data, the study investigators believe that a single infusion of NTLA-2001 may be capable of inducing durable knockdown of TTR protein expression.

Addressing concerns of off-target effects, the study authors noted that preclinical studies showed no evidence of off-target mutagenesis mechanisms in primary human hepatocytes, but that changes detected could help predict DNA structural variants that might occur in vivo, all of which are expected to be of low-risk.

“The CRISPR-Cas9 approach used for NTLA-2001 is modular and has the capacity to be adapted to treat other diseases with simple replacement of the sgRNA,” the study authors wrote. “Data from the initial groups of patients in this study provide clinical proof of concept for in vivo CRISPR-Cas9–mediated gene editing as a therapeutic strategy.”

1. Gillmore JD, Gane E, Taubel J, et al. CRISPR /Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. Published online June 26, 2021. doi: 10.1056/NEJMoa2107454
2. Intellia and Regeneron announce landmark clinical data showing deep reduction in disease-causing protein after single infusion of NTLA-2001, an investigational CRISPR therapy for transthyretin (ATTR) amyloidosis. News release. Intellia Therapeutics. June 26, 2021.
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