CRISPR gene editing was a nascent technology in 2016 when David Schaffer, PhD, Director of the Berkeley Stem Cell Center at the University of California, Berkeley, and one of his top PhD students founded a little company called Rewrite Therapeutics. The goal was to commercialize CRISPR-guided DNA polymerases invented by Schaffer’s then student, Shakked Halperin, PhD.
The technology was designed to introduce targeted changes into the genome without making double-stranded breaks, a known downside of traditional CRISPR-Cas9 gene editing, which can be harmful to cells. In 2018, Schaffer, Halperin and a quartet of Innovative Genomics Institute colleagues published details in Nature of an early version of their Rewriter™ tech platform (EvolvR), designed to spur the evolution of specific genes inside cells.
Halperin told GEN Edge that he decided to incorporate Rewrite: “This was just to secure an exclusive option to get a license to the intellectual property that I developed during the PhD.”
Halperin served as Rewrite’s President and CEO until this month, when the company and its technology was acquired by Intellia Therapeutics. One of the biggest CRISPR-based genome editing therapeutic companies, Intellia shelled out up to $200 million to buy the Berkeley startup and its DNA writing technology.
“Rewrite’s technology is highly complementary to our existing capabilities. By acquiring Rewrite, we can seamlessly integrate their technology with our own,” Intellia president and CEO John Leonard, MD, told GEN Edge. “These technologies, including our own base editor and additional CRISPR enzymes, provide us with the capabilities to achieve any editing strategy. The transaction is another example of how we are continuing to expand our industry-leading platform.”
“We are committed to staying at the forefront of the genome editing revolution,” Leonard added. “We will continue to advance our technology platform through a mix of both internal R&D and external opportunities in order to potentially serve more patients across an increasingly broad set of diseases.”
What attracted Intellia to Rewrite’s DNA-writing platform?
“Rewrite’s DNA writing technology may enable a range of precise editing strategies, including targeted corrections, insertions, deletions and the full range of single-nucleotide changes, which could provide new ways to edit disease-causing genes and broaden the therapeutic potential for genomic medicines,” Leonard said.
In their 2018 paper, Schaffer’s team programmed Cas9 to find a specific target sequence in an organism’s DNA, using a “nicking” version of Cas9 that only cut one of the two DNA strands. The nick provided a signal for DNA polymerase to peel back the nicked strand and replace it with new DNA.
The polymerase then wrote in a different DNA sequence than the original, introducing “typos” or random mutations creating potentially millions of different sequence combinations, in order to find a desired effect.
“After CRISPR introduces a nick at the target site, the DNA polymerase uses a template nucleic acid to introduce a new sequence at the target site,” said Schaffer, who has chaired Rewrite’s Scientific Advisory Board.
Rewrite’s EvolvR won praise later that year from Stanley Qi, PhD, of Stanford University and Timothy R. Abbott, then a PhD student at Stanford: “While there are other technologies for mutagenesis and directed evolution, EvolvR’s flexibility, ease of use, and sequence specificity distinguish it from the rest,” they wrote in Molecular Cell. “EvolvR is a broad technology amenable to a number of applications and is poised to evolve how mutagenesis and directed evolution are performed.”
Rewrite’s technology has been developed and improved in the four years since publication of the original Nature paper, including “additional components and novel guide nucleic acids to improve the precision, accuracy, and versatility of the edits that CRISPR-guided DNA polymerases can make,” Halperin said. However, details of the improvements have not been published and remain scant.
“We can’t go into details but we have developed several forms of templates that define the precise edit that gets synthesized by the DNA polymerase,” Halperin said. “I am confident that Intellia will make the best decisions surrounding publication to serve their mission to help patients.”
“Shakked made several innovations that have led to this technology being substantially more efficient compared to prime editing and earlier technologies,” said Schaffer, before adding, “we are not at liberty to discuss the technology in great detail.”
However, Intellia did say recently that Rewrite’s technology offers another attraction: Its ability to improve the efficiency of genome editing in non-dividing cell types, allowing for use on these as well as dividing cells.
Intellia is among companies scrambling to introduce genome editing technologies that go beyond first-generation tools like CRISPR-Cas9.
Prime Medicine, which applies a “search and replace” approach to gene editing, last year emerged from stealth mode with $315 million in financing. The technology hails from the lab of David Liu, PhD, and colleagues at the Broad Institute. Their 2019 paper in Nature laid out a new mechanism for genome editing called “prime editing” that did not make double-strand breaks in the target sequence or use a donor DNA template.
Liu’s team also developed base editing, which took advantage of CRISPR-Cas9 to target a specific DNA sequence, but without cutting it. He co-founded Beam Therapeutics to commercialize the technology, which also enables single-letter edits of the genome. raising $126.6 million in net proceeds by going public in 2020. (Beam CEO John Evans discussed the company last year on GEN’s video series “Close to the Edge”).
Since then, Beam gained access to a lipid nanoparticle (LNP) delivery technology by acquiring Guide Therapeutics (GuideTx), and in January began partnering with Pfizer on base-editing-based therapies, with Beam gaining $300 million upfront toward a potential $1.35 billion from the pharma giant.
Intellia concluded that Rewrite’s technology can provide safe and curative genome editing treatments like the ones it is working to develop.
Intellia electrified the field of genome editing—along with Regeneron Pharmaceuticals, and clinical partners—last year when they published the first-ever clinical data that support the safety and efficacy of in vivo CRISPR genome editing in humans.
In a study published in The New England Journal of Medicine, the researchers showed that the companies’ lead in vivo genome editing candidate NTLA-2001 generated a dose-dependent sustained reduction of protein linked to transthyretin (ATTR) amyloidosis following a single dose in six patients living with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Intellia said last month it plans to release additional data from the Phase I study (NCT04601051) later this quarter.
Beyond the pipeline
In announcing the acquisition, Intellia said Rewrite offered it “the potential to target diseases beyond those currently being explored in our pipeline.” Intellia isn’t yet saying which diseases those might be: “The technology is still in early-research stage, and we’ll share more as appropriate,” Leonard said.
NTLA-2001 is one of Intellia’s two lead in vivo therapy programs. The other is NTLA-2002, a single-dose therapy designed to prevent attacks in people living with hereditary angioedema through a knockout edit of the KLKB1 gene in hepatocytes. In December, Intellia dosed the first patient in a multi-national Phase I/I trial (NCT05120830) aimed at assessing the safety, tolerability, pharmacokinetics and pharmacodynamics of NTLA-2002 in adults with Type I or Type II HAE.
Intellia’s in vivo pipeline includes five other candidates. Two are in IND-enabling phases: NTLA-3001 for alpha-1 antitrypsin (AATD) deficiency-associated lung disease, for which the company plans to file an IND or equivalent in 2023; and a hemophilia B therapy partnered with Regeneron. The other three are research-phase programs: A Hemophilia A program partnered with Regeneron; wholly-owned research programs for AATD, primary hyperoxaluria and undisclosed indications; and unspecified research programs partnered with Regeneron and SparingVision.
At least two in vivo candidates will advance in development this year, Intellia said.
Intellia is also developing an ex vivo pipeline led by two clinical-phase programs, Novartis-partnered OTQ923/HIX763 for sickle cell disease, and wholly owned NTLA-5001 for acute myeloid leukemia. During the fourth quarter of 2021, Intellia began screening patients in a Phase I/IIa trial (NCT05066165) of NTLA-5001 that is expected to dose its first patient “in the coming weeks” and enroll patients throughout 2022, the company said.
Also in the ex vivo pipeline are wholly-owned programs in solid tumors and an undisclosed indication, plus undisclosed additional Novartis-partnered programs. Intellia said it expects to nominate its first allogeneic ex vivo development candidate by the first half of 2022.
Intellia further signaled plans to expand its pipeline by launching a collaboration with ONK Therapeutics that could generate up to $920 million for Intellia. Through the partnership, Intellia will grant the Galway, Ireland-based company with a U.S. subsidiary based in San Diego non-exclusive rights to its ex vivo genome editing and LNP delivery technologies and exclusive rights to guide RNAs for up to five allogeneic CRISPR-edited NK cell therapies.
According to Intellia, Rewrite’s technology can potentially be delivered using Intellia’s LNP technology and adeno-associated virus (AAV) vectors. AAV delivery would require two different vectors, while LNP delivery would entail a single particle, said Schaffer, who is also co-founder, Chief Scientific Advisor, and a board member of 4D Molecular Therapeutics.
“Rewrite developed an effective means to split the cargo such that it can effectively fit into AAV vectors. For LNP, it could be delivered as recombinant protein or encoded in mRNA,” Schaffer said.
He said LNP works well for some tissues, such as liver, while for other tissues AAV is considerably more efficient.
“I believe the far future of gene-editing is non-viral transient delivery which is achieved with mRNA formulated with LNP,” said Schaffer, who is also director of QB3-Berkeley, one of four interdisciplinary research centers of the California Institute for Quantitative Biosciences (QB3). “Today’s reality is that many target tissues still cannot be reached by LNP technologies. If you can reach the target cells with LNP, that would be preferable over AAV.”
“A Long Way to Go”
Rewrite did not become operational until early 2020, when it secured seed financing. Civilization Ventures led the seed round, which started at $500,000 and increased to $2.1 million, with Prefix Capital also backing the company.
The COVID-19 pandemic complicated efforts to build Rewrite. The startup was located in incubator lab space on the UC Berkeley campus in 2020 when the university completely shut down all non-COVID laboratory research from March to July of that year. As a result, Schaffer recalled, many labs lost a lot of research time.
“Once the campus opened labs again, they prudently placed a limit on personnel density in labs, which limited working hours since for many rooms, only one person could be in the room at a time,” Schaffer said. “Thankfully those limitations have been lifted now for over a year, and to my knowledge there are still no cases of COVID transmission within a campus research lab, so research is back up to its usual pace.”
In December 2020, Rewrite received a non-dilutive grant of unspecified amount from the Cystic Fibrosis (CF) Foundation, which said at the time it gave the funding “to demonstrate preclinical proof-of-concept for a genome editing treatment for CF.”
From Intellia, Rewrite shareholders will receive $45 million upfront and up to an additional $155 million tied to achieving research and regulatory approval milestones, through a mix of Intellia stock and cash.
Rewrite’s technology has been described as an example of “CRISPR 2.0.” Does the company agree?
“I think Rewrite can be considered part of the cohort of new technologies that are advancing the state of the art to systematically address the challenges of the first batch of CRISPR-based therapeutics, going well beyond ‘cutting,’” said Shahram Seyedin-Noor, general partner with Civilization Ventures. “The end goal is to address a wider range of indications with new kinds of precise and effective edits.”
Rewrite’s staff has consisted of four full-time employees—Shakked and three PhD scientists—as well as a business development consultant, an operations consultant, Schaffer and Patrick Hsu, PhD, an assistant professor at UC Berkeley who was the company’s genome editing advisor.
Intellia isn’t detailing how much it plans to grow its headcount as it further develops Rewrite’s technology, though Halperin said: “I am confident that Intellia will be committing the resources necessary to advance the technology towards helping patients.”
Seyedin-Noor acknowledged: “Of course, we’ve got a long way yet to go in the field, and that’s precisely what’s so exciting: tremendous innovation lies before us!”
He also predicted: “I believe there will be a $100 billion “pure-play” DNA/RNA editing-based therapeutics company before the end of this decade.”