Persistent Gene Editing Therapy Using LNP-Delivered mRNAs

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Gene editing technology, represented by CRISPR/Cas9, has greatly accelerated the development of gene therapy, bringing hope to many genetic diseases that otherwise had no cure.

In June 2021, Intellia Therapeutics’ NTLA-2001, a CRISPR gene editing therapy for the treatment of transthyretin amyloidosis (ATTR) invented by Nobel Laureate Jennifer Doudna, was proven to be safe and effective in a clinical trial involving six patients. This was the first clinical trial result of an in vivo CRISPR gene editing therapy that has been published.

The results of the clinical trial were published in the New England Journal of Medicine, a leading international medical journal, under the title: CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. The study demonstrates that a single intravenous infusion of the CRISPR-Cas9 gene editing system can be used to precisely edit disease-causing genes in vivo for the effective treatment of human genetic diseases.

There still remains one question: how long does this editing and treatment effect last?

Intellia Therapeutics recently presented updated data on NTLA-2001 therapy, building on Phase 1 clinical trial data released in June, which revealed that patients’ serum transthyretin (TTR) levels steadily declined during the 2-month to 12-month post-treatment follow-up period.

Transthyretin amyloidosis (ATTR), a serious and life-threatening rare genetic disorder with an estimated 50,000 patients worldwide, is characterized by the progressive accumulation of misfolded transthyretin (TTR) in tissues, primarily the nerves and heart, which in turn leads to a range of problems in the nervous system, heart, and other organs.

NTLA-2001 therapy, an in vivo gene editing therapy, delivers mRNA sequences carrying sgRNAs targeting the disease-causing TTR gene and optimized spCas9 protein to the liver via a lipid nanoparticle (LNP) vector.

Clinical data previously reported in the NEJM revealed that three of the six patients treated received the 0.1 mg/kg dose, whereas three received the 0.3 mg/kg dose. After 28 days of treatment, plasma levels of TTR protein dropped by an average of 52% and 87% in the two dosages, respectively. Furthermore, no serious side effects were observed.

The interim results reported included 15 patients treated with different doses, three in each of the 0.1 mg/kg, 0.3 mg/kg, and 0.7 mg/kg dose groups, and six in the 1.0 mg/kg dose group. On day 28 after treatment, plasma TTR protein levels decreased by 52%, 87%, and 86% in the first three groups, respectively, and serum TTR protein levels decreased by 93% in six individuals in the 1.0 mg/kg dose group, and patients’ serum transthyretin protein (TTR) levels continued to decrease during the 2-month to 12-month follow-up period. These interim data show that patients treated with lower doses did also significantly reduce serum transthyretin (TTR) levels, but that treatment was better in the higher dose group.

The CEO John Leonard said the company has finalized a dosing regimen for NTLA-2001 therapy that a fixed dose of 80 mg for all patients rather than a weight-based dose will be provided, in order to simplify future clinical treatment.

In addition, Intellia’s NTLA-2002 therapy for hereditary angioedema has initiated a Phase 1 clinical trial, with patient dosing currently beginning and clinical trial data expected later this year, according to John Leonard. Meanwhile, the first patient dosing of NTLA-5001 therapy for acute myeloid leukemia (AML) has been completed.

Both the in vivo gene editing therapy and in vitro TCR-T cell therapy utilize LNP-delivered CRISPR-Cas9 for gene editing.

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