First-ever RNA editing trial in US gets clearance, pitting ‘exon editing’ technology against vision loss
Ryan Cross
Senior Science Correspondent
The FDA told the Boston startup Ascidian Therapeutics that it can begin the first clinical tests of a therapy that “rewrites” RNA to correct roughly two-thirds of the genetic typos responsible for an inherited form of vision loss called Stargardt disease.
Tinkering with RNA, the short-lived cousin of DNA, could lower some of the hypothetical risks associated with technologies like CRISPR that make permanent changes to the genome. That argument, made by Ascidian and other biotechs developing RNA editing therapies, now has backing from US regulators.
Michael Ehlers
“The FDA puts it in a different category,” Ascidian president and interim CEO Michael Ehlers told Endpoints News in an exclusive interview. While the agency requires companies to monitor the health of patients treated with gene editing therapies for 15 years, the FDA is only requiring Ascidian to track patients in its RNA studies for five years, he said.
Ascidian borrows its name, and its technology, from sea squirts, squishy animals whose curious manner of shuffling tidbits of RNA code known as exons inspired the new technology, dubbed RNA exon editing. The company says the technique can swap large swathes of error-ridden code with a clean copy.
The startup has kept a relatively low profile since it launched 15 months ago. When the Stargardt disease trial begins enrolling patients in the coming months, it will not only be the first-in-human test of exon editing, but likely the first test of any form of RNA editing in the US.
Most companies developing RNA editing therapies are focused on a method that wrangles an enzyme called ADAR to alter a single letter of the genetic code. Last September, Endpoints reported that Wave Life Sciences was the first to ask regulators outside the US for permission to begin a study of this approach. Dosing in that trial began in the UK last month.
Robert Bell
The FDA has generally been slower to allow trials of in vivo gene editing therapies — which alter genes directly inside the body — than their regulatory counterparts in Europe and New Zealand, due to concerns that they may unintentionally alter the germline. But how the agency would view in vivo RNA editing therapies has been less clear, until now.
“When you make a mistake in editing DNA, every single [RNA] transcript that comes off of that DNA carries that mistake. It’s a little bit more binary,”Ascidian’s head of research Robert Bell said. “Whereas if there are million RNA molecules in a cell, and there’s a random [unwanted] edit of one of those transcripts, the likelihood of any type of biological impact is quite low.”
Complex genetic cause of vision loss
Stargardt is the most common form of inherited vision loss, affecting about 30,000 people in the US. The vision loss is progressive, and while it’s unlikely the therapy could restore lost vision, Ehlers said he’s hopeful it could stall and possibly halt the decline.
The disease has links to more than 1,000 typos in a gene called ABCA4, which encodes a protein vital for healthy vision. Designing separate therapies to fix each mutation is impractical. And while replacing the gene entirely would be ideal, that’s currently impossible because it’s too big to fit into the viruses commonly used in gene therapies to shuttle DNA into cells.
Ascidian believes that an exon editing approach can treat most cases of the disease with a single treatment. It works by hijacking a natural process called RNA splicing.
Before cells can read RNA blueprints to make proteins, they must slice up RNA molecules and remove the padding between tidbits of code called exons. Normally these exons, which contain the protein instructions, are stitched together from the same RNA strand. But sea squirts can curiously shuffle exons between different RNA molecules.
Taking inspiration from the sea squirts, Ascidian uses a synthetic RNA molecule to intervene in the splicing process and coax the cell to swap out a bad swathe of error-ridden exons for a corrected copy. By replacing the first 22 of 50 exons in the ABCA4 gene, the company believes it can treat roughly 60% to 70% of patients, Ehlers said.
The company has presented preclinical data from the Stargardt program at gene therapy and ophthalmology conferences, but has yet to publish papers on its exon editing technology and its applications.
Even though the therapy leaves DNA untouched, Ascidian’s approach could still be one-and-done. The company is using AAV — the workhorse viral vector of gene therapy — to inject the RNA editor therapy into the eye, where it will continually work to overwrite bad copies of the vital gene.
The trial is focused on safety, but the company could get a glimpse at efficacy as well, as soon as a year into testing, Ehlers said.
AUTHOR
Ryan Cross
Senior Science Correspondent
[email protected]
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