CRISPR/Cas9 (clustered regularly interspaced short palindrome repeats-associated Cas nuclease 9) gene editing technology, the basis for the Nobel prize in Chemistry in 2020, ingeniously harnesses an adaptive bacterial immune system to allow precise genetic manipulation across a wide variety of organisms, including eukaryotic cells. The CRISPR/Cas9 system consists of an endonuclease protein, Cas9, which is bound to a guide RNA molecule that targets the Cas9 protein to induce double-strand breaks at specific and defined genetic sequences. This major achievement has the potential to revolutionise treatment for a wide variety of genetic diseases, with initial efforts focusing on diseases involving the liver.
Previous CRISPR/Cas9 approaches in medicine have relied on removing cells from the body to be edited in vitro and then reintroduced to achieve therapeutic effect. Conversely, NTLA-2001, developed by Intellia Therapeutics and Regeneron, employs a lipid nanoparticle to efficiently target Cas9 mRNA and a guide RNA molecule to body tissues, where they assemble into the CRISPR/Cas9 system, resulting in specific and precise gene knockdown in vivo.
Transthyretin amyloidosis (ATTR), a protein misfolding disorder, can be hereditary or acquired; its hereditary form is less common, affecting around 50 000 people worldwide. Both forms are characterised by misfolding of the TTR protein, which is produced in the liver. The misfolded protein causes progressive accumulation of ‘clumps’, typically within the nerves and heart. Symptoms can vary, with some patients experiencing spreading nerve damage and others suffering from heart defects. The disease is progressive, incurable and typically fatal. Although treatments for ATTR amyloidosis are available, some are associated with disease progression, another is associated with serious side effects, and all require lifelong administration.
NTLA-2001, currently in Phase 1 clinical evaluations in ATTR amyloidosis, represents a substantial advance, offering the potential for permanent knockdown of the TTR gene after a single dose. Interim results from the Phase 1 trial found that NTLA-2001 resulted in significant decreases in TTR protein concentrations in the blood for all subjects, with only a few very minor side effects. Patients receiving the starting dose of NTLA-2001 exhibited an average TTR reduction of 52%, while patients receiving a higher dose showed an average TTR reduction of 87%. The results, which represent the first demonstration of efficacy of in vivo CRISPR/Cas9 gene editing, were described by CRISPR expert Kiran Musunuru as ‘a home run’.
Spirit is delighted to have contributed to the recent publication of these results in the New England Journal of Medicine (NEJM) under the title ‘CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis’, as well as simultaneous presentation at the Peripheral Nerve Society’s virtual annual meeting on 26 June. For more information about our gene editing and other gene therapy expertise, or for publications in general, please contact our Medical Strategy Director, Ben Caldwell.