In 2013, Benjamin Oakes was determined to earn his PhD while working on the cutting edge of molecular engineering: developing Crispr, a gene editing tool that promised to cut DNA as precisely as a pair of scissors.

At the time, there were two main research groups — one at the University of California, Berkeley, led by future Nobel Prize winner Jennifer Doudna, and the other at the Broad Institute, co-run by Harvard and MIT — and Oakes was bouncing back and forth between them. That’s how he ended up in Doudna’s house one day, as part of a group of promising students being considered for jobs in Berkeley’s labs.

There, he met David Savage, a Berkeley professor who had just launched his own lab focused on creating proteins similar to those used in Crispr systems. Oakes had also interviewed for a position at Savage’s lab, but in a more relaxed setting, they geeked out about the possibilities of new tools in the space that were precise enough to literally rip a function from one protein and paste it into another. Soon after, Oakes found a solution to his professional conundrum: he joined both labs, where his research focused on increasing Crispr’s gene-editing potential by making protein engineering tools more configurable and controlled.

Ten years later, he’s putting that knowledge to use in Scribe Therapeutics, a firm he cofounded with Doudna and Savage. The company is developing a biological platform of tailored gene-editing tools to combat a wide spectrum of difficult-to-treat diseases, including ALS, cancer, and sickle cell anemia. It has received approximately $120 million in venture funding from significant organizations such as Andreessen Horowitz and OrbiMed, and it already has relationships with large pharmaceutical companies valued up to $4 billion.

Crispr’s origins can be traced back to bacteria, whose immune systems developed to attack invading viruses by chopping up critical portions of their DNA. This discovery was originally used to edit genes in conjunction with a special class of bacterial proteins known as Cas9. This technology has immense potential: it allows us to explore fixing genetic problems with a one-and-done procedure. However, it is not without complications. Because viruses change, Crispr systems aren’t fully exact, raising the possibility that a gene-editing device will cut the wrong region of someone’s DNA.

Crispr’s promise has already begun to be realized a little more than a decade after its discovery, with potential uses in agriculture as well as diagnostic testing. Last April, Vertex Pharmaceuticals and Crispr Therapeutics filed the first full FDA application for approval of a Crispr/Cas-9 gene editing medication for sickle cell anemia patients. In clinical studies, the treatment produced impressive results, with 94% of individuals treated achieving the targeted outcomes. The FDA is likely to make an approval decision by the end of the year. Other Crispr-derived therapies for type 1 diabetes and cancer are being developed.

LAB WORK: According to Oakes, one of Scribe’s goals is to convert naturally discovered gene-editors into “scalpels” for more accurate work. THERAPEUTICS SCRIBE
Oakes, 34, is already working on the technology’s next iteration. His company employs a distinct set of Crispr proteins known as “CasX” that were discovered by Doudna’s research group. Scribe has created a platform called “Crispr-by-design” with CasX that allows the company to handle different types of disease. Its primary goal is to make gene editing therapy available to patients directly (“in vivo”) rather than removing cells from the body, modifying the genes, and returning them. The Vertex treatment for sickle cell, for example, entails taking stem cells from patients’ bone marrow, editing them, and returning them to the patient following chemotherapy to destroy non-edited stem cells.

CasX proteins have many advantages in drug development over Cas9 systems, according to Dr. Joshua Modell, an assistant professor at Johns Hopkins School of Medicine who studies Crispr systems in nature. “They’re smaller, which makes it easier to do certain kinds of applications,” adds Modell. Furthermore, CasX proteins may be more selective, meaning that they are more likely to just affect the specific portion of the DNA.

Crispr’s startup market is buzzing with activity. Pitchbook reports that $3.3 billion in venture financing has come into the industry since 2019. That sum does not include the over a half-dozen Crispr firms that have gone public in the last several years, or the hundreds of millions in funding from big pharma.

One big stumbling block for enterprises in this field is not technical, but rather legal. Many of these medicines rely on the Crispr/Cas9 system, although multiple research groups, most notably Jennifer Doudna’s lab at U.C. Berkeley and another group at the Broad Institute of MIT and Harvard, described advances with this system within a short period of time. This has resulted in enormous, ongoing international intellectual property conflicts that have been adjudicated differently in the United States and Europe, making it difficult for corporations looking to license the technology to identify with whom they should sign contracts. (The internet is rife with guides aimed towards assisting befuddled biotech corporations.)

Despite the fact that the Crispr market is somewhat crowded, Oakes’ Scribe has supporters. Major venture capital firms such as Andreessen Horowitz, Avoro Ventures, OrbiMed, and Menlo Ventures are among its investors. Pitchbook analyst Kazi Helal, who follows the biotech industry, also points out that Scribe’s novel class of CasX proteins puts it out of the existing lawsuit around Cas9 systems, making it more appealing for investment and partnerships. Doudna and Savage also continue to serve as scientific consultants to the company, which has employed veteran researchers from both of their labs.

“The group that has gone and built Scribe is really the next-generation team out of the Doudna Lab,” Menlo Ventures partner Greg Yap explains. He concedes that the company has a long way to go before it can bring medicines to market, but he sees its collaborations with big pharma as early proof of the technology’s promise.

Oakes claims that his PhD study was a collaboration between the labs of Doudna and Savage. Using the bioengineering focus of Savage’s lab, he concentrated on turbocharging the Crispr technique utilized in Doudna’s lab for gene editing. One of his experiments, for example, included creating a chemical “lock” for Cas9, so that it couldn’t begin working without the correct chemical “key.” This method coupled a particular set of Crispr tools developed in Doudna’s lab with a protein editing methodology developed in Savage’s group.

Following the completion of his PhD in 2017, Oakes was given an Entrepreneurial Fellowship at Berkeley, a program designed by the university to assist lab findings in making an easier transition to commercial use by offering cash, coaching, and business training. Scribe Therapeutics was formed in October 2018 by Oakes, Savage, and Doudna, together with Brett Staahl, a researcher in Doudna’s lab, and raised a $20 million series A financing headed by Andreessen Horowitz shortly after.

The firm emerged from stealth in October 2020, simultaneously announcing that it had secured a medication research agreement with Biogen for up to $400 million if key development milestones were completed. Scribe is also entitled to royalties from any approved drug as a result of the deal.

Doudna was co-awarded the Nobel Prize in Chemistry a few days after Scribe came from hiding. A few months later, in March 2021, Avoro Ventures led a $100 million series B financing, valuing the firm at $300 million. “Scribe’s platform is quite unique when compared to Cas9 systems,” says Avoro partner Behzad Aghazadeh, who joined Scribe’s board of directors after the round closed. According to him, Oakes “has really thought out and engineered his way to really addressing the challenges that other gene-editing companies still face.”

MANUFACTURING SHIFT: Scribe’s offices were originally used to construct ships, but now they house dozens of bioengineers. THERAPEUTICS SCRIBE
Scribe has experienced an increase in collaborations with other pharmaceutical companies during the last year and a half. In May 2022, it expanded its collaboration with Biogen to include a second potential medication. In September, the business announced a collaboration with Sanofi to develop cancer-fighting cells. This agreement provides the corporation with a $25 million upfront payment and has the potential to be worth more than $1 billion in royalties. In May 2023, the firm began a relationship with Lilly subsidiary Prevail to work on gene-editing therapeutic approaches to neurological illnesses in a transaction for up to $1.5 billion in royalties and an initial payment of $75 million to Scribe.

Despite the large sums at stake in these transactions, the corporation is being cautious in its collaborations, according to chief business officer Svetlana Lucas.”I’ve seen a lot of companies partner,” she says. “Which looks amazing at the time but is extremely difficult to execute on in the long run.” The risk, she warns, is losing focus and stretching resources too thin by attempting to run numerous projects at the same time.

Scribe said last week that it has signed a second agreement with Sanofi. This time, the two corporations will collaborate to find a solution for sickle cell disease, which affects millions of people worldwide and causes over 300,000 deaths each year but has few therapies. This agreement includes a $40 million down payment and is worth up to $1.2 billion.

Unlike Crispr Therapeutics and Vertex, this therapy would work similarly to Pfizer and Moderna’s Covid vaccines: Sanofi and Scribe will design a CasX protein and then encode it in messenger RNA, which serves as an instruction manual for the body’s own protein manufacturing systems. Those blueprints will be housed inside a minuscule nanoparticle that has been tailored to strike the proper target using the same techniques that the immune system use to identify viruses.

According to Oakes, this strategy is easier to scale without encountering manufacturing constraints that often plague other biological therapies — just look at how rapidly the Covid vaccinations were scaled up. This is due in part to the fact that nanoparticles are far easier to construct than other gene therapy approaches, which frequently rely on complex molecules such as bespoke viruses to deliver medications to the correct location in the body.

Scribe has created a second platform that focuses on employing Crispr tools to manage epigenetics, or the settings that determine whether a gene is switched on or off. According to Oakes, this has the potential to be a helpful tool since it might treat genetic illnesses without causing lasting alterations to DNA. This means that if complications emerge, the procedure could be reversed. “Basically, we can give you the one and done and, if necessary, reactivate you away from it,” he says.

An epigenetic platform is appealing because there is less risk of DNA damage. “The risks would be lower,” adds Modell of Johns Hopkins. He believes it could be effective for genetic problems in which the body produces too much of something. In that situation, you wouldn’t want to remove or modify the gene; instead, you’d want to slow it down. Meanwhile, because CasX proteins are smaller in size, it is easier to add more designed traits while still fitting them inside their minuscule delivery vehicles.

The epigenetic platform’s potential will most likely not be realized for years, and both Oakes and his team are aware that whenever a new biotechnology arises, many firms are born only to die without making an impact. “I am a history buff in the sense of ‘let’s learn from the mistakes of others.'” So I’m trying to be cautious,” Oakes says later, adding, “Where we’re going to be focusing is in areas where having highly developed systems that are best in class would make a tremendous impact.”


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