Benjamin L. Oakes, PhD, Scribe Therapeutics co-founder, president, and CEO

Scribe Therapeutics will partner with Prevail Therapeutics, a wholly owned subsidiary of Eli Lilly, to develop in vivo CRISPR-based therapies for “serious” neurological and neuromuscular diseases, the companies said today, through a collaboration that could generate more than $1.5 billion for Scribe.

Scribe has granted Prevail exclusive rights to its CRISPR X-Editing (XE) technologies for the development of in vivo therapies directed to an undisclosed number of specified neurological and neuromuscular disease targets. The collaboration is intended to combine those tools with Prevail’s expertise in developing genetically targeted therapies for neurological disorders.

“We have essentially highly evolved a bunch of novel bacterial, immune systems into really exquisite genome editors, and we can deliver them in a number of ways. This collaboration essentially builds on all of that work,” Benjamin L. Oakes, PhD, Scribe’s co-founder, president, and CEO, told GEN. “Taking these molecules that we’ve proven out now for greater activity, greater specificity, greater deliverability and really applying them towards specific genetic diseases that Prevail has a lot of interest in, being an expert in delivering gene therapy to neurological and neuromuscular diseases. There’s a lot of synergy that aligns with our technologies as well.”

Oakes is among the company’s co-founders—a group that includes 2020 Nobel laureate Jennifer Doudna, PhD, of UC Berkeley; and David Savage, PhD, also a Berkeley professor and a scientific advisor along with Doudna. The three launched Scribe in 2018, raised $20 million in Series A funding two years later, and completed a $100 million Series B financing in 2021.

Headquartered in Alameda, CA, Scribe develops CRISPR-based treatments through genetic modification platforms designed to build and apply the company’s suite of CRISPR technologies in neurodegenerative diseases and other therapeutic areas. These areas include ophthalmological diseases; multi-system, muscle, and metabolic disorders; and hematopoietic disorders.

Scribe’s X-Editing platform applies a proprietary genome editing approach, called CRISPR by Design™, which is intended to transform bacterial immune systems into therapeutically relevant technologies. Scribe’s in vivo genome editing tools directly modify genes within the body—an approach that according to the company delivers important safety, efficacy, and delivery benefits over existing methods.

One vector approach

“This allows us to, in some instances, fit all of the components necessary to do genome editing within a single AAV, one vector, and not having to deal with the multiple vectors that some other folks are trying to bring forward now, which makes it a much more efficient and safer platform,” Oakes said.

X-Editing is the first of several genome editing platforms Scribe envisions creating. Scribe has also developed genetic modifiers focused on epigenetic modification, which the company calls Wave 2. “And being an engineering organization, of course, we’ll have Wave 3, and beyond as well,” Oakes added.

Scribe’s platforms aim to address safety, delivery, poor editing outcomes, and the long-running bitter legal battle over who invented CRISPR-Cas9. To avoid intellectual property uncertainty, Scribe has engineered its own CRISPR effectors—CasX enzymes—that are more capable of delivering CRISPR packaged in a viral vector because the protein is less than 1,000 amino acids (aa), compared with the 1,200–1,400-aa size of Cas9.

Those “X-Editing” molecules are highly engineered CRISPR-based enzymes designed to provide combined aspects of greater efficacy, specificity, and deliverability than current CRISPR genome editing technologies.

On Friday at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, Oakes and colleagues are set to present via oral presentation data on Scribe’s engineered CasX (Cas12e) holoenzyme, which at <1000 aa is small enough to fit within an AAV vector with multiple guides or complex regulatory elements. The engineered Cas12e generated distinct deletion patterns, and showed less tolerance for mismatches between the guide RNA and dsDNA substrate.

“It’s not a proof of concept in any disease area per se, so much as it is explaining what it actually looks like to take a bacterial immune system, which is, of course, what all these CRISPR systems are, and actually transform it into a real genome editing tool,” Oakes explained.

In an abstract, the researchers described how they screened tens of thousands of distinct CasX molecules in both bacterial and human cell systems, identifying mutations that increase the stability, DNA-binding ability, and cleavage activity of the protein. Investigators then applied deep mutational scanning and selection methods to generate protein variants with broadened or respecified protospacer adjacent motif (PAM) preferences, thereby expanding genome targetability.

The researchers next applied high-throughput pooled screening with design to the CasX single-guide RNA (sgRNA) to create a guide they said showed significantly improved performance in both transcription-based and fully in vitro systems. That guide or X-Editor ribonucleoprotein (RNP) showed editing activity “orders of magnitude” higher than wild-type CasX molecules and achieved knock-out rates of immuno-oncology targets equal to or better than SpyCas9 when delivered as RNP to primary human immune cells.

“We demonstrate that XE is a potent and flexible platform for gene editing, with high activity, small size, and a range of accessible PAMs allowing it to be used across different delivery modalities and targets,” Oakes and colleagues concluded.

Neurodegenerative gene therapies

Prevail is a gene therapy developer based in New York City at the Alexandria Center for Life Science. The company was established in 2017 to develop and commercialize gene therapy products to treat Parkinson’s disease and other related neurodegenerative diseases.

Prevail was launched by the Silverstein Foundation for Parkinson’s with GBA, venture capital firm OrbiMed, and Asa Abeliovich, MD, PhD, then a Columbia University investigator who served as Prevail’s first CEO until 2021. That year, Lilly completed its acquisition of the company for up to $1.04 billion. (Abeliovich is now CEO and founder of Leal Therapeutics, a developer of precision therapies for major central nervous system disorders.)

Lilly’s acquisition of Prevail established the pharma giant’s gene therapy program, which is anchored by Prevail’s portfolio of neuroscience programs. Prevail’s gene therapies apply REGENXBIO’s novel adeno-associated virus, serotype 9 (AAV9) vector technology.

Prevail has disclosed two clinical gene therapy candidates, both in Phase I/II studies:

  • PR001 (LY3884961), a GBA1-targeting gene transfer therapy in development for Parkinson’s disease with GBA1 mutations, as well as types 1 and 2 Gaucher disease.
  • PR006 (LY3884963), a GRN-targeting gene transfer therapy in development for frontotemporal dementia with GRN

Also in Prevail’s pipeline are additional preclinical programs with undisclosed targets for neurodegenerative disorders; and additional discovery-phase neurodevelopmental and neurodegenerative disorders.

Prevail has agreed to pay Scribe $75 million consisting of an upfront payment and equity investment in the form of a convertible note; more than $1.5 billion in payments tied to achieving development and commercial milestones; as well as research funding and tiered royalties ranging into the low double-digits on net future sales.

Scribe has the right to opt-in to co-fund and share profits in the United States on one collaboration program.

Scribe is the second collaboration partner with which Prevail has partnered in the past five months. In January, Prevail and Capsida Biotherapeutics launched an up-to-$740 million collaboration to develop noninvasive gene therapies for central nervous system (CNS) diseases, by using Capsida’s AAV engineering platform to identify and advance clinically translatable capsids that will be paired with Prevail’s cargo.

Third biopharma giant

Through its subsidiary Prevail, Lilly is the third biopharma giant to partner with Scribe on developing CRISPR-based therapies. The first is Biogen, with which Scribe launched a collaboration to treat neurodegenerative disorders in 2020.

Back then, Biogen agreed to pay Scribe $15 million upfront, and up to $400 million tied to achieving milestones, to launch the alliance—which aligns with Biogen’s core growth area of neuromuscular disorders. The partnership started with a first target focused on a genetic cause of amyotrophic lateral sclerosis (ALS), and an option held by Biogen for a second “neurological disease target with high unmet need.”

Last year, Biogen expanded its collaboration with Scribe by exercising an option for a second, unnamed target through which they aim to treat disease. Also undisclosed was how much more Biogen will pay Scribe if the second target leads to a successful therapy.

And last September, Scribe granted Sanofi a nonexclusive license to use Scribe genome editing technologies to enable genetic modification of novel natural killer (NK) cell therapies, through a collaboration designed to create ex vivo NK cell therapies for cancer. Sanofi agreed to pay Scribe $25 million upfront, up to $1 billion in payments tied to achieving development and commercial milestones, and tiered royalties on net future sales of any products generated through the companies’ research collaboration.

Oakes said Scribe’s collaborations with Sanofi and Biogen have progressed since they were announced, but would not offer details.

He did say, however, that Scribe expects to continue gradually expanding its workforce, which now stands at about 100 people.

Last summer, Scribe Therapeutics expanded its Alameda, CA, headquarters at the Research Park at Marina Village, a waterfront life sciences campus that has been the company’s home base since 2020, to include the adjacent Shipway 4 building. The expansion doubled Scribe’s footprint of laboratory space to about 30,000 square feet and added amenities for employees such as new electric car chargers and outdoor space for meetings and recreation. [Scribe Therapeutics]

“We’ve been very intentional about how we’ve grown our business, and we will continue to be very intentional about how we grow our business,” Oakes said. “We will do so at a steady pace, and continue to add a few folks, but not many, to our workforce in order to continue to support not only the Prevail work, but our own internal work.”

Last summer, Scribe expanded its headquarters at the Research Park at Marina Village, a waterfront life sciences campus that has been the company’s home base since 2020, to include the adjacent Shipway 4 building. Shipway 4 is the second of two shipway buildings occupied by Scribe that originally opened in 1942 as construction sites for building and launching eight 23,000-ton troop ships during World War II, before their conversion into a core life science hub by Research Park owner Blue Rise Ventures.

The expansion doubled Scribe’s footprint of laboratory space to about 30,000 square feet and added amenities for employees such as new electric car chargers and outdoor space for meetings and recreation.

“That gives us room for the foreseeable future,” Oakes said.

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