David R. Liu, PhD, Prime Medicine co-founder

Prime Medicine, which applies a “search and replace” approach to gene editing, emerged today from stealth mode by announcing it has completed $315 million in financing.

The financing consists of a $115 million Series A round and a $200 million series B round. Prime said proceeds from the financing will be used to continue building the company, rapidly advance its gene editing therapy candidates towards clinical indications, and expand the capabilities of its platform.

Prime is currently advancing multiple drug discovery programs targeted at liver, eye, ex-vivo hematopoietic stem cell, and neuro-muscular indications. By the end of 2021, Prime said, it expects to employ more than 100 people full-time.

The emergence of Prime comes weeks after the field of genome editing was electrified when researchers from Intellia Therapeutics, Regeneron Pharmaceuticals, and clinical partners 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).

Prime Medicine applies a next-generation genome editing technology that it likens to the “search and replace” function of a word processor, only with DNA. The company trains its searching and replacing on disease-causing genetic sequences at their precise location in the genome, without resulting in double-strand DNA breaks that cause unwanted cellular changes.

According to the company, its genome editing approach has the potential to address more than 90% of known disease-causing mutations, and works in a variety of dividing and non-dividing primary human cells, as well as in animals.

Prime cites research by “multiple” independent laboratories that have shown they can use its technology to make genome edits with high fidelity, precisely at the desired location with minimal or no editing in other parts of the genome. The company says its technology is designed to overcome several technical barriers attributed to earlier gene editing technologies—such as off-target edits delivered by many versions of CRISPR genome editing.

‘Transformative Technology’

“Prime Editing is a transformative technology that we believe will make a significant impact by addressing the fundamental causes of genetic disease,” said Keith Gottesdiener, MD, CEO of Prime Medicine.

Prime editing uses a prime editor protein comprising a Cas nickase domain and a reverse transcriptase domain, together with a prime editing guide RNA (pegRNA) that carries both a targeting sequence and a template for a replacement sequence. The prime editor searches for the specific DNA sequence that needs to be edited.

Once located, the prime editor uses the pegRNA’s “replace” sequence to activate the reverse transcriptase domain, which makes a DNA copy of the template carried by the pegRNA, creating a corrected DNA sequence. The corrected sequence then preferentially replaces the original genomic DNA, resulting in a permanent edit of the DNA at the target location.

The technology behind Prime Medicine was first disclosed publicly in October 2019, when David Liu, PhD, and colleagues at the Broad Institute of MIT and Harvard published a paper in Nature that 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.

“This is the beginning of an aspiration to make any DNA change in any position of a living cell or organism,” Liu told GEN at the time. Liu is the Richard Merkin professor, director of the Merkin Institute of Transformative Technologies in Healthcare, core institute member, and vice chair of the faculty at the Broad Institute, as well as a professor of chemistry and chemical biology at Harvard University.

The Broad Institute has extended a license for prime editing technology to Prime Medicine for human therapeutic uses under the Broad Institute’s inclusive innovation model.

The work detailed in the Nature paper was led by Andrew Anzalone, MD, PhD, who at the time was a postdoc in Liu’s lab.

Ten days before publication of the paper, Liu unveiled the technology to a rapt audience of nearly 400 scientists at a genome editing conference at Cold Spring Harbor Laboratory. He closed his talk by saying, “I’m really looking forward to seeing what Andrew comes up with in the second year of his postdoc!”

Anzalone conceived of prime editing, then brought it to Liu’s laboratory, where Anzalone and Liu and colleagues developed the technology. Anzalone and Liu are scientific founders of Prime Medicine, with Anzalone also serving as the company’s head of prime editing platform.

Pioneering Base Editing 

Liu first made his proverbial mark in genome editing in 2016, when his lab published details of a genome editing system called base editing, which took advantage of CRISPR-Cas9 to target a specific DNA sequence, but without cutting it. As explained by GEN in 2019, base editing uses a catalytically “dead” Cas9 (dCas9) fused to the base editing machinery, which can engineer a particular class of base substitution (transition) without introducing a double-stranded DNA break.

Together with colleagues Keith Joung, MD, PhD, and Feng Zhang, PhD, Liu co-founded Beam Therapeutics to commercialize the technology. Beam completed an initial public offering in 2020 that raised $126.6 million in net proceeds.

Prime and Beam Therapeutics maintain a partnership aimed at establishing a collaborative approach to fighting disease and accelerating the development of prime editing to deliver therapies for patients—though both are separate companies that emerged from Liu’s lab. The two companies share research, expertise, and intellectual property for assays, know-how, delivery, and manufacturing.

Beam’s CEO, John Evans PhD, recently discussed that partnership, his company and its approach to base editing with GEN’s Editor-at-Large Kevin Davies, PhD and Senior Business Editor Alex Philippidis on Episode 5 of “Close to the Edge,” GEN’s new series of exclusive, in-depth interviews with scientific and business leaders across the biotech spectrum.

“Since Prime began operations in the summer of 2020, we have continued to make great progress in advancing the performance of Prime Editing, which allowed us to close our Series B financing nine months later,” Gottesdiener stated.

Investors in the Series A included ARCH Venture Partners, F-Prime Capital, GV, and Newpath Partners. All those investors took part in the series B—as did Casdin Capital, Cormorant Asset Management, Moore Strategic Ventures, Public Sector Pension Investment Board (PSP Investments), Redmile Group, Samsara BioCapital, funds and accounts advised by T. Rowe Price Associates, and numerous additional unnamed life sciences investment funds.

“We are operating from a position of financial strength, and look forward to further developing the technology and progressing our preclinical programs toward the clinic, with the hope that they may cure or halt the progression of genetic diseases for patients,” Gottesdiener added.