Amber Salzman, PhD, Epicrispr Biotechnologies (Epic Bio) CEO

A startup founded by one of the pioneers of CRISPR genome editing plans to grow big by thinking small—namely using the smallest-known Cas protein, Cas12f, to deliver genetic therapies that act on the epigenome by modulating gene expression in vivo.

Epicrispr (or Epic) Biotechnologies—a portmanteau of “epigenomic” and “CRISPR”—has completed a $55 million Series A financing, the proceeds of which help it advance its preclinical pipeline and carry out discovery for additional therapies.

“We’re leveraging the power of CRISPR, but at the epigenetic level rather than cutting the DNA,” Epic Bio CEO Amber Salzman, PhD, told GEN Edge. “We’re working at the layer above it to modulate how the DNA behaves. So it’s the epi-CRISPR.”

Founded in 2019, Epic emerged from stealth mode by announcing the Series A earlier this month. The company was established to commercialize the CRISPR-based discoveries of Lei Stanley Qi, PhD, a Stanford University bioengineer and a named co-inventor on the CRISPR patent held by the University of California (UC).

Qi is Epic’s scientific advisor as well as an associate editor of The CRISPR Journal (a sister publication of GEN Edge).

Epic has developed the Gene Expression Modulation System (GEMS) platform, designed to dial gene expression up or down without permanently altering the DNA. Using advanced functional and computational genomics capabilities, Epic uses GEMS to rapidly design guide RNAs specific to targeted genes, using what the company says is the largest known library of novel modulators.

GEMS consists of constructs with three basic components: A DNA-binding protein, one or more guide RNAs, and one or more modulators. When paired with a custom guide RNA, the DNA-binding protein recognizes and binds to the target sequence.

Among types of modulators identified by Epic:

  • Histone modulators designed to catalyze removal or addition of methyl or acetyl groups on histones. They can activate or repress expression of targeted genes.
  • Transcriptional activators designed to amplify a gene’s rate of transcription. They can directly increase gene expression.
  • Transcriptional repressors designed to reduce a gene’s rate of transcription. They can directly decrease expression.

In addition to activating or repressing transcription of the gene, modulators can customize the gene’s expression in numerous ways that including adding or removing epigenetic markers to the gene locus. By combining multiple modulators in one GEMS construct, it is possible to engineer even more specific effects upon a target gene.

Epic has licensed from Stanford for human use the CasMINI ultracompact Cas DNA-binding protein, first developed in Qi’s lab. CasMINI is a modified form of Cas12f, which according to the company has been engineered to function robustly in mammalian cells, and is less than half the size of Cas9 and Cas12a.

“That gives us a superpower,” Salzman said. “It also means that we have a completely clean IP landscape, because we don’t have to worry about being marred in some of the issues that have arisen relative to the original CRISPR Cas molecules”—namely the bitter legal battle over who invented CRISPR-Cas9, in which the U.S. Patent Trial and Appeal Board (PTAB) earlier this year sided with The Broad Institute of MIT and Harvard.

CasMINI’s small size enables its delivery via a single adeno-associated virus (AAV) vector to a range of target organs—though Epic says it can also be delivered via lipid nanoparticles (LNPs) or lentiviruses.

“We are not tied to AAV at all,” Salzman said. “The only reason why we’re using AAV is just that given the thousands of patients that have been dosed with AAV, there’s more clinical experience and we just want to de-risk our initial programs, to give us an opportunity to very rapidly validate that if you use our constructs with other known delivery methods, we can have the effect that is intended. AAV has a lot of experience if you want to go in vivo.”

Size Matters

Alexandra Collin de l’Hortet, PhD, Epic’s Head of Therapeutics

Alexandra Collin de l’Hortet, PhD, Epic’s Head of Therapeutics, adds: “Size has been a driving factor for us in terms of engineering. We want to have a very small protein. We also want to have good activity when it comes to activating gene or suppressing genes, so we want to optimize the Cas molecule for better activity,” she said. “And we’re looking at also additional factors to make the protein overall better.”

Collin said the Cas molecule dimerizes when it binds to the DNA. “When you bring a copy of the CasMINI with a modulator, you actually bring two copies of Cas and two modulators to the DNA. You have an increase of activity just by the fact that it dimerizes. But within the AAV packaging limits, we can add more than one modulator—two, three—we have very small modulators. We have the capacity to add more than one or to do multiplexing, or to even bring additional elements, like a coding sequence for a gene. We can get fancy!”

In a paper published last year in Molecular Cell, a research team led by Qi detailed their development of CasMINI, about half the size of existing CRISPR-Cas systems with potentially broad utility for gene therapy applications as well as cell engineering. Qi and colleagues reported that CasMINI could delete, activate, and edit target gene sequences just like its larger counterparts. But the smaller relative size of CasMINI enables it to be delivered more easily into human cells and the human body, making it a potential tool for treating a range of disorders that includes eye disease, organ degeneration, and genetic diseases.

“This provides a new method to engineer compact and efficient CRISPR-Cas effectors that can be useful for broad genome engineering applications, including gene regulation, gene editing, base editing, epigenome editing, and chromatin imaging,” Qi and colleagues wrote.

“We also hypothesize that its small size and non-human pathogen source make it likely less immunogenic compared with large protein payloads,” the researchers added. “Therefore, we envision that these synthetic compact Cas effectors developed in this study will be broadly useful for gene therapy and cell engineering applications.”

Epic has built a pipeline of five programs led by EPIC-321, a treatment for facioscapulohumeral muscular dystrophy (FSHD) that Salzman said is on track toward the clinic: “We’re looking at filing our IND by the end of next year.”

FSHD is believed to be caused by contraction of a repeat sequence inside the genome. EPIC-321 targets re-methylating the D4Z4 region and suppressing expression of the DUX4 gene, located within D4Z4 near the end of chromosome 4, to prevent further muscle cell death.

“Essentially the genome locus is hypomethylated. It’s an epigenetic disease,” Collin said. “We can bring our machinery and restore the methylation and restore the original genomic state of that particular locus… The overall goal is to suppress the expression of the DUX4 gene that is abnormally expressed due to hypomethylation of that locus.”

Also in Epic’s pipeline are four research-phase programs:

  • EPIC-221, a heterozygous familial hypercholesterolemia (HeFH) treatment designed to target key pathways known to reduce cholesterol.
  • EPIC-241, an alpha-1 antitrypsin deficiency (A1AD) treatment in which a single AAV vector simultaneously inhibits endogenous mutated A1AT protein expression and produces normal A1AT.
  • EPIC-141, a retinitis pigmentosa 4 (RP4) treatment in which a single AAV vector simultaneously inhibits endogenous mutated RHO (Rhodopsin) expression and produces normal RHO.
  • EPIC-111, a treatment for autosomal dominant retinitis pigmentosa 11 (AdRP11) designed to precisely restore PRPF31 gene expression to normal physiological levels.

“You can almost go after any disease if you understand it,” Salzman said. “I think our limitation is that we don’t understand diseases well enough.”

Jockeying for position

Epic is among companies jockeying for position in CRISPR-based gene-edited therapies. Last month, Zion Market Research projected that the global CRISPR genome editing market field will grow to $15.84 billion by 2028 from $1.08 billion last year—a compound annual growth rate of 29.5%.

Metagenomi completed a $175-million Series B financing earlier this year, and has lined up collaborations with partners ranging from Moderna to Affini-T Therapeutics. “Our first IND is probably within three years from now,” Simon Harnest, Metagenomi’s chief investment officer and SVP of Strategy, recently told GEN Edge.

In November 2021, Arbor Biotechnologies—a developer of gene-edited precision therapies co-founded by CRISPR pioneer Feng Zhang, PhD—completed a $215-million Series B financing toward developing its portfolio of tailored nuclease therapies. Arbor has discovered more than 60 nuclease families and 70 CRISPR transposases.

Mammoth Biosciences—whose co-founders include Doudna—is developing in vivo gene-edited therapies using novel CRISPR Cas12, Cas13, Cas14, and Casɸ systems whose foundational IP the company has exclusively licensed from UC Berkeley, where they were discovered in Doudna’s lab. Last year Mammoth inked an up-to-$695 million collaboration with Vertex Pharmaceuticals to develop in vivo gene-editing therapies for two genetic diseases.

Among biopharma giants, GlaxoSmithKline (GSK) has developed an oncology epigenetics group while Eli Lily has said publicly it will look to develop epigenetic-based therapies.

Epic, which is based in South San Francisco, CA, says its expansion plans also include growing its staff, which now numbers about 40.

“We have a good critical mass to achieve what we need to. As you progress down to the clinic, there’s more kinds of expertise you need to bring to the table, so we will be growing, but controllably,” Salzman said.

Epic has added expertise through its Scientific Advisory Board: David Schaffer, PhD, Professor of Chemical and Biomolecular Engineering, Bioengineering, and Neuroscience at UC Berkeley; Claire M. Fraser, PhD, director of the Institute for Genome Sciences at the University of Maryland School of Medicine; and Yang Shi, PhD, Professor of Epigenetics at the Ludwig Institute for Cancer Research, University of Oxford.

Horizons Ventures, the venture capital firm founded by Hong Kong billionaire entrepreneur and philanthropist Li Ka Shing, led the Series A financing, which included other undisclosed investors.

Salzman said Li’s eponymous philanthropic foundation became familiar with CRISPR by funding as far back as 2009 the UC Berkeley-based lab of Doudna, co-winner of the 2020 Nobel Prize in Chemistry with Emmanuelle Charpentier, PhD. The foundation asked Doudna about research into CRISPR conducted by Qi, a onetime doctoral student in her lab, only to learn he had moved on and established his own lab at Stanford.

“As he started to publish and take CRISPR to the very next level, that was when the impulse was to say, ‘we really need to spin out a company.’ And that’s when Stanley founded Epic, along with Horizon,” Salzman recalled.

Comfortable runway

Epic isn’t saying exactly how many months and years of a financial runway it has through the Series A financing, though Salzman added: “It gives us a very comfortable runway to allow us to prove the leading position that our platform has. The company has been very efficient with cash.”

Epic’s Series A financing was already in the works when Salzman joined the company in October 2021. She said the bear market and decrease in financings of recent months didn’t dampen investor enthusiasm: “Maybe because we’re in a transformative, exciting area, we were able to keep going, regardless of the backdrop of the environment.”

Before joining Epic, Salzman was President and CEO of Ohana Biosciences, a sperm biology-focused reproductive health drug developer backed by Flagship Pioneering. Ohana wound down last year after failing to raise enough funding to maintain operations.

Ohana is one of several companies where Salzman held CEO or other senior positions over more than a decade; the others included Adverum Biotechnologies, Annapurna Therapeutics, Cardiokine, and Venuvics Pharmaceuticals. Earlier, she spent nearly 25 years at GSK, leaving in 2008 as Senior Vice President, Medicine Development Operations.

While at GSK, Salzman said, members of her family were diagnosed with adrenoleukodystrophy (ALD), including a nephew who died of the disease at age 12. “That’s what threw me into rare disease and genetic medicine, from a very different space at GSK,” Salzman recalled. “I’ve been working in gene therapy and genetic diseases since that time. And while that has brought great innovation and promise, I started to become very acutely aware of what the limitations were.”

Those limitations, she said, included knowledge about the diseases themselves, as well as about what tools and technologies would be best to fight them.

The opportunity to address those limitations aroused Salzman’s interest in Epic when a recruiter called her last year to gauge her interest in leading the startup.

“My family and I live on the East Coast, this is a West Coast company. I was not talking to any West Coast companies,” she said. “But then they sent me a copy of Stanley (Qi)’s paper and more information. And they said, ‘Talk to Stanley.’” When she visited Qi’s lab at Stanford, she added, “I was completely blown away.”

“All of the limitations that I had seen in my years of developing medicine, it was like magically, Stanley and the team could figure out how to address it. Now, instead of limiting ourselves with what tools we had to address medicine, it was, ‘Oh my God! We don’t know enough about diseases.’ We had constrained our thinking all these years because of the tools we had to address them.”

Salzman also gained respect for Qi’s research, and Qi himself: “Stanley’s not only brilliant but he’s a humble, intellectually curious scientist. He and Horizon are recruiting those kinds of people in the company. And that combination, it’s like the sky’s the limit in terms of what we can be doing to help patients.”

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