Intellia Shows CRISPR Gene Editing in Humans Has Arrived

This approach may possibly be useful against age-related transthyretin amyloidosis as well.



Intellia has released clinical data for NTLA-2001, a gene therapy for hereditary transthyretin amyloidosis.

What is transthyretin amyloidosis?

Transthyretin (ATTR) amyloidosis is the buildup of misfolded transthyretin, a protein generated by the liver. Normally, this protein is partially responsible for the transport of thyroid hormones, hence its name; however, transthyretin is vulnerable to mutations and misfolding, which cause the protein to aggregate in clumps, much like Alzheimer’s and other amyloid diseases.

One of the main symptoms of ATTR amyloidosis is neuropathy, which is damage to the peripheral nervous system. Patients who suffer from this disease have weakness and pain in the extremities, carpal tunnel syndrome in both wrists, and multiple other physical ailments. The disease also attacks the heart through cardiomyopathy, and it can progress to coordination problems, dementia, and stroke.


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What does NTLA-2001 do?

NTLA-2001 is a gene therapy that uses the well-known CRISPR-Cas9 gene editing system in order to knock out the TTR gene, thus preventing the liver from forming transthyretin. This treatment showed few side effects. People who received a lower dose, .1 milligrams per kilogram, had their transthyretin halved/ people who received a higher dose, .3 milligrams per kilogram, lost a full five-sixths of their transthyretin.

It should be noted that this gene therapy is specifically marketed as targeting neuropathy patients rather than cardiac patients. This may be because there is already a transthyretin drug on the market: tafamidis, which works through a completely different principle, stabilizing transthyretin in the bloodstream rather than preventing its creation by the liver. This drug has been approved for cardiomyopathy caused by hereditary ATTR amyloidosis [1].

What this has to do with aging

While ATTR amyloidosis is a hereditary disease, people without the disease can still suffer from a version of ATTR amyloidosis known as senile systemic amyloidosis, which predominantly affects the very old. The two diseases are not the same; while people with the hereditary form of the disease accumulate amyloid in the sac and muscles surrounding the heart, people with senile systemic amyloidosis accumulate it in the walls of the heart [2].


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However, the solution for these diseases may ultimately be the same. If transthyretin is not necessary for life, then preventing the buildup of its amyloids may be more important in older ages. Therefore, an anti-transthyretin therapy, possibly NTLA-2001 or another gene therapy, may be useful in stopping these diseases.

A portion of Intellia’s press release is included here.

CAMBRIDGE, Mass. and TARRYTOWN, N.Y., June 26, 2021 (GLOBE NEWSWIRE) — Intellia Therapeutics, Inc. (NASDAQ:NTLA) and Regeneron Pharmaceuticals, Inc. (NASDAQ:REGN) today announced positive interim data from an ongoing Phase 1 clinical study of their lead in vivo genome editing candidate, NTLA-2001, which is being developed as a single-dose treatment for transthyretin (ATTR) amyloidosis. The Phase 1 study, run by Intellia as the program’s development and commercialization lead, is evaluating NTLA-2001 in people living with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). NTLA-2001 is the first CRISPR/Cas9-based therapy candidate to be administered systemically, via intravenous infusion, for precision editing of a gene in a target tissue in humans. NTLA-2001 is designed to inactivate the TTR gene in liver cells to prevent the production of misfolded transthyretin (TTR) protein, which accumulates in tissues throughout the body and causes the debilitating and often fatal complications of ATTR amyloidosis. The interim data were presented today at the 2021 Peripheral Nerve Society (PNS) Annual Meeting and published in The New England Journal of Medicine (nejm.org/doi/full/10.1056/NEJMoa2107454.)

“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, M.D. “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 interim data released today cover the first six ATTRv-PN patients across two single-ascending dose cohorts of the Phase 1 study, which is currently being conducted in the United Kingdom and New Zealand. Single doses of either 0.1 mg/kg or 0.3 mg/kg of NTLA-2001 were administered systemically. Reductions in serum TTR levels were measured from baseline to day 28. Treatment with NTLA-2001 led to dose-dependent reductions in serum TTR, with mean reductions of 52% among the three patients in the 0.1 mg/kg dose group, and 87% among the three patients in the 0.3 mg/kg dose group, including one patient with a 96% reduction. By contrast, the standard of care for ATTRv-PN, which requires chronic treatment, typically yields TTR reductions of approximately 80%.

“This is exciting early data both for people living with this devastating disease and for the entire scientific community working to maximize the potential of genetics-based medicines through cutting-edge research and technologies,” said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron, which first partnered with Intellia in 2016 to advance CRISPR/Cas9 gene-editing technology for in vivo therapeutic development. “Thanks to large-scale human genetics research, there have been many new genetic targets identified and confirmed to have an impact on human health. Combining this knowledge with the precision and enhanced convenience of a single CRISPR infusion unlocks new possibilities in treating – and potentially even curing – life-threatening and historically difficult-to-address diseases.”

At both dose levels, NTLA-2001 was generally well-tolerated by the six patients included in the interim analysis, with no serious adverse events and no liver findings by day 28. Given the safety and tolerability profile so far, NTLA-2001 is continuing to be evaluated in the dose-escalation portion of the study, to determine if a higher dose could result in a deeper reduction in disease-causing protein levels leading to the potential for more meaningful clinical benefit. As of the date of this release, Cohort 3, evaluating NTLA-2001 at the 1 mg/kg dose level, is actively enrolling.

Following the identification of a recommended dose in the dose-escalation portion of the study, Intellia expects to begin a single-dose expansion cohort in Part 2 of the Phase 1 trial later this year. After completion of the Phase 1 trial, the company plans to move to pivotal studies for both polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

“ATTR amyloidosis is a progressive and fatal disease that usually requires chronic, lifelong treatment. These interim Phase 1 data support NTLA-2001 as the only one-time treatment either on the market or in development,” said Julian Gillmore, M.D., Ph.D., Professor of Medicine, National Amyloidosis Centre, UCL Division of Medicine, Royal Free Hospital, U.K., and the Phase 1 study’s national coordinating investigator. “As the first-ever systemically administered CRISPR therapy candidate, NTLA-2001 shows strong potential to stop the production and accumulation of the misfolded TTR protein by inactivating the TTR gene at the root of the disease. This approach could deliver life-changing, lifelong benefits to patients with all forms of ATTR amyloidosis, who continue to experience debilitating symptoms and complications of disease while on the standard of care. While further investigation is needed, these results are highly encouraging.”

Intellia intends to present additional data from the study at a medical or scientific meeting later this year.

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[1] Lamb, Y. N. (2021). Tafamidis: A Review in Transthyretin Amyloid Cardiomyopathy. American Journal of Cardiovascular Drugs, 1-9.


[2] Ueda, M., Horibata, Y., Shono, M., Misumi, Y., Oshima, T., Su, Y., … & Ando, Y. (2011). Clinicopathological features of senile systemic amyloidosis: an ante-and post-mortem study. Modern Pathology, 24(12), 1533-1544.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.