Until this year, there were no treatments for transthyretin amyloidosis, a rare disease where misfolding transthyretin (TTR) proteins build up in the body’s tissues. Then, in quick succession, the FDA approved a pair of drugs that interfere with RNA to block the production of these proteins. Another drug in the pipeline works similarly, by stabilizing TTR and stopping it from folding incorrectly.
Intellia Therapeutics wants to intervene earlier, using a CRISPR-based treatment to edit the mutation underlying the disease. The company presented (PDF) preclinical data Thursday at the annual meeting of the European Society of Gene and Cell Therapy showing that delivering a CRISPR-Cas9 treatment to the liver could potentially reduce TTR levels and treat ATTR. It is partnering with Regeneron on the treatment.
Transthyretin amyloidosis, or ATTR, is caused by mutations in the TTR gene, which give rise to abnormal TTR proteins. These proteins then collect in aggregates called amyloids, most frequently in the peripheral nervous system, though ATTR can also affect the central nervous system and the heart. Most TTR is made in the liver, making it an attractive target for treatment.
The nonhuman primate data presented Thursday showed “a high correlation between liver editing and reduction of the transthyretin (TTR) protein,” Intellia said in a statement. Furthermore, the researchers found that a relatively low editing rate of 35% to 40% was needed to “achieve therapeutically meaningful reduction of TTR,” specifically, a drop in TTR protein of more than 60%.
With its liquid nanoparticle delivery, the treatment could be safer than other CRISPR approaches. The data showed both the nanoparticles and their cargo were cleared from the animals’ circulation within five days. This could allay concerns about off-target edits that come with “traditional” CRISPR, which is delivered using viral vectors, typically adeno-associated viruses (AAVs). While AAVs are the most advanced method of CRISPR delivery, they allow the Cas9 enzyme—known as CRISPR “scissors”—to persist in the cells and potentially make unintended edits to the genome after treatment is complete.
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The Intellia research is ongoing, but so far, one dose of the gene-editing treatment has kept circulating TTR levels down for more than six months. This could be attractive for patients and physicians, as the two approved therapies for ATTR are injected more frequently than that. A physician must administer Alnylam’s Onpattro every three weeks, while Ionis and Akcea’s Tegsedi can be self-injected, albeit more often at once a week.
Pfizer’s oral drug, tafamidis, seems to be playing catch-up, but it is designed to treat different manifestations of ATTR. While Onpattro and Tegsedi both target polyneuropathy, tafamidis specifically addresses cardiomyopathy. That said, patients often have both symptoms, and so could be treated with either Onpattro or tafamidis, according to Credit Suisse analysts. And physicians may end up using Onpattro off-label “to treat cardiomyopathy while getting reimbursement for polyneuropathy,” the analysts wrote.
Meanwhile, Intellia has big plans for its nanoparticle-based CRISPR system. As its researchers continue to perfect the technology, they hope they are "opening the door for the development of therapies for a wide range of genetic diseases that require stable gene insertion and expression," according to the statement.